Research and Clinical Trials

Asthma

A 52-week, Randomised, Double-blind, Double-dummy, Parallel Group, Multi-centre, Non-inferiority Study Assessing Exacerbation Rate, Additional Measures of Asthma Control and Safety in Adult and Adolescent Severe Asthmatic Participants With an Eosinophilic Phenotype Treated With GSK3511294 Compared With Mepolizumab or Benralizumab

Inflammatory Bowel Diseases, Crohn's Disease, Ulcerative Colitis, Indeterminate Colitis

A 5-year Longitudinal Observational Study of Patients Undergoing Therapy for Inflammatory Bowel Disease

• 9842340268
• ldalfonso@targetpharmasolutions.com

Acute Lymphoblastic Leukemia, Obesity

A Bilingual Virtually-based Intervention (PEDALL) for the Prevention of Weight Gain in Childhood ALL Patients Considering Key Genetic and Sociodemographic Risk Factors

Acute lymphoblastic leukemia (ALL) has been referred to as a "pre-obese state", with many studies describing the onset of obesity during treatment. Weight gain typically begins within the first month of ALL diagnosis, stabilizes, and then resumes at the beginning of maintenance and continues into survivorship. Children and adolescents with healthy weight at diagnosis are the most vulnerable to weight gain; up to 70% develop overweight/obesity (OW/OB) by the end of treatment (EOT). Weight gain during treatment is one of the most consistently reported risk factors for weight gain in survivorship and is associated with an increased odds of being OW/OB 5-years post-EOT. Significant clinical ramifications are associated with being OW/OB. A meta-analysis led by the Children's Oncology Group nutrition committee found that OW/OB is associated with a 31% increased risk of mortality in ALL. The objective of the study team is to prevent the development of OW/OB during maintenance chemotherapy using a six-month virtually delivered dietary education intervention (PEDALL) in English and Spanish speaking families of children and adolescents undergoing treatment for ALL. Once enrolled, subjects will be randomized to PEDALL or standard of care (SOC). Subjects in the PEDALL group will receive 26 contact hours of specialized nutrition education and counseling via a virtual platform. The purpose of this study is to determine the effectiveness of a virtually-delivered dietary education intervention in the prevention of OW/OB compared to SOC during maintenance chemotherapy. The clinical impact of this study will improve the understanding of pre-treatment factors predictive of the efficacy of intervention to prevent unhealthy weight gain among patients treated for ALL. Study findings may lead to the allocation of limited clinical resources to individuals most susceptible to OW/OB. Information obtained from this study may also direct the refinement of counseling techniques to enhance the likelihood of success over the course of treatment for ALL and into survivorship. The long-term goal is to enhance the likelihood of success of weight maintenance during therapy thereby mitigating excess toxicities during treatment and reducing nutrition-related late-effects associated with OW/OB among survivors of childhood ALL.

• 2123052631
• psv2103@cumc.columbia.edu

Biliary Atresia

A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Odevixibat (A4250) in Children With Biliary Atresia Who Have Undergone a Kasai Hepatoportoenterostomy

Up to 70 sites will be initiated for this study in North America, Europe, Middle East, and Asia Pacific.

Atopic Dermatitis, Alopecia Areata, Hidradenitis Suppurativa, Vitiligo, Psoriasis, Chronic Spontaneous Urticaria

A Longitudinal Observational Study of Patients Undergoing Therapy for Immune-Mediated Inflammatory Skin Conditions

TARGET-DERM is a longitudinal, observational study of adult and pediatric patients being managed for Atopic Dermatitis and other Immune-Mediated Inflammatory Skin Conditions (IMISC) in usual clinical practice. TARGET-DERM will create a research registry of patients with IMISC within academic and community real-world practices in order to assess the safety and effectiveness of current and future therapies. The duration of follow-up for participants enrolled in the EU is limited to 5-years. Those within in US and Canada may consent to indefinite follow-up.

• 9842340268
• ldalfonso@targetrwe.com

Nonalcoholic Fatty Liver, Nonalcoholic Steatohepatitis

A Longitudinal Observational Study of Patients With Nonalcoholic Steatohepatitis (NASH) and Related Conditions Across the Entire Spectrum of Nonalcoholic Fatty Liver Disease (NAFLD)

• emichalski@targetrwe.com

Lennox Gastaut Syndrome, Dravet Syndrome, Tuberous Sclerosis Complex

A Long-term Safety Study to Assess the Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution

Hematologic Malignancies, Inherited Disorders of Metabolism, Inherited Abnormalities of Platelets, Histiocytic Disorders, Acute Myelogenous Leukemia (AML or ANLL), Acute Lymphoblastic Leukemia (ALL), Other Acute Leukemia, Chronic Myelogenous Leukemia (CML), Myelodysplastic (MDS) / Myeloproliferative (MPN) Diseases, Other Leukemia, Hodgkin Lymphoma, Non-hodgkin Lymphoma, Multiple Myeloma/ Plasma Cell Disorder (PCD), Inherited Abnormalities of Erythrocyte Differentiation or Function, Disorders of the Immune System, Autoimmune Diseases, Severe Aplastic Anemia

A Multicenter Access and Distribution Protocol for Unlicensed Cryopreserved Cord Blood Units (CBUs) for Transplantation in Pediatric and Adult Patients With Hematologic Malignancies and Other Indications

Principal Investigators: The principal investigators (PIs) will be transplant physicians at all participating U.S. transplant centers. Study Design: This study is an access and distribution protocol for unlicensed cryopreserved cord blood units (CBUs) in pediatric and adult patients with hematologic malignancies and other indications. Primary Objective: The primary objective of this study is to examine the incidence of neutrophil recovery of ≥500/mm3 after cord blood transplantation in a multi-institution setting using CBUs that are not Food and Drug Administration (FDA) licensed. Secondary Objectives: In patients receiving a non-licensed CBU: * Assess incidence of transmission of infection * Assess incidence of serious infusion reaction * Determine 1 year overall survival after cord blood transplantation * Assess cumulative incidence of acute graft vs. host disease (GVHD) grades II to IV and grades III to IV * Assess cumulative incidence of chronic GVHD * Determine platelet engraftment of \>20,000 mcL and \>50,000 mcL

• 10-CBA@ndmp.org

Infusion Reactions

A Multicenter Safety Study of Unlicensed, Investigational Cryopreserved Cord Blood Units Manufactured by the National Cord Blood Program and Provided for Unrelated Hematopoietic Stem Cell Transplantation of Pediatric and Adult Patients

The primary aim of this study is to examine the safety of administration of the unlicensed investigational NCBP hematopoietic progenitor cell-cord blood (HPC-CORD BLOOD) products in a multi-institution setting. Therefore, the study will evaluate prospectively the incidence of serious adverse reactions as well as the incidence of all infusion related reactions after administration of the unlicensed, investigational NCBP CBU. Definitions of Infusion-related adverse reactions: Mild - Moderate: reactions during or after the infusion of the cord blood (CB) product that require some medical intervention but do not affect the overall patient status or outcome. Severe: serious, life-threatening or fatal infusion reactions, requiring major medical intervention. These include: anaphylactic shock, acute cardiac, pulmonary or renal failure, seizures, patient transfer to the Intensive Care Unit, or death within 48 hours of the CB infusion. Adverse Reactions will also be classified by grade, according to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE).

• 718-706-5202
• dsung@nybc.org

Idiopathic Short Stature

A Multicenter, Observational Study to Characterize Growth in Children With Idiopathic Short Stature

• 18009834587
• Medinfo@bmrn.com

Pulmonary Arterial Hypertension

A Multicenter, Open-label, Randomized, Study With Single-arm Extension Period to Assess the Pharmacokinetics, Safety and Efficacy of Macitentan Versus Standard of Care in Children With Pulmonary Arterial Hypertension

Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Mixed Phenotype Acute Leukemia, Myelodysplastic Syndrome

A Multi-Center, Phase 3, Randomized Trial of Matched Unrelated Donor (MUD) Versus HLA-Haploidentical Related (Haplo) Myeloablative Hematopoietic Cell Transplantation for Children, Adolescents, and Young Adults (AYA) With Acute Leukemia or Myelodysplastic Syndrome (MDS)

PRIMARY OBJECTIVE: I. To compare the 1-year cumulative incidence of severe Graft Versus Host Disease (GVHD) (from day of HCT) defined as grade III-IV acute GVHD (aGVHD) and/or chronic GVHD (cGVHD) that requires systemic immunosuppression and to compare the disease free survival (DFS) (from time of randomization) in children and young adults (AYA) with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), mixed phenotype acute leukemia (MPAL), and myelodysplastic syndrome (MDS) who are randomly assigned to haploHCT or to an 8/8 adult MUD-HCT. SECONDARY OBJECTIVES: I. To compare overall survival (OS) between children and AYA with AML/ALL/MPAL/MDS randomly assigned to haploHCT and MUD HCT. II. To compare differences in health-related quality of life (HRQOL) between haploHCT and MUD HCT from baseline (pre-transplant), at 6 months, 1 year and 2 years post-transplant. EXPLORATORY OBJECTIVES: I. To compare the median time to engraftment and cumulative incidences of neutrophil engraftment at 30 and 100 days post transplant and platelet engraftment at 60 and 100 days post transplant, primary graft failure by 60 days, secondary graft failure at 1 year post transplant, Grade II-IV and III-IV acute graft versus host disease (aGVHD) requiring systemic immunosuppression at 100 days and 6 months, and cumulative incidences of transplant-related mortality (TRM), relapse, and moderate and severe chronic graft versus host disease (cGVHD) at 6 months, 1 and 2 years after haploHCT and MUD HCT. II. To estimate 1 year, 18-month and 2-year cumulative incidence of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) with events defined as occurrence of any of the following from Day 0 of HCT: Grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse or progression, and death from any cause. IIa. To compare "chronic GVHD" (GRFS) after haploHCT and MUD HCT using landmark definitions. IIb. To compare "current" GRFS is defined as the time to onset of any of the following events from Day 0 of HCT: Grade III-IV acute GVHD, chronic GVHD that is STILL requiring systemic immunosuppressive treatment, disease relapse or progression, death from any cause at 18 months and 2 years. III. To evaluate the influence of key clinical variables: age (\<13 years and 13-21.99 years), disease (ALL/MPAL versus \[vs.\] AML/MDS), haploHCT approach (TCR alpha beta + T cell depletion vs. post-transplant cyclophosphamide \[PTCy\]); donor age (by ten-year increments), donor sex (maternal vs. paternal for parental donation), pre-HCT minimal residual disease status (MRD + vs MRD -); pediatric disease risk index (low, intermediate, and high, impact on OS and DFS only), conditioning regimen (chemotherapy based versus total-body irradiation \[TBI\] based), immunosuppressive regimen (anti-thymocyte globulin \[ATG\] exposure according to the weight and absolute lymphocyte count \[ALC\] dependent dosing approach vs no ATG exposure) time to transplant (interval between diagnosis/relapse and date of stem cell infusion) graft cell dose, use of relapse prevention therapy (yes or no) and weight on engraftment, OS, DFS, GRFS, relapse, transplant related mortality (TRM), aGvHD and cGvHD at 1 and 2 years after haplo and MUD HCT by performing stratified and multivariate analyses. IV. To compare other important transplant related outcomes after haplo and MUD HCT, such as: IVa. Incidence of any significant fungal infections (defined as proven or probable fungal infection) through 1 year post HCT; IVb. Incidence of viremia with or without end organ disease (i.e. cytomegalovirus \[CMV\], adenovirus, Epstein-Barr virus \[EBV\], human herpesvirus 6 \[HHV-6\], BK) requiring hospitalization and/or systemic antiviral therapy and/or cell therapy through 1 year post HCT; IVc. Incidence of sinusoidal obstruction syndrome (SOS) through 100 days post HCT; IVd. As defined by the Cairo criteria; IVe. To compare the incidence and outcome of SOS when different criteria are used (European Bone Marrow Transplant \[EBMT\], Cairo, Baltimore, and modified Seattle criteria); IVf. Incidence of transplant-associated thrombotic microangiopathy (TA-TMA) through 100 days post HCT. V. To compare immune recovery after haplo PTCy, haplo alpha-beta T cell depletion, and MUD HCT via: Va. Pace of reconstitution of T, B, and natural killer (NK) cells and immunoglobulins at 30 days, 60 days, 100 days, 180 days and 365 days after HCT; Vb. Response to vaccinations as determined by vaccination-specific antibody titers at 12-18 months post hematopoietic stem cell transplant (HSCT); Vc. Biobanking blood or marrow to analyze the impact of graft composition on GvHD, relapse and viremia; Vd. Biobanking whole blood and serum to compare immune recovery using extended immune phenotyping and immune functional assessments. VI. Biobanking whole blood or serum to measure rabbit antithymocyte globulin (rATG) exposure when dosed according to weight and absolute lymphocyte count (ALC) using established pharmacokinetic and pharmacodynamics assays (after last infusion, Day -4, Day 0, Day +7). VII. To compare resource utilization after haplo and MUD HCT. VIIa. Length of HCT hospital stay from Day 0 and readmissions within the first 100 days (number of readmissions, duration, and reason). VIIb. Inpatient costs within the first 100 days and at 2 years post HCT. VIII. To describe and compare outcomes (neutrophil and platelet engraftment, graft failure, OS, DFS, GRFS, NRM, relapse, GvHD and health-related quality of life \[HRQOL\] post HCT) by recipient race/ethnicity, annual household income, primary spoken language and conserved transcriptional response to adversity (CTRA). IX. To describe HRQoL outcomes in racial/ethnic minorities and compare HRQoL outcomes between White patients receiving haploHCT and racial/ethnic minority patients receiving haploHCT. X. To assess the feasibility of incorporating total body irradiation (TBI) delivered with volumetric modulated arc therapy (VMAT) or tomotherapy into a multi-institutional study, to describe the toxicities and oncologic outcomes (relapse, DFS, OS, and TRM) of the subgroup of patients treated with this approach, and to compare these outcomes to those of patients treated with conventional TBI. OUTLINE: Patients who have both a MUD and haplo donor are randomized to Arm A or Arm B. Patients who only have a haplo donor are nonrandomly assigned to Arm C. ARM A: Patients receive a haplo HCT following a TBI- based or chemotherapy-based myeloablative conditioning regimen with PTCy or alpha beta T cell depletion (center's choice). When PTCy is used, it Is administered on days 3 and 4 after HCT and additional immunsouppression is started on day 5 after SCT. ARM B: Patients receive a MUD HCT following a TBI-based or chemotherapy-based myeloablative conditioning regimen between days -9 and -2 Patients then receive GVHD prophylaxis on days 1-11. ARM C: Patients receive a haploHCT following a TBI-based or chemotherapy-based myeloablative conditioning regimen with PTCy or alpha beta T cell depletion (center's choice). When PTCy is used, it Is administered on days 3 and 4 after HCT and additional immunsouppression is started on day 5 after SCT. Patients in all arms undergo standard HCT screening prior to transplant including disease evaluation (lumbar puncture, bone marrow aspiration), and organ function evaluation including but not limited to echocardiogram (ECHO) or multigated acquisition scan (MUGA), PFTS, and bloodwork.Patients also undergo collection of blood throughout the trial. After completion of study treatment, patients are followed periodically for up to 5 years from HCT.

Crohn's Disease, Ulcerative Colitis, Indeterminate Colitis, Inflammatory Bowel Diseases

A Multicenter, Prospective, Long-term, Observational Registry of Pediatric Patients With Inflammatory Bowel Disease

This registry study will include volunteer pediatric patients: approximately 2,000 pediatric patients with Crohn's Disease who have been treated with infliximab and approximately 2,000 pediatric patients with Crohn's Disease who have received therapies other than infliximab. Approximately 1,000 pediatric patients with Ulcerative Colitis or Indeterminant Colitis will also be enrolled. All patient treatments for IBD will be decided by the treating physicians in consultation with their patients based on usual clinical practice. Patient information will be collected at the time of enrollment and every 6 months for approximately 20 years. Data collection will include disease characteristics, IBD medications, safety assessments to include adverse events. Patients will also be asked to complete a brief questionnaire describing school and/or work attendance in order to assess quality of life. Some patients may be asked to participate in a substudy that will evaluate blood levels of formation of proteins that may develop after treatment with infliximab. A small amount of additional blood may be taken at the time of a routine blood draw that is part of a patient's routine medical care as determined by a treating physician. There are three studies as part of the post marketing requirement for IBD - C0168Z02, REMICADEPIB4002 and REMICADEPIB4003. There is one combined database for these protocols and analyses are performed using the aggregate data. All reports and publications will be generated from the combined database. No study agents will be administered in this registry. All patients will receive standard-of-care treatments prescribed by the patient's physician.

Systemic Lupus Erythematosus

A Multi-center, Randomized, Placebo-Controlled Trial to Evaluate the Safety, Efficacy, and Pharmacokinetics of Belimumab, a Human Monoclonal Anti-BLyS Antibody, Plus Standard Therapy in Pediatric Patients With Systemic Lupus Erythematosus

This is a multi-center study to evaluate the safety, pharmacokinetics, and efficacy of belimumab intravenous (IV) in pediatric patients 5 to 17 years of age with active systemic lupus erythematosus (SELENA SLEDAI score ≥ 6). The study will consist of three phases: a 52-week randomized, placebo-controlled, double-blind phase; a long term open label continuation phase; and a long term safety follow up phase. The long term open label continuation and safety follow up periods will continue for at least 5 years and possibly up to 10 years from a subject's initial treatment with belimumab. Enrolment will be staggered by age cohorts to allow safety and PK interim analyses. Subjects will be randomized to belimumab 10mg/kg or placebo IV monthly dosing while continuing to receive background standard therapy throughout the study. An independent data monitoring committee (IDMC) will monitor the study as it progresses.

Asthma

A Multi-centre, Single Arm, Open-label Extension Study to Evaluate the Long-term Safety of GSK3511294 (Depemokimab) in Adult and Adolescent Participants With Severe Asthma With an Eosinophilic Phenotype From Studies 206713 or 213744

Pediatric Sarcoma, Refractory, Pediatric Sarcoma, Relapsed

A Multi-Institution Study of TGFβ Imprinted, Ex Vivo Expanded Universal Donor NK Cell Infusions as Adoptive Immunotherapy in Combination With Gemcitabine and Docetaxel in Patients With Relapsed or Refractory Pediatric Bone and Soft Tissue

This is a multi-center study with rolling safety and toxicity analysis, to determine the safety and efficacy of the addition of adoptive transfer of universal donor, TGFβ imprinted (TGFβi), expanded NK cells to the pediatric sarcoma salvage chemotherapeutic regimen gemcitabine/docetaxel (GEM/DOX) for treatment of relapsed and refractory pediatric sarcomas, identify toxicities related to treatment with GEM/DOX + TGFβi expanded NK cells, and assess in vivo persistence of expanded, universal donor, TGFβi NK cells after adoptive transfer and correlate with clinical outcomes. The planned therapy will involve 8 cycles of 21 days each consisting of gemcitabine, docetaxel, supportive dexamethasone and peg-filgrastim, and universal donor, TGFβi ex vivo expanded NK cells (Cycles 1-6).

• 813-745-6250
• jessica.crimella@moffitt.org

Ovarian Cancer, Endometrial Cancer, Germ Cell Tumor, Testicular Germ Cell Tumor, Ovarian Germ Cell Tumor

A Phase 1, First-in-Human, Dose Escalation and Expansion Study to Evaluate the Safety and Tolerability of XmAb541 in Advanced Solid Tumors

• mkistler@xencor.com

Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia, Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

A Phase 1/2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-X19 in Pediatric and Adolescent Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia or Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (ZUMA-4)

All participants who received KTE-X19, and have completed at least 24 months of protocol assessments, will be transitioned to a separate long-term follow-up (LTFU) study. The purpose of the LTFU study (KT-US-982-5968.) is to complete the remainder of the 15-year follow-up assessments.

Acute Leukemias, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia

A Phase 1/2, First-in-Human Study of the Menin-KMT2A (MLL1) Inhibitor Bleximenib in Participants With Acute Leukemia

• 844-434-4210
• Participate-In-This-Study1@its.jnj.com

Rett Syndrome

A Phase 1/2, Open-Label Clinical Study to Evaluate Safety, Tolerability, and Efficacy of NGN-401 in Pediatric Subjects with Rett Syndrome

The study is a phase 1/2, open-label study designed to assess the safety, tolerability, and efficacy of administration of an adeno-associated viral vector serotype 9 (AAV9), using Neurogene's proprietary transgene regulation technology. NGN-401 contains a full-length human MECP2 gene which is designed to express therapeutic levels of the MECP2 protein while avoiding overexpression. The study treatment will be administered under general anesthesia via intracerebroventricular (ICV) delivery. Each participant will be followed for safety and preliminary efficacy for 5 years after treatment and is expected to enroll in a long-term follow-up study for 10 years.

• +1 877-237-5020
• medicalinfo@neurogene.com

Leukemia, Myeloid, Acute

A Phase 1b Study of Bleximenib in Combination With AML-Directed Therapies for Participants With Acute Myeloid Leukemia Harboring KMT2A or NPM1 Alterations

• 844-434-4210
• Participate-In-This-Study1@its.jnj.com

High Risk Neuroblastoma, Recurrent Neuroblastoma, Refractory Neuroblastoma

A Phase 2 Randomized Study of Irinotecan/Temozolomide/Dinutuximab With or Without Eflornithine (DFMO) in Children With Relapsed, Refractory or Progressive Neuroblastoma

PRIMARY OBJECTIVE: I. To determine whether administration of eflornithine hydrochloride (eflornithine \[DFMO\]) in combination with dinutuximab, irinotecan hydrochloride (irinotecan) and temozolomide results in an improved response rate compared to dinutuximab, irinotecan and temozolomide in patients with relapsed or refractory neuroblastoma and therefore is a therapeutic regimen worthy of further testing in patients with newly-diagnosed high-risk neuroblastoma. SECONDARY OBJECTIVES: I. To compare progression-free survival and overall survival between patients receiving dinutuximab, irinotecan and temozolomide with and without the addition of DFMO. II. To define the toxicity profile of DFMO administered with dinutuximab, irinotecan and temozolomide. EXPLORATORY OBJECTIVES: I. To characterize the immune and cytokine profiles of patients treated with DFMO/chemotherapy/dinutuximab combination and correlate with response to therapy. II. To evaluate GD2 levels in tumor cells from patient bone marrow samples and correlate with response to therapy. III. To explore whether the addition of DFMO to the dinutuximab and chemotherapy backbone affects pain as determined by patient report and opiate usage. OUTLINE: Patients are randomized to 1 of 2 regimens. REGIMEN A: Patients receive temozolomide orally (PO), via nasogastric (NG), or gastric (G) tube on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over 2 hours on days 6-12 of a 21-day cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. REGIMEN B: Patients receive eflornithine PO, via NG, or G tube on days -6 to 7 and days 15-21 of cycle 1 and days 1-7 and 15-21 of subsequent cycles, temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Treatment lasts 28 days for cycle 1 and then every 21 days for subsequent cycles up to 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and periodically for 5 years.

Anaplastic Astrocytoma, Anaplastic Astrocytoma, Not Otherwise Specified, Anaplastic Ganglioglioma, Anaplastic Pleomorphic Xanthoastrocytoma, Glioblastoma, Malignant Glioma, WHO Grade 3 Glioma

A Phase 2 Study of Dabrafenib (NSC# 763760) With Trametinib (NSC# 763093) After Local Irradiation in Newly-Diagnosed BRAF V600-Mutant High-Grade Glioma (HGG)

PRIMARY OBJECTIVE: I. To estimate the event-free survival (EFS) distribution for newly-diagnosed patients with BRAF\^V600-mutant high-grade glioma (HGG) without H3 K27M mutations excluding anaplastic pleomorphic xanthoastrocytoma (aPXA) and anaplastic ganglioglioma (aGG) treated with radiation therapy followed by a maintenance combination of dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) and to compare this EFS to contemporary historical controls. SECONDARY OBJECTIVES: I. To describe the overall survival (OS) distribution for newly-diagnosed patients with BRAF\^V600-mutant HGG without H3 K27M mutations excluding aPXA and aGG treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib. II. To describe the EFS and overall survival (OS) distribution for newly-diagnosed patients with BRAF\^V600E-mutant aPXA and aGG without H3 K27M mutations treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib. III. To describe the EFS and overall survival (OS) distribution for newly-diagnosed patients with BRAF\^V600E-mutant HGG including aPXA and aGG with H3 K27M mutations treated with radiation therapy followed by a maintenance combination of dabrafenib and trametinib. IV. To define and evaluate the toxicities of combination therapy with dabrafenib and trametinib after radiation therapy in newly-diagnosed patients with HGG. EXPLORATORY OBJECTIVE: I. To bank tumor specimens and body fluids (blood, urine and cerebrospinal fluid) for future studies. OUTLINE: Patients undergo standardized local radiation therapy (RT) 5 days a week (Monday-Friday) for 6-7 weeks. Four weeks after completion of RT, patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl sulfoxide PO once daily (QD) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a magnetic resonance imaging (MRI) at baseline, on day 1 of cycles 1, 3, 5, 7, 11, 14, 17, 20, and 23 while on treatment, then at time of relapse, every 3 months for year 1, every 4 months for year 3, every 6 months for year 3, and annually for years 4-5. Patients may also undergo lumbar puncture for cerebral spinal fluid (CSF) testing during treatment. Patients also undergo collection of blood on study. After completion of study treatment, patients are followed up at disease relapse, every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, then annually for years 4-5.

Recurrent B Acute Lymphoblastic Leukemia, Recurrent B Lymphoblastic Lymphoma, Refractory B Acute Lymphoblastic Leukemia, Refractory B Lymphoblastic Lymphoma

A Phase 2 Study of Inotuzumab Ozogamicin (NSC# 772518) in Children and Young Adults With Relapsed or Refractory CD22+ B-Acute Lymphoblastic Leukemia (B-ALL)

PRIMARY OBJECTIVE: I. To determine the morphologic response rate (complete response \[CR\] + complete response with incomplete hematologic recovery \[CRi\]) following one cycle of treatment with inotuzumab ozogamicin in children with relapsed or refractory CD22+ B acute lymphoblastic leukemia (B-ALL). (Cohort 1) SECONDARY OBJECTIVES: I. To determine the CR/CRi rate following 2 cycles of inotuzumab ozogamicin therapy. (Cohort 1) II. To determine the safety of single agent inotuzumab ozogamicin administered at the adult recommended phase 2 dose (RP2D) to pediatric patients with relapsed or refractory CD22+ B-ALL. (Cohort 1) III. To determine the level of minimal residual disease (MRD) by flow cytometry in responding patients. (Cohorts 1 and 2) IV. To determine the incidence, severity, and outcomes of sinusoidal obstruction syndrome (SOS) of the liver in patients during inotuzumab ozogamicin therapy and following subsequent treatment, including myeloablative hematopoietic stem cell transplantation (HSCT). (Cohorts 1 and 2) V. To estimate the 3-year event-free survival (EFS), 3-year overall survival (OS), and among responders, duration of CR/CRi for pediatric patients with relapsed or refractory B-ALL treated with inotuzumab ozogamicin. (Cohort 1) VI. To describe inotuzumab ozogamicin pharmacokinetics and immunogenicity in pediatric patients in the presence of overt leukemia and in remission. (Cohort 1) VII. To determine the safe and tolerable dose of inotuzumab ozogamicin in combination with the augmented modified Berlin-Frankfurt-Munster (mBFM) consolidation chemotherapy backbone. (Cohort 2) EXPLORATORY OBJECTIVES: I. To describe the levels of leukemic blast CD22 surface expression and site density, and to explore the correlation with cytogenetics and clinical outcomes after treatment with inotuzumab ozogamicin. (Cohorts 1 and 2) II. To explore potential mechanisms of resistance to inotuzumab ozogamicin therapy including CD22 splice variants and intracellular signaling pathways. (Cohorts 1 and 2) III. To explore the impact of inotuzumab ozogamicin on humoral immune function and peripheral B cell populations. (Cohorts 1 and 2) IV. To describe the level of MRD by next-generation high-throughput sequencing (HTS) techniques which may detect low level leukemic blast populations that have altered CD22 expression. (Cohorts 1 and 2) V. To prospectively explore candidate SOS biomarkers including the endothelial marker of inflammation Angiopoietin 2 (Ang2) and the hepatic specific complement marker L-ficolin. (Cohorts 1 and 2) VI. To explore the use of prophylactic ursodeoxycholic acid (UDCA) to prevent hepatic damage and SOS during inotuzumab ozogamicin therapy and subsequent HSCT. (Cohorts 1 and 2) VII. To describe the interaction between inotuzumab ozogamicin and chimeric antigen receptor (CAR) T cell therapy before or after treatment with inotuzumab ozogamicin. (Cohorts 1 and 2) VIII. To estimate the CR/CRi rate following one cycle of inotuzumab ozogamicin plus augmented mBFM consolidation chemotherapy (first 42 days) and following 2 cycles within the confines of a pilot study. (Cohort 2) OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT I: Patients receive inotuzumab ozogamicin intravenously (IV) over 60 minutes on days 1, 8, and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. (COMPLETE) COHORT II: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, and 8. Patients also receive cyclophosphamide IV over 30-60 on day 1; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4 and 8-11; leucovorin calcium orally (PO) or IV on days 2, 9, 16, 23 and 37 of cycle 1 and days 9 and 37 of cycle 2; pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase intramuscularly (IM) on day 15; and vincristine IV on days 15 and 22. Patients receive methotrexate intrathecally (IT) on days 1, 8 and 36 of cycle 1 and day 36 of cycle 2 for CNS 1 patients, days 1, 8, 15, 22 and 36 of cycle 1, and day 36 of cycle 2 for CNS 2 patients. CNS 3 patients receive methotrexate intrathecal triple therapy (ITT) IT on days 1, 8, 15, 22 and 36 of cycle 1 and days 8 and 36 of cycle 2. There are 3 dose levels. If excessive toxicity is observed at dose level 1, the dosing of inotuzumab ozogamicin will be decreased for dose level -1 and 6-mercaptopurine omitted. If excessive toxicity is observed at this dose, then for dose level -2, the dosing of inotuzumab ozogamicin and cyclophosphamide will be decreased. Treatment repeats every 42 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration or biopsy, lumbar puncture, and blood sample collection throughout the trial. Patients also undergo imaging on screening and on study. After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, and then yearly for 4 years.

Medulloblastoma

A Phase 2 Study of Reduced Therapy for Newly Diagnosed Average-Risk WNT-Driven Medulloblastoma Patients

PRIMARY OBJECTIVE: I. To estimate the progression-free survival (PFS) of children \>= 3 years of age with wingless-type MMTV integration site family (WNT)-driven average-risk medulloblastoma using reduced craniospinal radiotherapy (CSI) (18 Gray \[Gy\]) with a limited target volume boost to the tumor bed of 36 Gy for a total of 54 Gy and reduced chemotherapy approach (no vincristine \[vincristine sulfate\] during radiotherapy and reduced-dose maintenance chemotherapy) and to monitor the PFS for early evidence that the outcome is unacceptable. SECONDARY OBJECTIVES: I. To prospectively test the hypothesis that deoxyribonucleic acid (DNA) methylation profiling will accurately classify WNT-driven medulloblastoma. II. To prospectively evaluate and longitudinally model the cognitive, social, emotional, behavioral, and quality of life (QoL) functioning of children who are treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced chemotherapy (reduced cisplatin, vincristine, and lomustine \[CCNU\]). EXPLORATORY OBJECTIVES: I. To explore whether DNA methylation profiling of medulloblastoma samples will result in a predictive classification scheme for the Sonic Hedgehog (SHH), Group 3, and Group 4 medulloblastoma subgroups according to the Heidelberg classifier. This will be addressed in a separate biology protocol. II. To describe the audiologic and endocrinologic toxicities, as well as peripheral neuropathy, in children treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced cisplatin and vincristine chemotherapy. OUTLINE: RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine orally (PO) on day 1, vincristine sulfate intravenously (IV) via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually for 6 years.

Medulloblastoma

A Phase 2 Study of Reduced Therapy for Newly Diagnosed Average-Risk WNT-Driven Medulloblastoma Patients

PRIMARY OBJECTIVE: I. To estimate the progression-free survival (PFS) of children \>= 3 years of age with wingless-type MMTV integration site family (WNT)-driven average-risk medulloblastoma using reduced craniospinal radiotherapy (CSI) (18 Gray \[Gy\]) with a limited target volume boost to the tumor bed of 36 Gy for a total of 54 Gy and reduced chemotherapy approach (no vincristine \[vincristine sulfate\] during radiotherapy and reduced-dose maintenance chemotherapy) and to monitor the PFS for early evidence that the outcome is unacceptable. SECONDARY OBJECTIVES: I. To prospectively test the hypothesis that deoxyribonucleic acid (DNA) methylation profiling will accurately classify WNT-driven medulloblastoma. II. To prospectively evaluate and longitudinally model the cognitive, social, emotional, behavioral, and quality of life (QoL) functioning of children who are treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced chemotherapy (reduced cisplatin, vincristine, and lomustine \[CCNU\]). EXPLORATORY OBJECTIVES: I. To explore whether DNA methylation profiling of medulloblastoma samples will result in a predictive classification scheme for the Sonic Hedgehog (SHH), Group 3, and Group 4 medulloblastoma subgroups according to the Heidelberg classifier. This will be addressed in a separate biology protocol. II. To describe the audiologic and endocrinologic toxicities, as well as peripheral neuropathy, in children treated with reduced CSI (18 Gy) with a limited target volume boost to the tumor bed (to a total of 54 Gy) and reduced cisplatin and vincristine chemotherapy. OUTLINE: RADIATION THERAPY: Beginning 4-5 weeks after surgery, patients undergo craniospinal radiation therapy 5 days a week for 6 weeks. MAINTENANCE THERAPY (WEEKS 1, 3, 5, and 7): Beginning 4-6 weeks after completion of radiation therapy patients receive lomustine orally (PO) on day 1, vincristine sulfate intravenously (IV) via minibag on days 1, 8, and 15, and cisplatin IV over 6 hours on day 1. Treatment repeats every 42 days in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY (WEEKS 2, 4, AND 6): Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 2, mesna IV over 15-30 minutes on days 1 and 2, and vincristine sulfate IV via minibag on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually for 6 years.

Recurrent Acute Leukemia of Ambiguous Lineage, Recurrent Acute Lymphoblastic Leukemia, Recurrent Acute Myeloid Leukemia Due to Lineage Switch From Acute Leukemia of Ambiguous Lineage, Recurrent Acute Myeloid Leukemia Due to Lineage Switch From B Acute Lymphoblastic Leukemia, KMT2A-Rearranged, Recurrent Acute Myeloid Leukemia Due to Lineage Switch From Mixed Phenotype Acute Leukemia, Recurrent Mixed Phenotype Acute Leukemia, Refractory Acute Leukemia of Ambiguous Lineage, Refractory Acute Lymphoblastic Leukemia, Refractory Acute Myeloid Leukemia Due to Lineage Switch From Acute Leukemia of Ambiguous Lineage, Refractory Acute Myeloid Leukemia Due to Lineage Switch From B Acute Lymphoblastic Leukemia, KMT2A-Rearranged, Refractory Acute Myeloid Leukemia Due to Lineage Switch From Mixed Phenotype Acute Leukemia, Refractory Mixed Phenotype Acute Leukemia

A Phase 2 Study of Revumenib (SNDX-5613) in Combination With Chemotherapy for Patients With Relapsed or Refractory KMT2A-Rearranged Infant Leukemia

PRIMARY OBJECTIVES: I. To determine the recommended phase 2 dose (RP2D) of revumenib administered in combination with chemotherapy in patients with relapsed or refractory (R/R) KMT2A-rearranged (KMT2A-R) acute lymphoblastic leukemia (ALL). II. To estimate the minimal residual disease (MRD) negative remission rate of patients with R/R infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. SECONDARY OBJECTIVES: I. To characterize the pharmacokinetics (PK) of revumenib administered with chemotherapy in patients with R/R infant KMT2A-R ALL. II. To estimate the 18-month event-free survival (EFS) of patients with R/R infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. III. To estimate 18-month overall survival (OS) of patients with R/R infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. IV. To characterize the tolerability of revumenib given as monotherapy in patients with R/R infant KMT2A-R ALL. EXPLORATORY OBJECTIVE: I. To assess the biologic activity of revumenib administered with chemotherapy in patients with R/R KMT2A-R ALL. II. To estimate the MRD negative remission rate of patients with R/R non-infant KMT2A-R ALL treated with revumenib in combination with chemotherapy. III. To characterize the PK of calaspargase pegol-mknl and describe associated toxicities for patients with R/R KMT2A-R ALL. IV. To describe the anti-cancer therapies received before and after administration of revumenib by patients with R/R KMT2A-R ALL. OUTLINE: Patients with acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage (ALAL), or mixed phenotype acute leukemia (MPAL) are assigned to 1 of 2 regimens, by physician discretion. Patients with acute myeloid leukemia (AML) are assigned to Regimen B. REGIMEN A: COMBINATION CYCLE 1: Patients receive revumenib orally (PO) or via nasogastric (NG), nasojejunal (NJ), nasoduodenal (ND) or gastrostomy tube (G-tube) every 12 hours continuously. Patients also receive "3-drug re-induction" consisting of vincristine intravenously (IV) on days 1, 8, 15, and 22, prednisone or prednisolone PO or via NG, ND, NJ, or G-tube twice daily (BID) on days 1-28, calaspargase pegol-mknl IV over 1-2 hours on day 4, as well as methotrexate (MTX) intrathecally (IT) on days 1 and 8 then optionally weekly, hydrocortisone IT, and cytarabine IT. Patients who have early progressive disease may continue to Combination Cycle 2 early before fully completing cycle 1. COMBINATION CYCLE 2: Patients receive revumenib PO or via NG, NJ, ND, or G-tube every 12 hours continuously, "FLA" consisting of fludarabine IV over 60 minutes and high-dose cytarabine IV over 1-3 hours on days 1-5. After completion of Combination Cycle 2, patients who experienced early progressive disease in Combination Cycle 1 continue to Combination Cycle 3. All other patients proceed to Monotherapy. COMBINATION CYCLE 3: Patients receive revumenib PO or via NG, NJ, ND, or G-tube every 12 hours continuously, "FLA" as in Combination Cycle 2, MTX IT, hydrocortisone IT, and cytarabine IT on day 0. MONOTHERAPY: Patients receive revumenib PO or via NG, NJ, ND, or G-tube every 12 hours continuously. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT as clinically indicated. REGIMEN B: COMBINATION CYCLES 1-2: Patients receive revumenib PO or via NG, ND, NJ, or G-tube every 12 hours continuously, "FLA" IV on days 1-5, MTX IT, hydrocortisone IT, and cytarabine IT on day 0 and optionally on days 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 2 cycles. MONOTHERAPY: Patients receive revumenib PO or via NG, ND, NJ, or G-tube every 12 hours continuously. Treatment repeats every 28 days for up to 12 cycles on study in the absence of disease progression or unacceptable toxicity. Patients may also receive MTX IT, hydrocortisone IT, and cytarabine IT on days 0, 8, 15 and 22 as clinically indicated. All patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA), collection of blood and cerebrospinal fluid (CSF) samples, lumbar puncture, and bone marrow aspiration throughout the trial.

Leukemia

A Phase 2 Study of the JAK1/JAK2 Inhibitor Ruxolitinib With Chemotherapy in Children With De Novo High-Risk CRLF2-Rearranged and/or JAK Pathway-Mutant Acute Lymphoblastic Leukemia

Anaplastic Astrocytoma, Glioblastoma, Malignant Glioma

A Phase 2 Study of Veliparib (ABT-888) and Local Irradiation, Followed by Maintenance Veliparib and Temozolomide, in Patients With Newly Diagnosed High-Grade Glioma (HGG) Without H3 K27M or BRAFV600 Mutations

PRIMARY OBJECTIVES: I. To determine whether veliparib (ABT-888), when added to radiotherapy (RT) and temozolomide, is efficacious for the treatment of patients with newly-diagnosed high-grade glioma (HGG) whose tumors' molecular profile are wild-type for H3 K27M, BRAF, and IDH1/2. II. To determine whether veliparib (ABT-888), when added to RT and temozolomide, is efficacious for the treatment of patients with newly-diagnosed HGG whose tumors' molecular profile are wild-type for H3 K27M and BRAF and harbor an IDH1/2 mutation. EXPLORATORY OBJECTIVES: I. To explore associations of genomic, transcriptomic, and/or epigenetic alterations of the tumors with treatment response and outcome. II. To explore the extent to which patients with BRCA1/2 gene alterations and other deoxyribonucleic acid (DNA) damaged genes display tumor genomic features consistent with homologous repair deficiency (HRD), including large scale state transitions (LSTs), mutational signature 3, and an enrichment for deletions flanked by sequences of (micro) homology. III. To explore the burden of high, moderate, and low penetrant germline alterations in HRD genes (such as BRCA1, BRCA2, PALB2, Fanconi complex genes, ATM, CHEK2, RAD51B/C/D), mis-match repair genes (such as MLH1, MSH2, MSH6, PMS2, EPCAM), and energy metabolism genes (such as SDHA, SDHB, SDHC, SDHAF2, SDHD, IDH1, IDH2, and FH). IV. To explore constitutional imprinting abnormalities associated with EP300 and IGF2 in peripheral blood from patients with HGGs. OUTLINE: CHEMORADIOTHERAPY PHASE: Patients receive veliparib orally (PO) twice daily (BID) and undergo 30 daily fractions of radiation therapy 5 days per week for 6-7 weeks in the absence of disease progression or unacceptable toxicity. MAINTENANCE CHEMOTHERAPY: Beginning 4 weeks after chemoradiotherapy phase, patients receive veliparib PO BID and temozolomide PO once daily (QD) on days 1-5. Treatment repeats every 28 days for up to 10 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for year 2, every 6 months for year 3, and then once yearly for years 4-10.

Stage II Nasopharyngeal Carcinoma AJCC v8, Stage III Nasopharyngeal Carcinoma AJCC v8, Stage IV Nasopharyngeal Carcinoma AJCC v8

A Phase 2 Study Using Chemoimmunotherapy With Gemcitabine, Cisplatin and Nivolumab in Newly Diagnosed Nasopharyngeal Carcinoma (NPC)

PRIMARY OBJECTIVE: I. To evaluate safety of combining chemotherapy (cisplatin and gemcitabine) with an anti-PD1 immune checkpoint inhibitor (nivolumab) in children, adolescents and young adults with nasopharyngeal carcinoma (NPC) by determining the rate of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher immune related adverse events (irAEs). SECONDARY OBJECTIVES: I. To estimate the 2-year event-free survival (EFS) of children, adolescents and young adults with NPC who are treated with induction chemoimmunotherapy (CIT), followed by consolidation chemoradioimmunotherapy (CRIT, cisplatin, nivolumab and response-adjusted, dose de-escalated radiation therapy), and nivolumab maintenance therapy. II. To evaluate the objective response rate (ORR) including complete responders and partial responders (complete response \[CR\] + partial response \[PR\]) of neoadjuvant CIT. III. To evaluate feasibility of combining chemotherapy (cisplatin and gemcitabine) with an anti-PD1 immune checkpoint inhibitor (nivolumab) in children, adolescents and young adults with nasopharyngeal carcinoma (NPC). IV. To evaluate the cumulative incidence of local and distant relapse. EXPLORATORY OBJECTIVES: I. To estimate 5-year EFS and overall survival (OS) of children with NPC who are treated with induction CIT followed by consolidation CRIT, and nivolumab maintenance therapy. II. To compare response assessed by fludeoxyglucose F18 (FDG) positron emission tomography (PET) versus magnetic resonance imaging (MRI). III. To determine treatment outcomes for patients treated with radiation per protocol versus (vs) deviation. IV. To evaluate outcomes comparing patients receiving intensity modulated radiation therapy (IMRT) to proton therapy. V. To objectively measure both acute and long-term toxicity including immune related adverse events and radiation late effects. VI. To evaluate swallowing dysfunction using patient reported outcome (PRO) measures for children and adults throughout the protocol for up to 5 years. VII. To evaluate quality of life (QOL) using Patient-Reported Outcomes Measurement Information System (PROMIS) multidimensional questionnaire throughout the protocol for up to 5 years. VIII. To correlate the lymphocyte to monocyte ratio on complete blood counts (CBCs) with treatment response and outcomes. IX. To collect and bank specimens (including tumor, blood and stool) for future research studies. OUTLINE: INDUCTION THERAPY: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle, gemcitabine IV over 30 minutes on days 1 and 8 of each cycle, and cisplatin IV over 3-6 hours on day 1 of each cycle. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cisplatin IV over 3-6 hours on day 1 of cycles 1-2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive concurrent radiation therapy on trial. MAINTENANCE THERAPY: Patients receive nivolumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and as clinically indicated on trial. Patients undergo MRI, FDG PET, and computed tomography (CT) throughout the trial and chest x-ray during follow-up. Patients also undergo dental x-ray imaging on the trial. Patients may optionally undergo tissue biopsy, blood and stool sample collection during screening and on trial. After completion of study treatment, patients are followed up every 3 months for 12 months, every 6 months until 24 months off therapy, and then yearly until 5 years off therapy.

Central Nervous System Nongerminomatous Germ Cell Tumor, Choriocarcinoma, Embryonal Carcinoma, Immature Teratoma, Malignant Teratoma, Mixed Germ Cell Tumor, Pineal Region Germ Cell Tumor, Pineal Region Immature Teratoma, Pineal Region Yolk Sac Tumor, Suprasellar Germ Cell Tumor

A Phase 2 Trial of Chemotherapy Followed by Response-Based Whole Ventricular &Amp; Spinal Canal Irradiation (WVSCI) for Patients With Localized Non-Germinomatous Central Nervous System Germ Cell Tumor

PRIMARY OBJECTIVES: I. To monitor outcome to ensure that children and young adults with localized central nervous system (CNS) non-germinomatous germ cell tumors (NGGCT) treated with induction chemotherapy followed by response evaluation and whole ventricular + spinal canal irradiation (WVSCI) will maintain the excellent 2-year progression free survival (PFS) rate as compared to ACNS0122 (NCT00047320). II. To improve disease control by decreasing the number of spinal relapses for patients who achieve a complete response (CR) or partial response (PR) and receive WVSCI as compared to whole ventricular radiation on ACNS1123 (NCT01602666). SECONDARY OBJECTIVES: I. To estimate the response rates to induction chemotherapy and WVSCI for localized NGGCT patients who achieve a CR/PR. II. To estimate the PFS and overall survival (OS) for localized NGGCT patients who achieve a CR/PR and receive WVSCI. III. To estimate the PFS and OS for patients with less than a CR/PR following Induction who subsequently receive high-dose chemotherapy with peripheral stem cell rescue (HDCSCR). IV. To estimate the response rate for patients with less than a CR/PR following Induction who subsequently receive HDCSCR. EXPLORATORY OBJECTIVES: I. To prospectively compare outcomes based on radiation modality, photon versus proton, including cognitive, social and behavioral functioning, auditory, and neuro-endocrine function. II. To compare spinal column growth and cell counts following radiation as measured by height and weight, and complete blood count (CBC) values during and after radiation therapy, based on treatment modality (photon versus \[vs.\] proton therapy) and planned inclusion/exclusion of the vertebral body in patients \< 13 years of age. III. To compare local vs. central review recommendations for second-look surgery and document barriers for performing such surgeries as well as their clinical benefit in pediatric NGGCT. IV. To prospectively evaluate and longitudinally model the cognitive, social, and behavioral functioning of children and young adults with localized CNS NGGCT with testing as per the Children's Oncology Group (COG) Standardized Neuropsychological and Behavioral Battery. V. To evaluate patterns of disease recurrence/failure with respect to radiation dose distribution. OUTLINE: INDUCTION CHEMOTHERAPY: Patients receive carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of cycles 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide IV over 60-120 minutes on days 1-5 of cycles 2, 4, and 6. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients are assigned to 1 of 2 plans (ventricular + spinal canal irradiation \[WVSCI\] or high-dose chemotherapy with peripheral stem cell rescue \[HDCSCR\]) based on response to induction chemotherapy: * Patients who achieve radiographic CR/PR with marker normalization proceed to WVSCI. Patients who achieve radiographic CR without marker normalization proceed to HDCSCR. * Patients who achieve less than radiographic CR/PR with marker normalization proceed to second-look surgery (unless contraindicated). If second-look surgery reveals mature teratoma or non-viable tumor, proceed to WVSCI. If second-look surgery reveals viable tumor, proceed to HDCSCR. Patients who are unable to undergo second-look surgery are removed from protocol therapy but remain on study for follow-up. * Patients who achieve less than radiographic CR/PR without marker normalization proceed to second-look surgery (unless contraindicated). Patients then proceed to HDCSCR regardless of whether or not a second-look surgery is performed. * Patients who achieve radiographic PR without marker normalization proceed to second-look surgery (unless contraindicated). Patients then proceed to HDCSCR regardless of whether or not a second-look surgery is performed. PLAN A (WVSCI THERAPY): Within 6 weeks of the end of induction chemotherapy or second-look surgery, patients undergo WVSCI once daily (QD) for 5 days weekly (17 fractions followed by a boost dose for 13 fractions) for 6 weeks in the absence of disease progression or unacceptable toxicity. PLAN B (CONSOLIDATION THERAPY \[HDCSCR\]): Within 6-8 weeks of the end of induction chemotherapy or second-look surgery, patients receive etoposide IV and thiotepa IV over 3 hours on days -5 to -3 and undergo peripheral blood stem cell (PBSC) transplant on day 0. Patients then undergo radiation therapy QD for 5 days weekly (20 fractions followed by a boost dose for 10 fractions) for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI), as well as collection of cerebral spinal fluid (CSF) and blood sample throughout the trial. After completion of study treatment, patients are followed for up to 10 years.

Idiopathic Short Stature

A Phase 2, Randomized, Controlled, Multicenter Study of Vosoritide in Children with Idiopathic Short Stature

Following a minimum 6 month observational period in which baseline growth is assessed, participants in the vosoritide and placebo groups will complete a minimum of 6 months of randomized treatment (maximum of 6 months of placebo treatment), followed by open-label treatment with vosoritide until they reach near-final adult height, or at least 16 years of age for females or 18 years of age for males, whichever comes later. Participants randomized to the hGH group will receive open-label hGH for a minimum of 4 years.

• +1 415.475.5852
• medinfo@bmrn.com

Short Stature Homeobox- Containing Gene SHOX Deficiency, Noonan Syndrome, Turner Syndrome

A Phase 2, Randomized, Human Growth Hormone-Controlled, Multicenter, Basket Study of Vosoritide in Children With Turner Syndrome, Short Stature Homeobox-Containing Gene Deficiency, and Noonan Syndrome With an Inadequate Response to Human Growth Hormone

This is a Phase 2, randomized, active-controlled, multicenter, basket study of vosoritide in children with Turner syndrome, short stature homeobox-containing gene (SHOX) deficiency, or Noonan syndrome who have an inadequate response to human growth hormone (hGH) treatment. The study is intended to characterize the short-term efficacy and safety of 3 dosing regimens of vosoritide versus hGH. The efficacy and safety of the vosoritide therapeutic dose will be further evaluated, with a comparison to hGH after 2 years of treatment, and an analysis of the impact of vosoritide on final adult height (FAH).

• 1-800-983-4587
• medinfo@bmrn.com

Sickle Cell Disease (SCD)

A Phase 2,Multicenter,Open-Label Study to Assess Appropriate Dosing and to Evaluate Safety of Crizanlizumab,With or Without Hydroxyurea/Hydroxycarbamide,in Sequential,Descending Age Groups of Pediatric Sickle Cell Disease Patients With Vaso-Occlusive Crisis

• 1-888-669-6682
• novartis.email@novartis.com

Sickle Cell Disease (SCD)

A Phase 2,Multicenter,Open-Label Study to Assess Appropriate Dosing and to Evaluate Safety of Crizanlizumab,With or Without Hydroxyurea/Hydroxycarbamide,in Sequential,Descending Age Groups of Pediatric Sickle Cell Disease Patients With Vaso-Occlusive Crisis

• 1-888-669-6682
• novartis.email@novartis.com

Proteinuric Kidney Disease

A Phase 2/3 Adaptive, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of VX-147 in Adult and Pediatric Subjects With APOL1-mediated Proteinuric Kidney Disease

• 617-341-6777
• medicalinfo@vrtx.com

Heart Failure, Left Ventricular Systolic Dysfunction

A Phase 2/3 Randomized, Placebo-Controlled, Double-blind, Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Vericiguat in Pediatric Participants With Heart Failure Due to Systemic Left Ventricular Systolic Dysfunction (VALOR)

As of Protocol Amendment 2, the separate open-label extension arm of study MK-1242-043 (NCT06428383) will be incorporated into the present MK-1242-036 study as an extension period. Participants from the Base Period will be provided the opportunity to participate in the optional open-label Extension Period if eligible. After all ongoing participants are transferred into the extension period of MK-1242-036, MK-1242-043 (NCT06428383) will be formally closed.

• 1-888-577-8839
• Trialsites@msd.com

Acquired Immune Deficiency Syndrome (AIDS), HIV Infections

A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, and Antiviral Activity of the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Single Tablet Regimen (STR) in HIV-1 Infected Antiretroviral Treatment-Naive Adolescents and Virologically Suppressed Children

Plexiform Neurofibroma, Neurofibromatosis Type 1 (NF1)

A Phase 2b Trial of the MEK 1/2 Inhibitor (MEKi) PD-0325901 in Adult and Pediatric Patients With Neurofibromatosis Type 1 (NF1)-Associated Inoperable Plexiform Neurofibromas (PNs) That Are Causing Significant Morbidity

Neurofibromas are benign peripheral nerve sheath tumors, which are classified as plexiform neurofibromas (PNs) if they extend longitudinally along a nerve and involve multiple fascicles. PNs are a major cause of morbidity and disfigurement in individuals with NF1, and as the tumor growth progresses, can cause a multitude of clinical deficits including pain and impaired physical function. PNs have the potential to undergo malignant transformation to Malignant Peripheral Nerve Sheet Tumors (MPNST). Mirdametinib (PD-0325901) is an orally delivered, highly selective small-molecule inhibitor of the dual specificity kinases, MEK1 and MEK2 (MAPK/ERK Kinase) which prevents the phosphorylation and subsequent activation of mitogen-activated protein kinase (MAPK). Previous studies of mirdametinib (PD-0325901) demonstrated PN shrinkage and sustained inhibition of pERK. Reduced tumor volume indicated that cell proliferation or cell death may be altered in PNs with administration of mirdametinib (PD-0325901).

Ulcerative Colitis (UC)

A Phase 3 Multicenter, Long-Term Extension Study to Evaluate the Safety and Efficacy of Upadacitinib (ABT-494) in Subjects With Ulcerative Colitis

Arthritis, Juvenile

A Phase 3 Multicenter, Open-label Study to Evaluate the Efficacy, Pharmacokinetics, Safety, and Immunogenicity of Subcutaneously Administered Ustekinumab or Guselkumab in Pediatric Participants With Active Juvenile Psoriatic Arthritis (PSUMMIT-Jr)

• 844-434-4210
• Participate-In-This-Study@its.jnj.com

Metastatic Malignant Neoplasm in the Lung, Metastatic Osteosarcoma, Osteosarcoma

A Phase 3 Randomized Controlled Trial Comparing Open vs Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma

PRIMARY OBJECTIVE: I. To determine if open surgical resection is superior to thoracoscopic resection for thoracic event-free survival (tEFS) in patients with resectable oligometastatic pulmonary osteosarcoma. SECONDARY OBJECTIVES: I. To determine if open surgical resection is superior to thoracoscopy for event free survival (EFS) in patients with resectable oligometastatic pulmonary osteosarcoma. II. To determine if open surgical resection is superior to thoracoscopy for overall survival (OS) in patients with resectable oligometastatic pulmonary osteosarcoma. III. To determine if thoracoscopy is superior to open surgical resection for post-operative pain interference in patients with resectable oligometastatic pulmonary osteosarcoma. EXPLORATORY OBJECTIVES: I. To compare 30-day rates of perioperative surgical complications for both open surgical resection and thoracoscopy. II. To compare patterns of recurrence (ipsilateral and/or contralateral) in patients who undergo open or thoracoscopic resection for unilateral or bilateral pulmonary metastases. III. To describe the use of localization techniques and its relationship with both surgical approach and pathologic findings. IV. To assess the prognostic significance of a decision to change the post-operative treatment plan. V. To describe the relationship between the preoperative chest computed tomography (CT) imaging, intraoperative surgical findings, and pathologic results, comparing radiological features to the presence of viable tumor. VI. To prospectively compare between treatment arms the relationship between surgical approach and patient-reported outcomes (PROs), specifically patient functional impairment of the upper extremities, pain intensity, and health-related quality of life (HRQoL). VII. To generate well-characterized, clinically-annotated, distributable models of metastatic osteosarcoma. VIII. To collect and bank pulmonary metastatic lesions (including frozen tissues and paired metastatic lesions coming from the same patient) to facilitate study of metastatic disease and serial blood samples for future tumor profiling, germline and circulating tumor deoxyribonucleic acid (DNA) studies. OUTLINE: Patients are randomized into 1 of 2 arms. ARM A: Patients undergo open thoracic surgery (thoracotomy). ARM B: Patients undergo thoracoscopy (video-assisted thoracoscopic surgery or VATS). All patients undergo computed tomography (CT) throughout the trial. Patients may also undergo collection of tissue on study and blood throughout the trial. After completion of study treatment, patients are followed up at 7-14 days, 4-6 weeks, and 3 months post-surgery and then every 3 months for up to 2 years.

Metastatic Malignant Neoplasm in the Lung, Metastatic Osteosarcoma, Osteosarcoma

A Phase 3 Randomized Controlled Trial Comparing Open vs Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma

PRIMARY OBJECTIVE: I. To determine if open surgical resection is superior to thoracoscopic resection for thoracic event-free survival (tEFS) in patients with resectable oligometastatic pulmonary osteosarcoma. SECONDARY OBJECTIVES: I. To determine if open surgical resection is superior to thoracoscopy for event free survival (EFS) in patients with resectable oligometastatic pulmonary osteosarcoma. II. To determine if open surgical resection is superior to thoracoscopy for overall survival (OS) in patients with resectable oligometastatic pulmonary osteosarcoma. III. To determine if thoracoscopy is superior to open surgical resection for post-operative pain interference in patients with resectable oligometastatic pulmonary osteosarcoma. EXPLORATORY OBJECTIVES: I. To compare 30-day rates of perioperative surgical complications for both open surgical resection and thoracoscopy. II. To compare patterns of recurrence (ipsilateral and/or contralateral) in patients who undergo open or thoracoscopic resection for unilateral or bilateral pulmonary metastases. III. To describe the use of localization techniques and its relationship with both surgical approach and pathologic findings. IV. To assess the prognostic significance of a decision to change the post-operative treatment plan. V. To describe the relationship between the preoperative chest computed tomography (CT) imaging, intraoperative surgical findings, and pathologic results, comparing radiological features to the presence of viable tumor. VI. To prospectively compare between treatment arms the relationship between surgical approach and patient-reported outcomes (PROs), specifically patient functional impairment of the upper extremities, pain intensity, and health-related quality of life (HRQoL). VII. To generate well-characterized, clinically-annotated, distributable models of metastatic osteosarcoma. VIII. To collect and bank pulmonary metastatic lesions (including frozen tissues and paired metastatic lesions coming from the same patient) to facilitate study of metastatic disease and serial blood samples for future tumor profiling, germline and circulating tumor deoxyribonucleic acid (DNA) studies. OUTLINE: Patients are randomized into 1 of 2 arms. ARM A: Patients undergo open thoracic surgery (thoracotomy). ARM B: Patients undergo thoracoscopy (video-assisted thoracoscopic surgery or VATS). All patients undergo computed tomography (CT) throughout the trial. Patients may also undergo collection of tissue on study and blood throughout the trial. After completion of study treatment, patients are followed up at 7-14 days, 4-6 weeks, and 3 months post-surgery and then every 3 months for up to 2 years.

Low Grade Astrocytoma, Low Grade Glioma, Metastatic Low Grade Astrocytoma, Metastatic Low Grade Glioma

A Phase 3 Randomized Non-Inferiority Study of Carboplatin and Vincristine Versus Selumetinib (NSC# 748727) in Newly Diagnosed or Previously Untreated Low-Grade Glioma (LGG) Not Associated With BRAFV600E Mutations or Systemic Neurofibromatosis Type 1 (NF1)

PRIMARY OBJECTIVE: I. To demonstrate that the efficacy of treatment with selumetinib as measured by event-free survival (EFS) is non-inferior compared to treatment with carboplatin/vincristine (CV) in previously-untreated low-grade glioma (LGG) not associated with BRAFV600E mutations or systemic neurofibromatosis type 1 (NF1). SECONDARY OBJECTIVES: I. To estimate tumor response rates to each regimen of chemotherapy. II. To evaluate visual acuity (VA) outcomes utilizing Teller Acuity Cards (TAC) and HOTV letter acuity testing in previously-untreated optic pathway gliomas (OPGs). III. To describe the improvement in motor function as measured by the Vineland Scale in children with previously-untreated LGG that have motor deficits at enrollment. IV. To estimate the difference in EFS and tumor response rate between BRAF rearranged and non-BRAF rearranged patients treated on each chemotherapy regimen. V. To prospectively evaluate the quality of life of children with LGG not associated with BRAFV600E or systemic NF1 treated with either CV or selumetinib. VI. To prospectively evaluate the cognitive, social, emotional, and behavioral functioning of children with LGG not associated with BRAFV600E or systemic NF1 treated with either CV or selumetinib. EXPLORATORY OBJECTIVE: I. To obtain paired blood and tumor specimens for future biology studies as well as data from Molecular Characterization Initiative (MCI) testing, to correlate genomic drivers to efficacy outcomes. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: INDUCTION: Patients receive vincristine sulfate intravenously (IV) on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64, and carboplatin IV over 60 minutes on days 1, 8, 15, 22, 43, 50, 57, and 64 in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and magnetic resonance imaging (MRI) at baseline and end of induction. MAINTENANCE: Patients receive vincristine sulfate IV on days 1, 8, and 15, and carboplatin IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 42 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up. ARM II: Patients receive selumetinib sulfate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and undergo MRI at baseline, throughout the trial, and during follow up. After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and then annually for years 4-10.

Acute Myeloid Leukemia

A Phase 3 Randomized Trial for Patients With De Novo AML Comparing Standard Therapy Including Gemtuzumab Ozogamicin (GO) to CPX-351 With GO, and the Addition of the FLT3 Inhibitor Gilteritinib for Patients With FLT3 Mutations

PRIMARY OBJECTIVE: I. To compare event-free survival (EFS) in children with de novo acute myeloid leukemia (AML) without FLT3 mutations who are randomly assigned to standard induction therapy on Arm A with daunorubicin, cytarabine (DA) and gemtuzumab ozogamicin (GO) (DA-GO) versus Arm B with CPX-351 and GO. SECONDARY OBJECTIVES: I. To compare overall survival (OS) and rates of end of Induction 1 (EOI1) minimal residual disease (MRD) in children with de novo AML without FLT3 mutations who are randomly assigned to standard induction therapy (Arm A) with DA-GO versus CPX-351 and GO (Arm B). II. To estimate the EFS and rate of EOI1 MRD in FLT3 internal tandem duplication mutation positive patients (FLT3/ITD+; as defined by allelic ratio \> 0.1) without favorable cytomolecular characteristics (NPM1 and/or CEBPA) receiving gilteritinib fumarate (gilteritinib) in combination with DA-GO (Arm AC). III. To estimate the EFS and rate of EOI1 MRD in patients with non-ITD FLT3 activating mutations who receive backbone therapy (DA-GO or CPX-351 and GO) with gilteritinib (Arms AD and BD). IV. To determine the feasibility of combining gilteritinib and DA-GO or CPX-351 and GO in patients with FLT3/ITD and FLT3/TKD mutations (Arm AC/Arm BC/Arm AD/Arm BD). V. To compare EOI1 MRD and EFS in patients with FLT3/ITD AML+ (allelic ratio \[AR\] \> 0.1) without favorable cytogenetic/molecular characteristics treated with DA-GO-gilteritinib versus (vs) CPX-GO-gilteritinib (Arm AC vs Arm BC). VI. To compare the incidence of significant left ventricular systolic dysfunction (LVSD) in children with de novo AML without FLT3 mutations who are randomly assigned to standard induction therapy (Arm A) with DA-GO versus CPX-351 and GO (Arm B). VII. To compare the changes in echocardiography-derived measures of cardiac function, including left ventricular ejection fraction (EF) and global longitudinal strain (GLS), throughout AML therapy in patients with low and high risk AML without FLT3 mutations receiving Arm A vs Arm B. VIII. Determine if early changes in sensitive echocardiographic measures of cardiac function (i.e., post-Induction 1 decline in GLS) and elevations in circulating cardiac biomarkers (i.e., cardiac troponin T and N-terminal pro b-type natriuretic peptide) are associated with subsequent declines in left ventricular ejection fraction in patients with non-FLT3 mutant AML receiving therapy on Arms A or B. IX. To compare longitudinal acute changes in neuropsychological functioning and neurocognitive late effects between those with central nervous system (CNS) disease and those without CNS disease and between those treated with hematopoietic stem cell transplant (HSCT) and those treated with chemotherapy only for patients on Arms A and B. X. To compare cardiotoxicity measures (EF, GLS, and cardiac biomarkers) in patients receiving standard induction with dexrazoxane hydrochloride (dexrazoxane) vs. CPX-351 in the context of gilteritinib therapy and explore whether the differential cardiotoxicity across arms varies from that observed in non-FLT3 mutant AML without gilteritinib exposure. EXPLORATORY OBJECTIVES: I. To estimate the EFS and rate of EOI1 MRD in patients with high allelic ratio (HAR) FLT3/ITD+ patients, as historically defined by an AR \> 0.4, receiving gilteritinib in combination with DA-GO (Arm AC with AR \> 0.4). II. To estimate the EFS, OS, and rate of EOI1 MRD in FLT3/ITD+ patients (as defined by allelic ratio \> 0.1) with NPM1 and/or bZIP CEBPA mutations receiving gilteritinib in combination with DA-GO (Arm AC). III. Compare the changes in high sensitivity troponin and natriuretic peptide elevations throughout AML therapy, as measured at the end of each chemotherapy course, in patients with low and high risk AML without FLT3 mutations receiving Arm A vs Arm B. IV. Quantify the association of host factors (age, sex, body mass index \[BMI\], race), treatment exposures (cumulative anthracycline dose, anthracycline arm, hematopoietic stem cell transplant vs. chemotherapy alone), early declines in GLS, and elevations in cardiac biomarkers (cTnT and NT-proBNP) with subsequent LVSD. V. To describe the rates of CNS disease utilizing an updated strategy for diagnosing and defining CNS disease in pediatric AML. VI. To describe the rates of CNS relapse (both isolated CNS and combined bone marrow/CNS) when utilizing this updated strategy as well as changing CNS prophylaxis and treatment to include triple intrathecal chemotherapy. VII. To describe the rate of bone marrow measurable residual disease, detected by multi-dimensional flow cytometry, prior to hematopoietic stem cell transplant (HSCT). VIII. To describe plasma metabolomics that may impact efficacy, toxicity, and/or pharmacokinetics of allogeneic HSCT. IX. To estimate the prevalence of non-risk stratifying cytogenetic/molecular variants and assess their impact on outcome in childhood AML. X. To describe the pharmacokinetic parameters of plasma cytarabine and daunorubicin after CPX-351 administration to pediatric and young adult patients with new diagnosis of AML. XI. To describe the pharmacokinetic parameters of orally administered gilteritinib when administered to pediatric and young adult patients with new diagnosis of AML. XII. To describe the pharmacodynamic parameters of gilteritinib using the FLT3 plasma inhibitory activity assay (PIA) when administered to children and young adults with new diagnosis of AML and FLT3 mutations. XIII. To estimate OS in patients with FLT3/ITD+ AML (AR \> 0.1) without favorable cytogenetic/molecular characteristics treated with DA-GO-gilteritinib or CPX-351-GO-gilteritinib (Separate analyses will be conducted for Arm AC vs Arm BC). OUTLINE: Patients are randomized to either Arm A or B and assigned to Arm C or D based on FLT3 testing results. As of 11/19/24 arms B, BC and BD are closed and new patients receive treatment in Arm A Low Risk Group 2 Induction 1 or Arm A High Risk Induction 1, and then assigned to arm AC or AD per FLT3 results. Risk group assignments are calculated based on cytogenetic, molecular and genomic findings (details in protocol) 1. Low Risk 1 2. Low Risk 2 3. High Risk TREATMENT FOR PATIENTS WITHOUT FLT3 MUTATIONS: ARM A LOW RISK GROUP 1: INDUCTION 1: Patients receive cytarabine intravenously (IV) over 1-30 minutes every 12 hours (Q12H) on days 1-10, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate intrathecally (IT), therapeutic hydrocortisone (hydrocortisone) IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT once weekly (QW) starting on day 8 for 4-6 weeks (may continue into Induction 2) until the cerebral spinal fluid (CSF) is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8 and dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi intramuscularly (IM) on days 2 and 9 or IV over 1-2 hours on days 2 and 9. ARM B LOW RISK GROUP 1: INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM on days 2 and 9 or IV over 1-2 hours on days 2 and 9. ARM A LOW RISK GROUP 2: INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8 and dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4 and dexrazoxane IV over 15 minutes and mitoxantrone hydrochloride (mitoxantrone) IV over 5-15 minutes on days 3-6. INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM on days 2 and 9 or IV over 1-2 hours on days 2 and 9. ARM B LOW RISK GROUP 2: INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4 and dexrazoxane IV over 15 minutes and mitoxantrone hydrochloride (mitoxantrone) IV over 5-15 minutes on days 3-6. INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM on days 2 and 9 or IV over 1-2 hours on days 2 and 9. ARM A HIGH RISK GROUP: INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8 and dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen, patients undergo allogeneic HSCT. ARM B HIGH RISK GROUP: INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5. INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5. HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen, patients undergo allogeneic HSCT. TREATMENT FOR PATIENTS WITH FLT3/ITD MUTATIONS (ITD AR \> 0.1): ARM AC LOW RISK GROUP 2: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib orally (PO)/nasogastric (NG)/gastrostomy (G)-tube once daily (QD) on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO/NG/G-tube QD on days 11-31. INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO/NG/G-tube QD on days 6-26. INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4, dexrazoxane IV over 15 minutes and mitoxantrone IV over 5-15 minutes on days 3-6, and gilteritinib PO/NG/G-tube QD on days 7-27. INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours, and gilteritinib PO/NG/G-tube QD on days 10-30. POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO/NG/G-tube QD on days 1-365. ARM BC LOW RISK GROUP 2: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO/NG/G-tube QD on days 11-31. INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO/NG/G-tube QD on days 6-26. INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4, dexrazoxane IV over 15 minutes and mitoxantrone IV over 5-15 minutes on days 3-6, and gilteritinib PO/NG/G-tube QD on days 7-27. INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours, and gilteritinib PO/NG/G-tube QD on days 10-30. POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO/NG/G-tube QD on days 1-365. ARM AC HIGH RISK GROUP: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO/NG/G-tube QD on days 11-31. INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO/NG/G-tube QD on days 6-26. HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen, patients undergo allogeneic HSCT. POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients receive gilteritinib PO/NG/G-tube QD on days 1-365. ARM BC HIGH RISK GROUP: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO/NG/G-tube QD on days 11-31. INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO/NG/G-tube QD on days 6-26. HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen, patients undergo allogeneic HSCT. POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients receive gilteritinib PO/NG/G-tube QD on days 1-365. TREATMENT FOR NON-ITD FLT3 ACTIVATING MUTATIONS: ARM AD LOW RISK GROUP 2: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO/NG/G-tube QD on days 11-31. INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO/NG/G-tube QD on days 6-26. INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4, dexrazoxane IV over 15 minutes and mitoxantrone IV over 5-15 minutes on days 3-6, and gilteritinib PO/NG/G-tube QD on days 7-27. INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours, and gilteritinib PO/NG/G-tube QD on days 10-30. POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO/NG/G-tube QD on days 1-365. ARM BD LOW RISK GROUP 2: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO/NG/G-tube QD on days 11-31. INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO/NG/G-tube QD on days 6-26. INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days 1-4, dexrazoxane IV over 15 minutes and mitoxantrone IV over 5-15 minutes on days 3-6, and gilteritinib PO/NG/G-tube QD on days 7-27. INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours, and gilteritinib PO/NG/G-tube QD on days 10-30. POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO/NG/G-tube QD on days 1-365. ARM AD HIGH RISK GROUP: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8, dexrazoxane IV over 15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5, and gilteritinib PO/NG/G-tube QD on days 11-31. INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-26. HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen, patients undergo allogeneic HSCT. POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients receive gilteritinib PO or NG or G tube QD on days 1-365. ARM BD HIGH RISK GROUP: CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO QD on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2). INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and gilteritinib PO QD on days 11-31. INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on days 6-26. HSCT: After completion of Intensification 1 and investigator assigned conditioning regimen, patients undergo allogeneic HSCT. POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT, patients receive gilteritinib PO or NG or G tube QD on days 1-365. NOTE: During Induction 2 or Intensification 2, patients in Arms A and B with left ventricular systolic dysfunction receive a replacement course of high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9, and asparaginase Erwinia chrysanthemi IM or IV over 1-2 hours. Patients in Arms AC, BC, AD, and BD receive treatment as in Arms A and B and also receive gilteritinib PO QD on days 10-30 (Induction 2) or days 10-30 (Intensification 2). OPTIONAL NEUROCOGNITIVE STUDY: Patients may complete the Cogstate assessment battery at the end of Induction 1, at the end of therapy, and at 9 and 60 months post-enrollment.

B Acute Lymphoblastic Leukemia, B Lymphoblastic Lymphoma, Central Nervous System Leukemia, Mixed Phenotype Acute Leukemia, Testicular Leukemia

A Phase 3 Randomized Trial of Inotuzumab Ozogamicin (NSC#: 772518) for Newly Diagnosed High-Risk B-ALL; Risk-Adapted Post-Induction Therapy for High-Risk B-ALL, Mixed Phenotype Acute Leukemia, and Disseminated B-LLy

PRIMARY OBJECTIVE: I. To compare in a randomized manner the 5-year disease-free survival (DFS) for children and young adults with High Risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) treated with modified Berlin-Frankfurt-Munster (mBFM) chemotherapy without delayed intensification (DI) part 2, but with the addition of two blocks of inotuzumab ozogamicin, versus those treated with full mBFM chemotherapy backbone including DI Part 2 without the addition of inotuzumab ozogamicin. SECONDARY OBJECTIVES: I. To describe the 5-year DFS for a favorable risk subset of National Cancer Institute (NCI) HR B-ALL (HR-Fav) when treated with mBFM chemotherapy with a single high-dose methotrexate (HD-MTX) interim maintenance (IM) phase and treatment duration of 2 years from the start of IM regardless of sex. II. To determine the toxicity and tolerability of inotuzumab ozogamicin integrated into the mBFM chemotherapy backbone in HR B-ALL including toxicity experienced during phases of therapy subsequent to inotuzumab ozogamicin. III. To describe the 5-year event-free survival (EFS) for patients with mixed phenotype acute leukemia (MPAL) receiving mBFM HR B-ALL therapy that includes a second IM phase with Capizzi intravenous (IV) methotrexate without leucovorin rescue plus pegaspargase or calaspargase pegol (C-MTX). IV. To describe the 5-year EFS for patients with disseminated (Murphy stage III-IV) B-cell lymphoblastic lymphoma (B-LLy) receiving mBFM HR B-ALL therapy that includes a second IM phase with C-MTX. EXPLORATORY OBJECTIVES: I. To describe the therapy administered, disease response, and survival outcomes of patients with MPAL who come off protocol therapy due to poor disease response to ALL therapy either during Induction, at end of induction (EOI), or at end of consolidation (EOC). II. To define the prevalence and significance of minimal marrow disease (MMD) at diagnosis and bone marrow minimal residual disease (MRD) at EOI in disseminated B-LLy. III. To determine the impact of proposed adherence-enhancing interventions on adherence to oral 6-mercaptopurine in patients with ALL. OUTLINE: All patients receive the same Induction and Consolidation chemotherapy. Patients with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL are assigned to Arm IV, and patients with B-LLy are assigned to Arm V. All patients with B-ALL receive Induction and Consolidation therapy: INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1 and central nervous system (CNS)2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine intravenously (IV) on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients \< 10 years old receive dexamethasone orally (PO) twice daily (BID) or IV on days 1-14; patients \>= 10 years old receive prednis(ol)one PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO once daily (QD) on days 1-14 and 29-42, and methotrexate IT on days 1, 8, 15, and 22 (CNS3 patients receive methotrexate IT on days 1 and 8). Patients also receive vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Additionally, patients with testicular disease at diagnosis that does not resolve by the end of induction will undergo radiation therapy over 12 once daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age. POST-CONSOLIDATION THERAPY: After Consolidation, based on clinical features and response, patients with B-ALL are designated as HR-Fav or HR B-ALL. Patients with HR-Fav B-ALL are assigned to Arm I. Patients with HR B-ALL are randomized to Arm II or III. Patients with MPAL and B-LLy are assigned to therapy arms (Arms IV and V) that are identical to Arm II. Patients that are \< 10 years, have CNS1, no testicular leukemia, with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies \[4 and 10\]), =\< 24 hours of steroids in the two weeks prior to diagnosis, and EOI MRD \< 0.01% are assigned to Arm I. Patients with HR B-ALL who are surface CD22 positive at diagnosis and have MRD \< 0.01% by the end of Consolidation, are randomized to either Arm II or III. ARM I: HR-FAV B-ALL (Patients that are \< 10 years, have CNS1 status, no testicular leukemia, with favorable cytogenetics (ETV6 RUNX1 fusion or double trisomies \[4 and 10\]), =\< 24 hours of steroids in the two weeks prior to diagnosis, and EOI MRD \< 0.01%) INTERIM MAINTENANCE: Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. MAINTENANCE: Patients receive methotrexate IT on days 1 and 29 for cycles 1-4, and day 1 for subsequent cycles. Patients also receive vincristine IV on day 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO QD on days 1-84, and methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1-4), 36, 43, 50, 57, 64, 71, and 78. Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with HR B-ALL who have MRD \< 0.01% by the end of Consolidation, and leukemic blasts positive for surface CD22 at diagnosis are randomized to Arm II or Arm III. ARM II: HR B-ALL (CONTROL) INTERIM MAINTENANCE I: Patients receive vincristine IV on days 1, 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29 and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, 45-46, mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. INTERIM MAINTENANCE II: Patients receive vincristine on days 1, 11, 21, 31 and 41, methotrexate IV over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or 23 (calaspargase) or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. ARM III: HR B-ALL (EXPERIMENTAL) INOTUZUMAB OZOGAMICIN (InO) BLOCK 1: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15 and methotrexate IT on day 1. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity. INTERIM MAINTENANCE I: Patients receive vincristine IV on days 1, 15, 29 and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, and methotrexate IT on days 1 and 29. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION (Part I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. InO BLOCK 2: Patients receive inotuzumab ozogamicin IV over 60 minutes on days 1, 8, and 15. Treatment continues for 4 weeks in the absence of disease progression or unacceptable toxicity. INTERIM MAINTENANCE II: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or 23 (calaspargase) or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. ARMS II AND III: HR B-ALL MAINTENANCE: Patients receive vincristine IV on day 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71 and 78, and methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with CNS3 disease undergo cranial radiation therapy over 10 fractions during the first 4 weeks. ARM IV: MPAL INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients \< 10 years old receive dexamethasone PO BID or IV on days 1-14; patients \>= 10 years old receive prednisolone PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22 for CNS3 patients), vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the end of induction will and continued evidence of testicular disease at end of induction undergo testicular radiation over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age. ARM V: B-LLY INDUCTION: Patients receive cytarabine IT on day 1 and CNS2 patients also receive cytarabine IT on days 4, 5 or 6 and 11 or 12. Patients also receive vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes days 1, 8, 15, and 22, pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4, and methotrexate IT on days 8 and 29 (and on days 15 and 22 for CNS3 patients). Patients \< 10 years old receive dexamethasone PO BID or IV on days 1-14; patients \>= 10 years old receive prednisolone PO BID or IV on days 1-28. Treatment continues for 5 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 (excluded on days 15 and 22 CNS3 patients), vincristine IV on days 15, 22, 43, and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on days 15 and 43. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients with testicular disease at diagnosis that does not resolve by the end of induction will and continued evidence of testicular disease at end of induction undergo testicular radiation therapy over 12 once-daily fractions. Calaspargase pegol can only be given to patients less than 22 years of age. ARM IV AND V: MPAL AND B-LLY (Post-Consolidation Therapy) INTERIM MAINTENANCE I: Patients receive vincristine IV on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, methotrexate IT on days 1 and 29 and mercaptopurine PO QD on days 1-14, 15-28, 29-42, and 43-56. Treatment continues for 9 weeks in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION (PART I): Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, doxorubicin IV over 1-15 minutes or up to 1 hour on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 4. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. DELAYED INTENSIFICATION (PART II): Patients receive cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine IV or IV push over 1 minute on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours or pegaspargase IM on day 43. Treatment (Parts I and II of Delayed Intensification) continues for 9 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. INTERIM MAINTENANCE II: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV or infusion over 2-15 minutes or 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 22 (pegaspargase) or (calaspargase) 23 or pegaspargase IM on days 2 and 22. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Calaspargase pegol can only be given to patients less than 22 years of age. MAINTENANCE: Patients receive vincristine IV on days 1, prednisolone PO BID or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate PO on days 8, 15, 22, 29 (excluded in cycles 1 and 2), 36, 43, 50, 57, 64, 71, and 78, and methotrexate IT on days 1 (and 29 of cycles 1-2 for patients who do not receive cranial radiation). Cycles repeat every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with CNS3 disease at diagnosis undergo cranial radiation therapy for 10 fractions over 4 weeks. Patients undergo blood sample collection and bone marrow aspiration and biopsy on study. B-LLy patients undergo computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and/or bone scan on study. After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for 2 years, every 4-6 months for the third year, then every 6-12 months for years 4-5.

Central Nervous System Carcinoma

A Phase 3 Randomized, Placebo-Controlled Trial Evaluating Memantine (IND# 149832) for Neurocognitive Protection in Children Undergoing Cranial Radiotherapy as Part of Treatment for Primary Central Nervous System Tumors

PRIMARY OBJECTIVE: I. To determine the efficacy, as measured by the slope of change of the Cogstate composite Z score from baseline to 12 months, of oral memantine hydrochloride (memantine) administered for a period of 6 months, when compared to placebo, in children ages 4-18 receiving cranial or craniospinal radiotherapy for primary central nervous system tumors. EXPLORATORY OBJECTIVES: I. To determine if memantine is associated with improved cognitive function as measured for participants in the optional Children's Oncology Group (COG) Standardized Battery at 12 months. II. To determine if memantine is associated with change in cognitive function versus (vs.) placebo as measured by Cogstate composite score at end of radiation therapy (RT), 3 and 6 months. III. To determine if memantine is associated with differences in cognitive function vs. placebo as measured by Cogstate composite score at 24 and 48 months for participants in the optional COG Standardized Battery. IV. To correlate early cognitive changes (end of RT, 3, 6, 12 months Cogstate composite score) with late cognitive function (24 and 48 months Cogstate composite score). V. To correlate COG Standardized Battery scores to Cogstate composite scores at 12, 24, and 48 months. VI. To estimate the 36-month disease-free and overall survival (of primary brain tumor) after memantine treatment compared to placebo. VII. To correlate changes in quantitative volumetric magnetic resonance imaging (MRI) measurements of critical brain regions with cognitive function over time. VIII. To evaluate impact of memantine versus placebo on molecular biomarkers associated with cognitive decline after radiotherapy. IX. To determine whether oral memantine, when compared to placebo, is associated with reduction in the incidence of decline of composite Cogstate score at 12 months in children ages 4-18 receiving cranial radiotherapy for primary central nervous system tumors. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive memantine hydrochloride orally (PO) once daily (QD) for week 1 and then twice daily (BID) for weeks 2-24 in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 24, and 48 months. Patients undergo MRI and may optionally undergo blood sample collection throughout the trial. ARM II: Patients receive placebo PO QD for week 1 and then BID for weeks 2-24 in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 24, and 48 months. Patients undergo MRI and may optionally undergo blood sample collection throughout the trial.

Central Nervous System Carcinoma

A Phase 3 Randomized, Placebo-Controlled Trial Evaluating Memantine (IND# 149832) for Neurocognitive Protection in Children Undergoing Cranial Radiotherapy as Part of Treatment for Primary Central Nervous System Tumors

PRIMARY OBJECTIVE: I. To determine the efficacy, as measured by the slope of change of the Cogstate composite Z score from baseline to 12 months, of oral memantine hydrochloride (memantine) administered for a period of 6 months, when compared to placebo, in children ages 4-18 receiving cranial or craniospinal radiotherapy for primary central nervous system tumors. EXPLORATORY OBJECTIVES: I. To determine if memantine is associated with improved cognitive function as measured for participants in the optional Children's Oncology Group (COG) Standardized Battery at 12 months. II. To determine if memantine is associated with change in cognitive function versus (vs.) placebo as measured by Cogstate composite score at end of radiation therapy (RT), 3 and 6 months. III. To determine if memantine is associated with differences in cognitive function vs. placebo as measured by Cogstate composite score at 24 and 48 months for participants in the optional COG Standardized Battery. IV. To correlate early cognitive changes (end of RT, 3, 6, 12 months Cogstate composite score) with late cognitive function (24 and 48 months Cogstate composite score). V. To correlate COG Standardized Battery scores to Cogstate composite scores at 12, 24, and 48 months. VI. To estimate the 36-month disease-free and overall survival (of primary brain tumor) after memantine treatment compared to placebo. VII. To correlate changes in quantitative volumetric magnetic resonance imaging (MRI) measurements of critical brain regions with cognitive function over time. VIII. To evaluate impact of memantine versus placebo on molecular biomarkers associated with cognitive decline after radiotherapy. IX. To determine whether oral memantine, when compared to placebo, is associated with reduction in the incidence of decline of composite Cogstate score at 12 months in children ages 4-18 receiving cranial radiotherapy for primary central nervous system tumors. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive memantine hydrochloride orally (PO) once daily (QD) for week 1 and then twice daily (BID) for weeks 2-24 in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 24, and 48 months. Patients undergo MRI and may optionally undergo blood sample collection throughout the trial. ARM II: Patients receive placebo PO QD for week 1 and then BID for weeks 2-24 in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 24, and 48 months. Patients undergo MRI and may optionally undergo blood sample collection throughout the trial.

Atopic Dermatitis

A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study to Evaluate Upadacitinib in Adolescent and Adult Subjects With Moderate to Severe Atopic Dermatitis

This study includes a 35-day screening period, a 16-week double-blind period, a blinded extension period up to Week 260, and a 30-day follow-up visit. Participants who meet eligibility criteria in the main study will be randomized in a 1:1:1 ratio to receive a daily oral dose of upadacitinib 30 mg or upadacitinib 15 mg or matching placebo. Upon completion of enrollment of 810 participants in the main study, a supplemental study will continue to enroll adolescents (adolescent sub-study) until a total of 180 adolescent participants are enrolled in the overall study (main study + adolescent sub-study). Randomization for the main study will be stratified by baseline disease severity (validated Investigator Global Assessment scale for Atopic Dermatitis \[vIGA-AD\] score of moderate \[3\] versus severe \[4\]), by geographic region (United States \[US\]/Puerto Rico/Canada, Japan, China, and Other), and by age (adolescent \[ages 12 to 17\] versus adult \[ages 18 to 75\]). The separate randomization for the adolescent sub-study will be stratified by baseline disease severity (moderate \[vIGA-AD 3\] vs. severe \[vIGA-AD 4\]) and by geographic region (US/Puerto Rico/Canada and Other). At Week 16 of the main study and the adolescent sub-study, participants in the placebo group will be re-randomized in a 1:1 ratio to receive daily oral doses of upadacitinib 30 mg or upadacitinib 15 mg in the blinded extension period. In the main study the re-randomization at Week 16 will be stratified by Week 16 50% improvement in Eczema Area and Severity Index \[EASI 50\] responder \[yes/no\], geographic region \[US/Puerto Rico/Canada, China \[Mainland\], Japan, and other\], and age group \[adolescent/adult\]. For the adolescent sub-study, the re-randomization will be stratified by EASI 50 responder (Yes/No) and by geographic region (US/Puerto Rico/Canada and Other). Participants originally randomized to upadacitinib will continue upadacitinib in the extension period at the same dose. Starting at the Week 4 visit, rescue treatment for AD may be provided at the discretion of the investigator if medically necessary. The Primary Analysis for the main study will be conducted after all ongoing participants have completed Week 16. In addition, a Primary Analysis for the adolescent population (including the adolescent participants from the main study and the adolescent sub-study) will be conducted after all ongoing adolescent participants have completed Week 16.

Sickle Cell Disease

A Phase 3 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the BB305 Lentiviral Vector in Subjects With Sickle Cell Disease

• +1-833-999-6378
• clinicaltrials@bluebirdbio.com

Ganglioneuroblastoma, Neuroblastoma

A Phase 3 Study of 131I-Metaiodobenzylguanidine (131I-MIBG) or ALK Inhibitor Therapy Added to Intensive Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma (NBL)

PRIMARY OBJECTIVES: I. To determine in the context of a randomized trial whether the event-free survival (EFS) of patients with newly diagnosed high-risk neuroblastoma (NBL) is improved with the addition of iobenguane I-131 (131I-MIBG) during induction, prior to tandem autologous stem cell transplantation (ASCT). II. To determine whether the addition of lorlatinib to intensive multimodality therapy for patients with high-risk NBL whose tumors harbor activating point mutations in the ALK gene with a variant allele frequency (VAF) \>= 5% results in superior EFS compared to a contemporaneously treated cohort of patients with tumors without documented ALK activating mutations. SECONDARY OBJECTIVES: I. To describe the toxicities associated with treatment for high-risk NBL with and without the addition of 131I-MIBG or ALK inhibitor therapy. II. To estimate EFS and describe toxicity in patients with newly diagnosed high-risk NBL randomized to treatment with an 131I-MIBG-containing induction prior to busulfan/melphalan (BuMel) ASCT. III. To describe the overall survival (OS) and response rates (evaluated per International Neuroblastoma Response Criteria \[INRC\] criteria prior to ASCT and prior to post-consolidation therapy) for patients with high-risk neuroblastoma treated with or without 131I-MIBG or ALK inhibitor therapy. IV. To prospectively evaluate the relationship of response rate per revised International Neuroblastoma Response Criteria (INRC) to EFS and OS in patients with high-risk NBL treated with and without the addition of 131I-MIBG or ALK inhibitor therapy. EXPLORATORY OBJECTIVES: I. To evaluate whole body radiation dose, tumor factors, and host factors as potential predictors of efficacy and/or toxicity associated with 131I-MIBG therapy and transplant conditioning. II. To describe end-Induction response, EFS, and OS according to specific ALK mutations, VAF, ALK amplification, the presence of additional genomic findings, or the ALK inhibitor administered. III. To characterize changes in tumor markers (circulating tumor deoxyribonucleic acid \[DNA\], including ALK and other tumor specific genetic aberrations, and circulating GD2) over time in response to protocol therapy. IV. To correlate results of tumor and host profiling with end-induction response and EFS. V. To prospectively evaluate EFS for patients with MIBG non-avid high-risk NBL compared to patients with MIBG-avid high-risk NBL who are randomized to treatment without 131I-MIBG. VI. To correlate Curie scores calculated from 131I-MIBG post-treatment scans with end-induction response, EFS and OS. VII. To describe changes in image defined risk factors (IDRFs) over the course of induction therapy, with correlation to surgical outcomes and local failure rates following primary tumor resection. VIII. To define patterns of failure at time of first relapse or progression in patients with high-risk NBL. IX. To determine the feasibility of prospectively monitoring adverse events using electronic health records. X. To compare local, central, and computer assisted Curie score assignment at baseline and during therapy in patients with MIBG-avid high-risk NBL. XI. To compare late toxicities (including impaired organ function and secondary tumor occurrence) in patients treated with 131I-MIBG or ALK inhibitor therapy to late toxicities in patients who have not received these therapies. XII. To determine the association between household material hardship (HMH) and clinical outcomes, including event free and overall survival, and 131I-MIBG receipt. XIII. To compare the outcomes (EFS, OS, and toxicity) of patients treated with post-consolidation therapy that does not contain aldesleukin to historical outcome data for patients treated with similar induction and consolidation regimens followed by post-consolidation therapy that contained aldesleukin. XIV. To characterize and describe longitudinal neuropsychological and behavioral effects of high-risk neuroblastoma therapy. XV. To evaluate change in neurobehavioral outcomes over time in patients with neuroblastoma treated with high-risk neuroblastoma therapy plus lorlatinib compared to high-risk therapy alone using parent- or self-report measures of adaptive, executive, and psychosocial functioning. XVI. To characterize the pharmacokinetics and pharmaceutical properties of lorlatinib in children with high-risk neuroblastoma. OUTLINE: Patients are randomized or assigned to 1 of 5 arms. All patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 during cycle 1 of induction therapy in the absence of disease progression or unacceptable toxicity. Patients not assigned to an Arm by the end of cycle 1 may receive an addition cycle of cyclophosphamide and topotecan. ARM A: INDUCTION THERAPY: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 of cycle 2 and cisplatin IV over 4 hours and etoposide phosphate IV over 2 hours on days 1-3 of cycles 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on day 1 and dexrazoxane hydrochloride IV over 5-15 minutes, doxorubicin hydrochloride IV over 1-15 minutes, and cyclophosphamide IV over 1-6 hours on days 1-2 of cycle 4 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: HSCT#1: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 in the absence of disease progression or unacceptable toxicity. HSCT#2: Patients receive melphalan hydrochloride IV over 30 minutes on days -7 to -5, and etoposide phosphate IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4 in the absence of disease progression or unacceptable toxicity. POST-CONSOLIDATION THERAPY: Patients receive sargramostim subcutaneously (SC) on days 1-14, dinutuximab IV over 10 hours on days 4-7 of cycles 1-5, and isotretinoin orally (PO) twice daily (BID) on days 11-24 of cycles 1-5, and days 15-28 during cycle 6 in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or multigated acquisition (MUGA) scan, magnetic resonance imaging (MRI) or computed tomography (CT) scan, receive 123I-MIBG and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study. ARM B: INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, and etoposide phosphate as in Arm A, iobenguane I-131 IV over 1.5-2 hours on day 1 beginning 3 weeks after the start of cycle 3, and vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm A beginning no sooner than 35 days after the infusion of iobenguane I-131. CONSOLIDATION THERAPY: HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. HSCT#2: Patients receive melphalan, etoposide phosphate, and carboplatin as in Arm A. POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and isotretinoin as in Arm A-D. Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study. ARM C (CLOSED TO ACCRUAL AS OF DECEMBER 17, 2020): INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, etoposide phosphate, iobenguane I-131, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm B. CONSOLIDATION THERAPY: Patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan hydrochloride IV over 30 minutes on day -1 in the absence of disease progression or unacceptable toxicity. POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and isotretinoin as in Arm A. Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study. ARM D: Patients receive treatment identical to Arm A. Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo fludeoxyglucose- positron emission tomography (PET) scan on study. ARM E: INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, etoposide phosphate, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO once daily (QD) starting cycle 2 prior to HSCT #1 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO QD until day -8 of HSCT#2 in the absence of disease progression or unacceptable toxicity. HSCT#2: Patients receive melphalan hydrochloride, etoposide phosphate, carboplatin as in Arm A. Lorlatinib is restarted when patient has reached at least day +14 post-HSCT#2 and is able to tolerate enteral medications, provided there is no evidence of disease progression or unacceptable toxicity. RADIATION THERAPY: Patients receive lorlatinib PO QD concurrently with radiation therapy in the absence of disease progression or unacceptable toxicity. POST-CONSOLIDATION THERAPY: Patients receive sargramostim and dinutuximab as in Arm A-D. Patients also receive isotretinoin PO BID on days 11-24 of cycles 1-5 and days 15-28 of cycle 6, and lorlatinib PO QD on days 15-28 of cycles 2-5 and days 1-28 of cycle 6 in the absence of disease progression or unacceptable toxicity. CONTINUATION THERAPY: Patients receive lorlatinib PO QD on days 1-28. Cycles repeat every 28 days for 18 months in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo MRI and PET scan on study. After completion of study therapy, patients in Arms A-D are followed up every 3 months for 18 months, and then every 6 months for 42 months; patients in Arm E are followed up every 3 months for 6 months, and then every 6 months for 42 months.

Ganglioneuroblastoma, Neuroblastoma

A Phase 3 Study of 131I-Metaiodobenzylguanidine (131I-MIBG) or ALK Inhibitor Therapy Added to Intensive Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma (NBL)

PRIMARY OBJECTIVES: I. To determine in the context of a randomized trial whether the event-free survival (EFS) of patients with newly diagnosed high-risk neuroblastoma (NBL) is improved with the addition of iobenguane I-131 (131I-MIBG) during induction, prior to tandem autologous stem cell transplantation (ASCT). II. To determine whether the addition of lorlatinib to intensive multimodality therapy for patients with high-risk NBL whose tumors harbor activating point mutations in the ALK gene with a variant allele frequency (VAF) \>= 5% results in superior EFS compared to a contemporaneously treated cohort of patients with tumors without documented ALK activating mutations. SECONDARY OBJECTIVES: I. To describe the toxicities associated with treatment for high-risk NBL with and without the addition of 131I-MIBG or ALK inhibitor therapy. II. To estimate EFS and describe toxicity in patients with newly diagnosed high-risk NBL randomized to treatment with an 131I-MIBG-containing induction prior to busulfan/melphalan (BuMel) ASCT. III. To describe the overall survival (OS) and response rates (evaluated per International Neuroblastoma Response Criteria \[INRC\] criteria prior to ASCT and prior to post-consolidation therapy) for patients with high-risk neuroblastoma treated with or without 131I-MIBG or ALK inhibitor therapy. IV. To prospectively evaluate the relationship of response rate per revised International Neuroblastoma Response Criteria (INRC) to EFS and OS in patients with high-risk NBL treated with and without the addition of 131I-MIBG or ALK inhibitor therapy. EXPLORATORY OBJECTIVES: I. To evaluate whole body radiation dose, tumor factors, and host factors as potential predictors of efficacy and/or toxicity associated with 131I-MIBG therapy and transplant conditioning. II. To describe end-Induction response, EFS, and OS according to specific ALK mutations, VAF, ALK amplification, the presence of additional genomic findings, or the ALK inhibitor administered. III. To characterize changes in tumor markers (circulating tumor deoxyribonucleic acid \[DNA\], including ALK and other tumor specific genetic aberrations, and circulating GD2) over time in response to protocol therapy. IV. To correlate results of tumor and host profiling with end-induction response and EFS. V. To prospectively evaluate EFS for patients with MIBG non-avid high-risk NBL compared to patients with MIBG-avid high-risk NBL who are randomized to treatment without 131I-MIBG. VI. To correlate Curie scores calculated from 131I-MIBG post-treatment scans with end-induction response, EFS and OS. VII. To describe changes in image defined risk factors (IDRFs) over the course of induction therapy, with correlation to surgical outcomes and local failure rates following primary tumor resection. VIII. To define patterns of failure at time of first relapse or progression in patients with high-risk NBL. IX. To determine the feasibility of prospectively monitoring adverse events using electronic health records. X. To compare local, central, and computer assisted Curie score assignment at baseline and during therapy in patients with MIBG-avid high-risk NBL. XI. To compare late toxicities (including impaired organ function and secondary tumor occurrence) in patients treated with 131I-MIBG or ALK inhibitor therapy to late toxicities in patients who have not received these therapies. XII. To determine the association between household material hardship (HMH) and clinical outcomes, including event free and overall survival, and 131I-MIBG receipt. XIII. To compare the outcomes (EFS, OS, and toxicity) of patients treated with post-consolidation therapy that does not contain aldesleukin to historical outcome data for patients treated with similar induction and consolidation regimens followed by post-consolidation therapy that contained aldesleukin. XIV. To characterize and describe longitudinal neuropsychological and behavioral effects of high-risk neuroblastoma therapy. XV. To evaluate change in neurobehavioral outcomes over time in patients with neuroblastoma treated with high-risk neuroblastoma therapy plus lorlatinib compared to high-risk therapy alone using parent- or self-report measures of adaptive, executive, and psychosocial functioning. XVI. To characterize the pharmacokinetics and pharmaceutical properties of lorlatinib in children with high-risk neuroblastoma. OUTLINE: Patients are randomized or assigned to 1 of 5 arms. All patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 during cycle 1 of induction therapy in the absence of disease progression or unacceptable toxicity. Patients not assigned to an Arm by the end of cycle 1 may receive an addition cycle of cyclophosphamide and topotecan. ARM A: INDUCTION THERAPY: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan hydrochloride IV over 30 minutes on days 1-5 of cycle 2 and cisplatin IV over 4 hours and etoposide phosphate IV over 2 hours on days 1-3 of cycles 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on day 1 and dexrazoxane hydrochloride IV over 5-15 minutes, doxorubicin hydrochloride IV over 1-15 minutes, and cyclophosphamide IV over 1-6 hours on days 1-2 of cycle 4 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: HSCT#1: Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 in the absence of disease progression or unacceptable toxicity. HSCT#2: Patients receive melphalan hydrochloride IV over 30 minutes on days -7 to -5, and etoposide phosphate IV over 24 hours and carboplatin IV over 24 hours on days -7 to -4 in the absence of disease progression or unacceptable toxicity. POST-CONSOLIDATION THERAPY: Patients receive sargramostim subcutaneously (SC) on days 1-14, dinutuximab IV over 10 hours on days 4-7 of cycles 1-5, and isotretinoin orally (PO) twice daily (BID) on days 11-24 of cycles 1-5, and days 15-28 during cycle 6 in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or multigated acquisition (MUGA) scan, magnetic resonance imaging (MRI) or computed tomography (CT) scan, receive 123I-MIBG and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study. ARM B: INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, and etoposide phosphate as in Arm A, iobenguane I-131 IV over 1.5-2 hours on day 1 beginning 3 weeks after the start of cycle 3, and vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm A beginning no sooner than 35 days after the infusion of iobenguane I-131. CONSOLIDATION THERAPY: HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. HSCT#2: Patients receive melphalan, etoposide phosphate, and carboplatin as in Arm A. POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and isotretinoin as in Arm A-D. Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study. ARM C (CLOSED TO ACCRUAL AS OF DECEMBER 17, 2020): INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, etoposide phosphate, iobenguane I-131, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm B. CONSOLIDATION THERAPY: Patients receive busulfan IV over 3 hours on days -6 to -3 and melphalan hydrochloride IV over 30 minutes on day -1 in the absence of disease progression or unacceptable toxicity. POST-CONSOLIDATION THERAPY: Patients receive sargramostim, dinutuximab, and isotretinoin as in Arm A. Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study. ARM D: Patients receive treatment identical to Arm A. Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo fludeoxyglucose- positron emission tomography (PET) scan on study. ARM E: INDUCTION THERAPY: Patients receive cyclophosphamide, topotecan hydrochloride, cisplatin, etoposide phosphate, vincristine sulfate, dexrazoxane hydrochloride, doxorubicin hydrochloride, and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO once daily (QD) starting cycle 2 prior to HSCT #1 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: HSCT#1: Patients receive thiotepa and cyclophosphamide as in Arm A. Patients also receive lorlatinib PO QD until day -8 of HSCT#2 in the absence of disease progression or unacceptable toxicity. HSCT#2: Patients receive melphalan hydrochloride, etoposide phosphate, carboplatin as in Arm A. Lorlatinib is restarted when patient has reached at least day +14 post-HSCT#2 and is able to tolerate enteral medications, provided there is no evidence of disease progression or unacceptable toxicity. RADIATION THERAPY: Patients receive lorlatinib PO QD concurrently with radiation therapy in the absence of disease progression or unacceptable toxicity. POST-CONSOLIDATION THERAPY: Patients receive sargramostim and dinutuximab as in Arm A-D. Patients also receive isotretinoin PO BID on days 11-24 of cycles 1-5 and days 15-28 of cycle 6, and lorlatinib PO QD on days 15-28 of cycles 2-5 and days 1-28 of cycle 6 in the absence of disease progression or unacceptable toxicity. CONTINUATION THERAPY: Patients receive lorlatinib PO QD on days 1-28. Cycles repeat every 28 days for 18 months in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or MUGA scan, MRI or CT scan, receive 123I-MIGB and undergo MIBG imaging, bone marrow aspiration and biopsy and blood sample collection throughout the study and may undergo MRI and PET scan on study. After completion of study therapy, patients in Arms A-D are followed up every 3 months for 18 months, and then every 6 months for 42 months; patients in Arm E are followed up every 3 months for 6 months, and then every 6 months for 42 months.

Ganglioneuroblastoma, Nodular, Neuroblastoma

A Phase 3 Study of Dinutuximab Added to Intensive Multimodal Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma

PRIMARY OBJECTIVE: I. To determine if the event-free survival (EFS) of patients with newly diagnosed high-risk neuroblastoma assigned to early chemoimmunotherapy during Induction differs from that of patients who are not assigned to treatment that includes early chemoimmunotherapy. SECONDARY OBJECTIVES: I. To determine if early chemoimmunotherapy during Induction therapy improves end of Induction (EOI) response rates and overall survival (OS) for patients with newly diagnosed high-risk neuroblastoma. II. To determine response rates, EFS, and OS following an Extended Induction regimen with chemoimmunotherapy in patients with progressive disease or a poor response to Induction therapy. III. To compare the toxicities experienced by patients treated with chemoimmunotherapy during Induction versus those experienced by patients treated with standard Induction and to describe toxicities experienced during Extended Induction. IV. To determine GD2 expression on tumor tissue and tumor cells in bone marrow and assess for associations with response and outcome. EXPLORATORY OBJECTIVES: I. To describe the association between tumor and host factors and outcomes in patients receiving protocol therapy. II. To evaluate circulating biomarkers and markers of minimal residual disease at baseline and during therapy, and assess for associations with response and outcome. III. To compare patterns of failure between patients treated with and without dinutuximab during induction. IV. To determine the effect of telomere maintenance mechanisms on end of Induction response rates, EFS, and OS. V. To explore the impact of high-risk neuroblastoma (HRNBL) and its therapy, including the addition of dinutuximab to Induction chemotherapy, on functional and quality of life outcomes in patients with HRNBL, as measured by caregiver (parent/legal guardian) and patient questionnaires. VI. To describe the adequacy of diagnostic biopsy specimens, including those obtained by percutaneous core needle biopsy. VII. To explore the associations between family-reported adverse social determinants of health and both clinical outcomes and biology. VIII. To develop and validate deep learning predictors of Induction response based on diagnostic MIBG scans. (Imaging Objective) IX. To compare institutional versus central determination of overall response, individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease), and poor end of induction response (PEIR) and good end of induction response (GEIR) determination. (Imaging Objective) X. To describe late toxicities (including impaired organ function, neuropsychiatric toxicity, and incidence of secondary malignancy) in patients treated with dinutuximab during Induction or Extended Induction to late toxicities in patients who have not received dinutuximab during these phases of therapy. XI. To evaluate whether reduced dose radiotherapy to the primary site clinical target volume (CTV) in patients with complete response of the primary site at EOI results in comparable local control relative to historical cohorts. XII. To compare post-transplant complications between treatment arms, and assess for associations with outcome. XIII. To assess for associations between EOI response (including good end of Induction response \[GEIR\] and poor end of Induction response \[PEIR\]) and individual response components (primary tumor, soft tissue and bone metastatic disease, and bone marrow metastatic disease) with outcome (EFS and OS). XIV. To describe and compare the changes in image-defined risk factors (IDRFs) between patients treated with and without dinutuximab during Induction and associate with surgical outcomes and local failure rates following primary tumor resection. XV. To bank serial samples of blood, bone marrow, and tumor tissue for future research. OUTLINE: Patients receive Induction cycle 1 and are then randomized to 1 of 2 treatment arms. INDUCTION CYCLE 1: Patients receive cyclophosphamide intravenously (IV) over 30 minutes and topotecan IV over 30 minutes on days 1-5 in the absence of unacceptable toxicity. ARM A: INDUCTION CYCLES 2-5: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5 of cycle 2 in the absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis. Patients then receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 of cycles 3 and 5, and vincristine IV on day 1, doxorubicin IV over 15 minutes, and cyclophosphamide IV over 1 hour on days 1-2 of cycle 4 in the absence of unacceptable toxicity. Patients undergo primary tumor resection after Induction cycle 4 or 5. Following Induction cycle 5, patients undergo testing to determine response to Induction therapy. Patients with a good tumor response proceed to Consolidation, while patients with a poor tumor response proceed to Extended Induction. EXTENDED INDUCTION: Patients with a poor tumor response or progression during Induction receive temozolomide orally (PO), via nasogastric tube (NG), or via gastric tube (G-tube) on days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximab IV over 10 hours. Treatment repeats every 21 days for up to a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. If at any time during Extended Induction testing shows a good tumor response, patients proceed to Consolidation. If after 6 cycles of Extended Induction or if at any time progression is noted, patients are removed from the study. CONSOLIDATION: Patients undergo two autologous hematopoietic stem cell transplantations (HSCTs) during Consolidation. Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 during HSCT 1. Patients then receive stem cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion, patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to -4 during HSCT 2. Patients receive stem cell infusion IV on day 0. Between day +42 and day +80 after HSCT 2. Patients receive radiation daily for 12 treatments in the absence of disease progression or unacceptable toxicity. POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and isotretinoin PO twice daily (BID) on days 11-24 of cycles 1-5. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle, cycle 6. Patients undergo blood and urine sample collection, echocardiogram (ECHO) or multigated acquisition scan (MUGA), bone marrow aspiration and/or biopsy, computed tomography (CT) scan, magnetic resonance imaging (MRI), iodine-123 meta-iodobenzylguanidine (I-MIBG) scan and possible fluorodeoxyglucose position emission tomography (FDG-PET) scan throughout the study. ARM B: INDUCTION CYCLES 2-5: Patients receive cyclophosphamide IV over 30 minutes, topotecan IV over 30 minutes on days 1-5, and dinutuximab IV over 10 hours on days 2-5 of cycle 2 in the absence of unacceptable toxicity. Patients then undergo stem cell harvest via apheresis. Patients receive cisplatin IV over 4 hours and etoposide IV over 2 hours on days 1-3 and dinutuximab IV over 10 hours on days 2-5 of cycles 3 and 5, and vincristine IV on day 1, doxorubicin IV over 15 minutes, and cyclophosphamide IV over 1 hour on days 1-2, and dinutuximab IV over 10 hours on days 2-5 of cycle 4 in the absence of unacceptable toxicity. Patients undergo primary tumor resection after Induction cycle 4 or 5. Following Induction cycle 5, patients undergo testing to determine response to Induction therapy. Patients with a good tumor response proceed to Consolidation, while patients with a poor tumor response proceed to Extended Induction. EXTENDED INDUCTION: Patients with a poor tumor response or progression during Induction receive temozolomide PO, via NG tube, or via G-tube on days 1-5, irinotecan IV over 90 minutes on days 1-5, and dinutuximab IV over 10 hours. Treatment repeats every 21 days for up to a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. If at any time during Extended Induction testing shows a good tumor response, patients proceed to Consolidation. If after 6 cycles of Extended Induction or if at any time progression is noted, patients are removed from the study. CONSOLIDATION: Patients undergo two autologous HSCTs during Consolidation. Patients receive thiotepa IV over 2 hours on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2 during HSCT 1. Patients then receive stem cell infusion IV on day 0. Between 6 and 10 weeks after stem cell infusion patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide IV over 24 hours on days -7 to -4, and carboplatin over 24 hours on days -7 to -4 during HSCT 2. Patients receive stem cell infusion IV on day 0. Between day +42 and day +80 after HSCT 2, patients receive radiation daily for 12 treatments in the absence of disease progression or unacceptable toxicity. POST CONSOLIDATION: Patients receive dinutuximab IV over 10 hours on days 4-7 and isotretinoin PO BID on days 11-24 of cycles 1-5. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive isotretinoin PO BID on days 15-28 for 1 additional cycle, cycle 6. Patients undergo blood and urine sample collection, ECHO or MUGA, bone marrow aspiration and/or biopsy, CT scan, MRI, I-MIBG scan and possible FDG-PET scan throughout the study. After completion of study treatment, patients are followed up at 3, 6, 9,12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months and then periodically for up to 10 years from enrollment.

Recurrent Low Grade Astrocytoma, Recurrent WHO Grade 2 Glioma, Refractory Low Grade Astrocytoma, Refractory Low Grade Glioma, Refractory WHO Grade 1 Glioma

A Phase 3 Study of Selumetinib (NSC# 748727) or Selumetinib in Combination With Vinblastine for Non-NF1, Non-TSC Patients With Recurrent or Progressive Low-Grade Gliomas (LGGs) Lacking BRAFV600E or IDH1 Mutations

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of selumetinib sulfate (selumetinib) + vinblastine sulfate (vinblastine) for children with progressive or recurrent low-grade gliomas (LGGs). II. To determine if selumetinib + vinblastine will lead to improved event-free survival (EFS) outcome compared with selumetinib alone for children with progressive or recurrent LGGs. SECONDARY OBJECTIVES: I. To estimate the objective response rates and overall survival associated with treatment with selumetinib + vinblastine versus single-agent selumetinib. II. To estimate the difference in EFS and response rate between patients with BRAF rearranged LGG and patients with non-BRAF rearranged LGG after treatment with selumetinib + vinblastine versus single-agent selumetinib. III. To evaluate toxicities associated with selumetinib + vinblastine and single-agent selumetinib for children with progressive or recurrent LGGs. IV. To compare the quality of life among patients treated with selumetinib + vinblastine and single-agent selumetinib. V. To examine the vision outcomes among patients with optic pathway gliomas (OPGs) treated with selumetinib + vinblastine and single-agent selumetinib. EXPLORATORY OBJECTIVE: I. To obtain paired blood and tumor specimens for future biology studies, including studies to correlate genomic drivers to response. OUTLINE: This is a dose-escalation feasibility study of vinblastine sulfate in combination with selumetinib, followed by a randomized efficacy study. Patients in the feasibility study are assigned to Arm I, while patients in the efficacy study are randomized to Arm I or Arm II. ARM I: Patients receive vinblastine sulfate intravenously (IV) over 1 minute or IV infusion on days 1, 8, 15, and 22 and selumetinib sulfate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days. Patients receive selumetinib and vinblastine for a total duration of 17 cycles followed by 10 additional cycles of selumetinib alone in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) throughout the trial. Patients also undergo blood sample collection during screening and on study. ARM II: Patients receive selumetinib sulfate PO BID on days 1-28. Treatment repeats every 28 days for up to 27 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the trial. Patients also undergo blood sample collection during screening and on study. After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and annually for years 4-5.

Childhood Medulloblastoma

A Phase 3 Study of Sodium Thiosulfate for Reduction of Cisplatin-Induced Ototoxicity in Children With Average-Risk Medulloblastoma and Reduced Therapy in Children With Medulloblastoma With Low-Risk Features

PRIMARY OBJECTIVES: I. To evaluate the efficacy of sodium thiosulfate (STS) infusion administered during cisplatin-containing chemotherapy cycles (compared to a historical cohort selected from ACNS0331 which received chemotherapy without STS) in reducing hearing loss in children with newly-diagnosed average-risk medulloblastoma. II. To estimate and monitor event-free survival (EFS) in this study against a carefully selected cohort from ACNS0331 to guard against loss of efficacy due to STS. SECONDARY OBJECTIVES: I. To estimate and monitor overall survival (OS) in this study against a carefully selected control cohort from ACNS0331. II. To estimate the incidence of ototoxicity-related cisplatin dose modifications in the average-risk cohort. III. To estimate the incidence of cisplatin-related nephrotoxicity in both the average-risk and low-risk cohorts. IV. To evaluate full scale intelligence neurocognitive outcomes and trajectories of patients with average-risk medulloblastoma treated with STS compared to the control cohort from ACNS0331. V. To evaluate quality of life and psychosocial outcomes and trajectories of patients with average-risk medulloblastoma treated with STS compared to published norms. VI. To estimate and monitor EFS, OS, and patterns of recurrence in patients with low-risk features treated using a reduced craniospinal radiation approach. VII. To evaluate the trajectory of hearing loss in medulloblastoma patients treated with STS. VIII. To evaluate household material hardship as a social determinant of neurocognitive, quality of life, and psychosocial outcomes in patients with average-risk and low risk medulloblastoma. EXPLORATORY OBJECTIVES: I. To obtain paired blood and tumor tissue to be banked for future biology studies involving comprehensive molecular analysis, including but not limited to whole exome sequencing, ribonucleic acid (RNA) sequencing, and methylation. II. To bank blood and cerebrospinal fluid for future studies. III. To evaluate attention, processing speed, memory, and executive function neurocognitive outcomes and trajectories, as well as hearing-related quality of life outcomes and trajectories, of patients with average-risk medulloblastoma treated with STS. IV. To evaluate neurocognitive, quality of life, and psychosocial outcomes of patients with low-risk features treated using a reduced craniospinal radiation approach. OUTLINE: CHEMORADIOTHERAPY: Patients undergo radiation therapy 5 days per week for 6 weeks (weeks 1-6) and receive vincristine intravenously (IV) once weekly on weeks 2-7 in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Beginning 4 weeks after chemoradiotherapy, patients receive lomustine orally (PO) on day 1 of cycles 1, 2, 4, 5, 7, and 8, cisplatin IV over 6 hours on day 1 of cycles 1, 2, 4, 5, 7, and 8, sodium thiosulfate IV over 15 minutes on day 1 of cycles 1, 2, 4, 5, 7, and 8, and cyclophosphamide IV over 30-60 minutes on days 1 and 2 of cycles 3, 6, and 9. Patients also receive vincristine IV on days 1, 8, and 15 of cycles 1, 2, 4, 5, 7, and 8, and on days 1 and 8 of cycles 3, 6, and 9. Treatment repeats every 6 weeks (cycles 1, 2, 4, 5, 7 and 8) or every 4 weeks (cycles 3, 6, and 9) for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo magnetic resonance imaging (MRI) and collection of cerebrospinal fluid (CSF) throughout the study. Patients may also optionally undergo blood sample collection throughout the study. After completion of study treatment, patients are followed up every 3 months for years 1-2, every 6 months for years 3-4, and then annually for years 5-10.

B Acute Lymphoblastic Leukemia, B Lymphoblastic Lymphoma, Down Syndrome

A Phase 3 Trial Investigating Blinatumomab (NSC# 765986) in Combination With Chemotherapy in Patients With Newly Diagnosed Standard Risk or Down Syndrome B-Lymphoblastic Leukemia (B-ALL) and the Treatment of Patients With Localized B-Lymphoblastic Lymphoma (B-LLy)

PRIMARY OBJECTIVES: I. To determine in a randomized manner if the addition of 2 cycles of blinatumomab to standard therapy improves disease-free survival (DFS) in patients with standard risk (SR) B-ALL and higher risk features (SR-High), and patients with standard-risk average (SR-Avg) B-ALL who are negative for minimal residual disease (MRD) by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS) at end of induction (EOI). II. To confirm that boys in the standard-risk favorable (SR-Fav) subset of B-ALL, with or without Down syndrome (DS), will maintain a 5-year DFS of greater than 93% when treated with a standard chemotherapy regimen with a treatment duration of 2 years from the start of interim maintenance I (IM1). SECONDARY OBJECTIVES: I. To describe the DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of IM1, regardless of sex. II. To describe the DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated with a standard chemotherapy regimen. III. To determine if patients with DS-High achieve a reduction of treatment-related mortality (TRM) after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in induction, omission of the second month of delayed intensification \[DI\]) with 3 cycles of blinatumomab. IV. To describe the DFS characterized by the replacement of intensive elements of standard chemotherapy with 3 cycles of blinatumomab in patients with DS-High B ALL. V. To describe the DFS for patients with localized (Murphy stage I and II) B lymphoblastic lymphoma (B-LLy) receiving standard risk B-ALL therapy. VI. To compare the change in neurocognitive functioning, as measured by the CogState Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4- \< 10 years at the time of diagnosis between children from poor families (defined as presence of household material hardship \[HMH\], including either food, housing or energy insecurity) and non-poor families (absence of HMH). VII. To describe the impact of blinatumomab on caregiver burden and patient/proxy-reported symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study. VII. To evaluate available peripheral blood (PB) samples at EOI using HTS MRD and compare the results against bone marrow (BM) results. IX. To evaluate available end of Consolidation (EOC) BM samples using HTS in patients who were Day 29 MRD positive by flow cytometry and who have submitted EOC BM flow cytometry results. EXPLORATORY OBJECTIVES: I. To explore adaptive and innate immune functions and host genetic factors associated with severe infectious complications in children with DS B-ALL. II. To explore the impact of acute lymphoblastic leukemia (ALL) and its therapy on neurocognitive, functional, and quality of life outcomes in patients with DS and ALL, as measured by caregiver (parent/legal guardian) questionnaires. III. To define the prevalence of minimal marrow disease (MMD) in B-LLy and to correlate MMD at diagnosis with outcome in patients with B-LLy. IV. To explore the significance of and genomic landscape of Ig clonal composition in pediatric B-ALL. V. To explore the incidence of HTS MRD ≥ 0.01% versus (vs.) HTS MRD \< 0.01% in patients with multiparameter flow cytometry defined MRD \< 0.01% at end of Induction and genetically characterize those with discordance defined by the 0.01% threshold. OUTLINE: All patients are assigned to, and complete an INDUCTION treatment regimen. Patients are then assigned to a CONSOLIDATION treatment regimen. Finally, following CONSOLIDATION, patients are either assigned or randomized to 1 of 7 arms. NON-DS SR B-ALL INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1, vincristine intravenous (IV) push over 1 minute on days 1, 8, 15, and 22, dexamethasone orally (PO) or IV twice daily (BID) on days 1-28, pegaspargase IV over 1-2 hours or intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8 and 29 methotrexate is administered. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * After Non-DS SR B-ALL INDUCTION, SR-Fav and SR-Avg patients complete SR CONSOLIDATION, while patients with SR-High complete high-risk (HR) CONSOLIDATION. DS B-ALL INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1 minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30. Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28, and patients 10 years of age or older receive prednisone or prednisolone PO or IV BID on days 1-28. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8 and 29 IT methotrexate is administered. CNS3 patients also receive methotrexate IT on days 15 and 22, and leucovorin PO or IV every 6 hours for 2 doses on days 16 and 23. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * After DS B-ALL INDUCTION, patients without high risk features and MRD \< 0.01 % complete SR CONSOLIDATION. Patients without high risk features and MRD \>= 0.01%, OR with high risk features and any MRD complete HR CONSOLIDATION. NON-DS B-LLy INDUCTION: Patients receive cytarabine IT on day 1 and twice weekly if CNS2, vincristine IV push over 1 minute on days 1, 8, 15, and 22, dexamethasone PO or IV BID on days 1-28, pegaspargase IV over 1-2 hours or IM on day 4, and methotrexate IT on days 8 and 29. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * After NON-DS B-LLy INDUCTION, all B-LLy patients then complete SR CONSOLIDATION. DS B-LLY INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1 minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30. Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28, and patients 10 years of age or older receive PO or IV prednisone or methylprednisolone on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * After DS B-LLy INDUCTION, patients then complete SR CONSOLIDATION. SR CONSOLIDATION: Patients receive vincristine IV push over 1 minute on day 1, mercaptopurine PO on days 1-28, and methotrexate IT on days 1, 8, and 15. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, and 16. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. * After SR CONSOLIDATION, patients with MRD undetectable are assigned to ARM A, and patients with MRD detectable/indeterminate/unavailable are randomized to ARM A or B. Patients with SR-Fav and all B-LLy patients are assigned to treatments identical to that in ARM A. HR CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, vincristine IV push over 1 minute on days 15, 22, 43, and 50, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22 , and pegaspargase IV over 1-2 hours or IM on days 15 and 43. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, 16, and 23 (on days 2 and 9 only for DS CNS3 patients). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. Patients with continued clinical evidence of DS or testicular leukemia (from diagnosis through the end of Induction) undergo testicular radiation therapy over 12 fractions once daily (QD). * After HR CONSOLIDATION, patients are randomized to ARM C or D. DS B-ALL patients with MRD \< 1% are assigned to an arm including three blocks of blinatumomab. ARM A: * INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes undiluted or 10-15 minutes diluted on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * MAINTENANCE: Non-DS patients receive methotrexate IT on day 1, vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients receive vincristine IV push over 1 minute on day 1, methotrexate IT on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78, and leucovorin IV or PO on day 2 if DS. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the absence of disease progression or unacceptable toxicity. ARM B: * BLINATUMOMAB BLOCK I: Patients receive dexamethasone IV or PO on day 1, methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive leucovorin IV or PO every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * BLINATUMOMAB BLOCK II: Patients receive methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone PO or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * MAINTENANCE: Non-DS patients receive methotrexate IT on day 1 (omit cycles 5-6), vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1 when coinciding with IT methotrexate). DS patients receive methotrexate IT on day 1 (omit cycles 5-6), dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1 when coinciding with IT methotrexate), for DS patients and leucovorin IV or PO every 6 hours for 2 doses on day 2 (omit on final 2 cycles). Treatment repeats every 84 days until a total duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the absence of disease progression or unacceptable toxicity. ARM C: * INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on day 1 and 29, and leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * MAINTENANCE: Patients receive vincristine IV over 1 minute on day 1, prednisone or prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on days 1 and 29 of cycles 1-2 and on day 1 of subsequent cycles, methotrexate PO on days 8, 15, 22, 29 (for cycle 3 and later only), 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity. ARM D: * BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, methotrexate IT on day 1, and blinatumomab IV continuously on days 1-28. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28 and methotrexate IT on day 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21, 31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * MAINTENANCE: Patients receive methotrexate IT on day 1, vincristine IV over 1 minute on day 1, prednisone, prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity. DS-HIGH B-ALL: * BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, blinatumomab IV continuously on days 1-28, methotrexate IT on day 1 (or on day 56 of Consolidation), and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE: Patients receive vincristine IV push over 1 minute on days 1, 15, 29, and 43, intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-46, methotrexate IT on days 1 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 2-4, 16-18, 30-32, and 44-46. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. * BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28, methotrexate IT on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION: Patients receive vincristine IV over 1 minute on days 1, 8, and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on days 1-7 and 15-21, methotrexate IT on day 1, leucovorin PO or IV every 6 hours for 2 doses on day 2, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. * BLINATUMOMAB BLOCK III: Patients receive blinatumomab IV on days 1-28, methotrexate IT on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. * MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, prednisone, prednisolone or methylprednisolone PO or IV BID on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, methotrexate PO on days 8, 15, 22, 29 (omit day 29 for first 3 cycles for patients who do not receive cranial radiotherapy), 36, 43, 50, 57, 64, 71, and 78, and leucovorin PO on days 2 and 30 (day 30 dose is for cycles 1-3 and for patients who do not receive cranial radiotherapy). CNS3 patients receive cranial radiotherapy during first 4 weeks of cycle 1. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity. All B-LLy patients: * INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * DELAYED INTENSIFICATION: Patients receive vincristine IV push over 1 minute on days 1, 8 and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on days 1-7 and 15-21, methotrexate IT on days 1 and 29, pegaspargase IV over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients additionally receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. * MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment repeats every 84 days until a total duration of therapy of 2 years from start of interim maintenance I is reached in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 4 weeks until complete blood count(CBC)/differential/platelet count recovery, then every 3 months for the first 2 years, then every 4-6 months for the 3rd year, and every 6-12 months for the 4th and 5th years.

Areata Alopecia, Alopecia, Hypotrichosis, Hair Diseases, Skin Diseases, Pathological Conditions, Anatomical

A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics (PK) of Baricitinib in Children From 6 Years to Less Than 18 Years of Age With Alopecia Areata

• -317-615-4559
• clinical_inquiry_hub@lilly.com

Immune Thrombocytopenia

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo Controlled, Parallel-Group Study With an Open-Label Extension to Evaluate the Efficacy and Safety of Oral Rilzabrutinib (PRN1008) in Adults and Adolescents With Persistent or Chronic Immune Thrombocytopenia (ITP)

Irritable Bowel Syndrome With Constipation, Functional Constipation

A Phase 3, Open-label, Long-term Safety Study of Oral Linaclotide Administered to Pediatric Participants With Functional Constipation (FC) or Irritable Bowel Syndrome With Constipation (IBS-C)

Atopic Dermatitis

A Phase 3, Randomized, 52-week, Placebo-controlled, Double-blind Study With Rerandomization to Assess the Efficacy, Safety, and Tolerability of Rocatinlimab (AMG 451) in Adolescent Subjects With Moderate-to-severe Atopic Dermatitis (AD) (ROCKET-ASTRO)

Migraine

A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Rimegepant in Migraine Prevention in Children and Adolescents ≥ 6 to <18 Years of Age

• 1-800-718-1021
• ClinicalTrials.gov_Inquiries@pfizer.com

Dermatitis Atopic

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallelgroup, 3-arm, Multinational, Multicenter Study to Evaluate the Efficacy and Safety of Amlitelimab Monotherapy by Subcutaneous Injection in Participants Aged 12 Years and Older With Moderate-to-severe Atopic Dermatitis

• 800-633-1610
• contact-us@sanofi.com

Chronic Kidney Disease; Iron Deficiency Anemia

A Phase 3, Randomized, Open-Label, Multicenter Study to Evaluate the Safety (Compared to Iron Sucrose), Efficacy and Pharmacokinetics of Ferumoxytol for the Treatment of Iron Deficiency Anemia (IDA) in Pediatric Subjects With Chronic Kidney Disease (CKD)

This is a Phase 3, randomized, open-label, multicenter, study of the safety (compared to iron sucrose), efficacy, and PK/PD of ferumoxytol (7.0 mg Fe/kg x 2 \[max 510 mg/dose\]) in pediatric subjects with iron deficiency anemia (IDA) and CKD. There will be a total of approximately 125 subjects randomized to treatment in a 2:1 ratio to either ferumoxytol or iron sucrose. Total subject participation in the study will be up to 7 weeks, which includes a 2-week Screening Period and a 5-week Treatment Period. Subjects receive the following: • Two IV infusions of ferumoxytol 7.0 mg Fe/kg (max 510 mg/dose), the first administered on Day 1 and the second 2-8 days later OR • Iron sucrose (Venofer®): For Hemodialysis Dependent (HDD) patients: 2 mg Fe/kg, administered on consecutive dialysis sessions, for 10 doses (max 100mg/dose with a total max treatment course of 1000mg) For Non-hemodialysis Dependent (NDD) or Peritoneal Dialysis De pendent(PDD) patients: 4 mg Fe/kg, administered up to 3 times/week, for 5 doses (max 200mg/dose with a total max treatment course of 1000mg).

• 1-877-374 -4177
• CTInterest@covispharma.com

Psoriasis

A Phase 3b, Multi Center, Open-label, Long-term Extension Study of Apremilast (CC-10004) in Pediatric Subjects From 6 Through 17 Years of Age With Moderate to Severe Plaque Psoriasis

Osteosarcoma, Osteosarcoma in Children, Osteosarcoma Recurrent, Sarcoma

A Phase Ib/II Study to Evaluate the Safety, Feasibility and Efficacy of Nivolumab or Nivolumab in Combination With Azacitidine in Patients With Recurrent, Resectable Osteosarcoma

Treatment will be administered in 28 day cycles with the first cycle in the neoadjuvant setting. This will be followed by surgery to render the participant in surgical remission. Subsequently the participant will continue to receive treatment for up to 12 additional cycles or until recurrence, whichever occurs first. For participants with known bilateral lung recurrence, the nodule\[s\] in one lung should be resected, prior to the first cycle of chemotherapy. This trial was initially designed as a Phase 1/2 study; However, phase 2 will not proceed.

B-cell Acute Lymphoblastic Leukemia

A Phase II Pilot Trial to Estimate Survival After a Non-total Body Irradiation (TBI) Based Conditioning Regimen in Patients Diagnosed With B-acute Lymphoblastic Leukemia (ALL) Who Are Pre-allogeneic Hematopoietic Cell Transplantation (HCT) Next-generation-sequence (NGS) Minimal Residual Disease (MRD) Negative

A Phase II pilot trial will estimate survival after a non-TBI based conditioning regimen in patients diagnosed with B-acute lymphoblastic leukemia (ALL) who are pre-allogeneic hematopoietic cell transplantation (HCT) next-generation-sequence (NGS) minimal residual disease (MRD) negative. The relationship of NGS-MRD status to survival in children, adolescents, and young adults with B-ALL undergoing any approach to allogeneic HCT will be explored in a larger cohort (treatment \[phase II\] and observational arms of the study). The primary objective is to estimate 2-year event free survival (EFS) in pre-HCT NGS-MRD negative patients with B-ALL undergoing a non-TBI based conditioning regimen through a multi-center prospective trial. The accrual period is 3 years. Patients that are NGS-MRD negative with B-ALL may be eligible for the Treatment Arm, which is myeloablative non-TBI conditioning with busulfan, fludarabine, and thiotepa followed -matched related, unrelated, and umbilical cord blood transplants. Patients that are NGS-MRD positive will be followed on the observational arm for outcome. Study sampling will include NGS-MRD bone marrow (BM) aspirate and peripheral blood (PB) samples collected \[same day when possible\] pre-HCT (within 4 weeks), and post-HCT on days 42 ± 14, 100 ± 20, and 365 ± 60; PB samples only will also be collected day 180± 60 and 270± 60; day +30, day +100, and 1-year post-HCT. NGS-MRD peripheral blood sample only at 6 months and 9 months post-HCT; (Blast specimen at time of diagnosis or relapse is required for NGS-MRD testing).

• 323-361-6652
• EndRAD@chla.usc.edu

Melanoma of Unknown Primary, Recurrent Melanoma, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7

A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High-Dose Interferon a-2b for Resected High-Risk Melanoma

PRIMARY OBJECTIVES: I. To evaluate recurrence-free survival (RFS) between patients randomized to receive post-operative adjuvant ipilimumab given at either 10 mg/kg (high dose ipilimumab; HIP) or 3 mg/kg (low dose ipilimumab: LIP) versus those randomized to receive high-dose interferon alfa-2b (HDI) utilizing a hierarchical design assessing HIP versus HDI first and LIP versus HDI second (if the first comparison is significant). II. To evaluate overall survival (OS) between patients randomized to receive post-operative adjuvant ipilimumab given at either 10 mg/kg (HIP) or 3 mg/kg (LIP) versus those randomized to receive HDI utilizing a hierarchical design assessing HIP versus HDI first and LIP versus HDI second (if the first comparison is significant). SECONDARY OBJECTIVES: I. To evaluate safety and tolerability of post-operative adjuvant ipilimumab therapy given at either 10 mg/kg (HIP) or 3 mg/kg (LIP). II. Among patients enrolled by Clinical Community Oncology programs (CCOPs), to compare the global quality of life (QOL) between the ipilimumab arms versus HDI using Functional Assessment of Cancer Therapy (FACT)-General (G) form and to evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of QOL using Functional Assessment of Chronic Illness Therapy (FACIT)-diarrhea (D) and FACT-biological response modifiers (BRM). OUTLINE: Patients age \>= 18 are randomized to Arms A, B, or C and patients ages 12-17 are randomized to Arms D, E, or F. ARM A: Patients receive induction high-dose ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 cycles in the absence of disease progression or unacceptable toxicity. (closed accrual as of 4/4/14) (adult accrual has completed to Arms A, B, and C as of 8/15/2014) ARM B: Patients receive induction high-dose recombinant interferon alfa-2b IV over 20 minutes on days 1-5, 8-12, 15-19, and 22-26 in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance high-dose recombinant interferon alfa-2b subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every week for 48 weeks in the absence of disease progression or unacceptable toxicity. (adult accrual has completed to Arms A, B, and C as of 8/15/2014) ARM C: Patients receive induction low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 cycles in the absence of disease progression or unacceptable toxicity. (adult accrual has completed to Arms A, B, and C as of 8/15/2014) ARM D: Patients receive induction high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance high-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 cycles in the absence of disease progression or unacceptable toxicity. ARM E: Patients receive induction high-dose recombinant interferon alfa-2b IV over 20 minutes on days 1-5, 8-12, 15-19, and 22-26 in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance high-dose recombinant interferon alfa-2b SC on days 1, 3, and 5. Treatment repeats every week for 48 weeks in the absence of disease progression or unacceptable toxicity ARM F: Patients receive induction low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for a total of 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning on week 24, patients receive maintenance low-dose ipilimumab IV over 90 minutes on day 1. Treatment repeats every 90 days for a maximum of 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for up to 15 years.

B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, BCR-ABL1-Like, Central Nervous System Leukemia, Testicular Leukemia

A Phase III Randomized Trial for Newly Diagnosed High Risk B-Lymphoblastic Leukemia (B-ALL) Including a Stratum Evaluating Dasatinib (NSC#732517) in Patients With Ph-like Tyrosine Kinase Inhibitor (TKI) Sensitive Mutations

PRIMARY OBJECTIVES: I. To determine if the administration of post-Induction age-adjusted intrathecal triple therapy (ITT) on a Modified Berlin-Frankfurt-Munster (MBFM) interim maintenance high-dose methotrexate (IMHDM) backbone will improve 5-year disease-free survival (DFS) of children with high-risk (HR) B-acute lymphoblastic leukemia (ALL) compared to age-adjusted intrathecal (IT) methotrexate (MTX). (Completed effective March 19, 2018) II. To determine, in a randomized fashion, if the cyclophosphamide + etoposide containing regimen (Experimental Arm 1) will improve the 4-year DFS of children, adolescents, and young adults with very high-risk (VHR) B-ALL compared to a modified MBFM-IMHDM regimen that contains a second IM (Control Arm). (Completed effective February 15, 2017) SECONDARY OBJECTIVES: I. To determine the toxicity and tolerability of post-Induction age-adjusted ITT compared to age-adjusted IT MTX in children with HR B-ALL. (Completed effective March 19, 2018) II. To determine the toxicity and tolerability of Experimental Arm 1 compared to the Control Arm in children, adolescents, and young adults with VHR B-ALL. (Completed effective February 15, 2017) III. To determine whether a single-arm, modified Induction with limited anthracycline exposure and post-Induction therapy regimen with MBFM-interim maintenance intermediate dose methotrexate (IMIDM) and reduced vincristine (vincristine sulfate)/steroid pulse frequency and enhanced supportive care in children with Down syndrome (DS) and HR B-ALL will result in a \>= 65% 5-year DFS and \< 10% Induction mortality. IV. To describe the outcomes for children and young adults with Philadelphia chromosome (Ph)-like B-ALL and a predicted TKI-sensitive mutation treated with dasatinib plus MBFM-IMHDM. V. To determine the toxicity and tolerability of MBFM-IMIDM in children with DS and HR B-ALL. VI. To estimate overall survival (OS) rates both overall and by regimen a) for HR B-ALL and b) VHR B-ALL patients. VII. To determine the incidence of osteonecrosis (ON), defined by magnetic resonance (MR) imaging, and to characterize the natural history of clinically silent ON in children, adolescents, and young adults 10 years of age and greater and to assess the role of drugs (i.e., asparaginase and methotrexate) in addition to corticosteroids, in the risk for development of ON. (Completed accrual July 2016) VIII. To determine if the prevalence of cognitive deficits measured by CogState, in children (ages 6 to \< 13 years) with HR- and VHR B-ALL at 1 year off therapy, is significantly higher than the normative population (\> 14%) in the following domains: working memory, executive function, visual motor, processing speed, and visual attention. EXPLORATORY OBJECTIVE: I. To determine if the reduction of minimal residual disease (MRD) from end-Induction to end-Consolidation is greater for children, adolescents, and young adults with VHR B-ALL receiving Experimental Arm 1 compared to the Control Arm. (Closed effective October 20, 2017) OUTLINE: INDUCTION THERAPY: Patients without Down syndrome receive induction chemotherapy comprising cytarabine intrathecally (IT) on day 1 (and twice weekly thereafter for CNS2 patients \[except for days 8 and 29\]); vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, and 22; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily (BID) on days 1-14 (patients under 10 years old) or prednisone PO or IV BID on days 1-28 (patients at least 10 years old); pegaspargase IV over 1-2 hours on day 4; and methotrexate IT on days 8 and 29 for CNS1 and CNS2 patients (plus days 15 and 22 for CNS3 patients). Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. Participants are stratified to 1 of 3 disease groups: HR B-ALL, VHR B-ALL and PH-like B-ALL a predicted TKI-sensitive mutation. GROUP I - HR B-ALL: Patients are randomized to 1 of 2 treatment arms. (RANDOMIZATION CLOSED 03/19/2018) CONSOLIDATION THERAPY (C): ARM A HR B-ALL C: Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15, and 22; vincristine sulfate IV over 1 minute on days 15, 22, 43, and 50; and pegaspargase IV over 1-2 hours on days 15 and 43. Patients with continuing clinical evidence of testicular leukemia undergo radiotherapy (RT) QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. ARM B HR B-ALL C: Patients receive consolidation therapy as in Arm I HR B-ALL C. Patients also receive ITT comprising methotrexate, hydrocortisone sodium succinate, and cytarabine on days 1, 8, 15, and 22. Patients with testicular leukemia also undergo RT as in Arm I HR B-ALL C. (CLOSED 03/19/2018) INTERIM MAINTENANCE THERAPY (IM) ARM A HR B-ALL IM: Patients receive IM therapy comprising vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; methotrexate IT on days 1 and 29; and mercaptopurine PO on days 1-56. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. ARM B HR B-ALL IM: Patients receive ITT on days 1 and 29 and IM therapy as in Arm I HR-ALL IM. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. (CLOSED 03/19/2018) DELAYED INTENSIFICATION THERAPY (DI): ARM A HR B-ALL DI: Patients receive DI therapy comprising vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on days 1, 29, and 36; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO QD on days 29-42. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. ARM B HR B-ALL DI: Patients receive ITT on days 1, 29, and 36 and DI therapy as in Arm I HR B-ALL DI. (CLOSED 03/19/2018) MAINTENANCE THERAPY (M): ARM A HR B-ALL M: Patients receive maintenance therapy comprising vincristine sulfate IV over 1 minute on days 1, 29, and 57; methotrexate IT on day 1 (also day 29 of courses 1-4); prednisone PO BID on days 1-5, 29-33 (may receive methylprednisolone IV if PO is not tolerated), and 57-61; mercaptopurine PO QD on days 1-84; and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. ARM B HR B-ALL M: Patients receive ITT on day 1 (also day 29 of courses 1-4) and maintenance therapy as in Arm I HR B-ALL M. Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicity. (CLOSED 03/19/2018) GROUP II: VHR B-ALL: Patients are randomized to 1 of 3 treatment arms. (RANDOMIZATION CLOSED 02/15/2017) CONSOLIDATION THERAPY PART I: In all arms, patients receive cyclophosphamide IV over 30-60 minutes on day 1; cytarabine IV over 1-30 minutes or SC on days 1-4 and 8-11; mercaptopurine PO QD on days 1-14; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 patients); vincristine sulfate IV over 1 minute on days 15 and 22; and pegaspargase IV over 1-2 hours on day 15. Patients with continuing clinical evidence of testicular leukemia undergo RT QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY PART II: ARM A VHR B-ALL C (CONTROL ARM): Patients receive consolidation therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; mercaptopurine PO QD on days 29-42; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. ARM B VHR B-ALL C (EXPERIMENTAL ARM 1): Patients receive consolidation therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 60-120 minutes on days 29-33; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED 02/15/2017) ARM C VHR B-ALL C (EXPERIMENTAL ARM 2): Patients receive clofarabine IV over 2 hours on days 29-33 and consolidation therapy as in Arm B VHR B-ALL C. (CLOSED 9/12/2014) INTERIM MAINTENANCE THERAPY PART I: In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION THERAPY PART I: In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 8, and 15; dexamethasone PO or IV BID on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; methotrexate IT on day 1; and pegaspargase IV over 1-2 hours on day 4. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION THERAPY PART II: ARM A VHR B-ALL DI (CONTROL ARM): Patients receive DI therapy comprising cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; thioguanine PO QD on days 29-42; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. ARM B VHR B-ALL DI (EXPERIMENTAL ARM 1): Patients receive DI therapy comprising cyclophosphamide IV over 15-30 minutes on days 29-33; etoposide IV over 60-120 minutes on days 29-33; methotrexate IT on days 29 and 36; vincristine sulfate IV over 1 minute on days 43 and 50; and pegaspargase IV over 1-2 hours on day 43. Treatment continues for 28 days in the absence of disease progression or unacceptable toxicity. (CLOSED 02/15/2017) ARM C VHR B-ALL DI (EXPERIMENTAL ARM 2): Patients receive clofarabine IV over 2 hours on days 29-33 and DI therapy as in Arm II B VHR B-ALL DI. (Closed as of 9/12/2014) INTERIM MAINTENANCE THERAPY PART II: In all arms, patients receive vincristine sulfate IV over 1 minute and methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. MAINENTANCE THERAPY: Patients with CNS3 disease at diagnosis undergo RT QD over 4 weeks (10 fractions total). In all arms, patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; prednisone PO BID on days 1-5, 29-33, and 57-61 (may receive methylprednisolone IV if PO is not tolerated); methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (except on methotrexate IT days); mercaptopurine PO QD on days 1-84; methotrexate IT on day 1 (also day 29 of courses 1 and 2 for CNS patients who did not undergo RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. GROUP III: PH-LIKE PREDICTED TKI-SENSITIVE KINASE MUTATION: CONSOLIDATION THERAPY: Patients receive dasatinib PO QD on days 1-56, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32 and 36-39, mercaptopurine PO on days 1-14 and 29-42, methotrexate IT on days 1, 8, 15 and 22 (days 1 and 8 only for CNS3 patients), vincristine sulfate IV over 1 minute on days 15, 22, 43 and 50, and pegaspargase IV over 1-2 hours on days 15 and 43. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. INTERIM MAINTENANCE THERAPY I: Patients receive dasatinib PO QD on days 1-63, vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43, high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin calcium PO or IV on days 3-4, 17-18, 31-32, and 45-46, methotrexate IT on days 1 and 29, and mercaptopurine PO on days 1-56. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION THERAPY: Patients receive dasatinib PO QD on days 1-56, vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50, dexamethasone PO or IV on days 1-7 and 15-21, doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8 and 15, methotrexate IT on days 1, 29 and 36, pegaspargase IV over 1-2 hours on days 4 and 43, cyclophosphamide IV over 30-60 minutes day 29, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, and thioguanine PO on days 29-42. Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. INTERIM MAINTENANCE THERAPY II: Patients dasatinib PO QD on days 1-56, vincristine sulfate IV over 1 minute days 1, 11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31 and 41, methotrexate IT on days 1 and 31, and pegaspargase IV over 1-2 hours days 2 and 22. MAINTENANCE THERAPY: Patients receive dasatinib PO QD on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29 and 57, prednisone PO BID or IV on days 1-5, 29-33 and 57-61, methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 (omit on days when MTX \[IT\] is given), mercaptopurine PO on days 1-84, methotrexate IT on day 1 (also day 29 of course 1 and 2, for patients who did not receive CNS radiation). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. Participants with Down syndrome are assigned to DS HR B-ALL: INDUCTION THERAPY: All patients receive cytarabine IT on day 1; vincristine sulfate IV over 1 minute on days 1 and 8, dexamethasone PO or IV BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 1-14 (may receive methylprednisolone IV if PO is not tolerated), pegaspargase IV over 1-2 hours on day 4; methotrexate IT on day 8; and leucovorin calcium PO on days 10-11. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. RAPID EARLY RESPONDERS (RER): Patients receive induction therapy comprising vincristine sulfate IV over 1 minute on days 15 and 22; dexamethasone PO BID (patients under 10 years old) or prednisone PO BID (patients at least 10 years old) on days 15-28; methotrexate IT on day 29 (also days 15 and 22 for CNS3 patients); and leucovorin calcium PO on days 31-32 (also days 17-18 and 24-25 for CNS3 patients). Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. SLOW EARLY RESPONDERS (SER): Patients receive daunorubicin hydrochloride IV over 1-15 minutes on day 15 and Induction therapy as RER patients. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. CONSOLIDATION THERAPY: All patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO QD on days 1-14 and 29-42; vincristine sulfate IV over 1 minute on days 15, 22, 43, and 50; pegaspargase IV over 1-2 hours on days 15 and 43; methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 patients); and leucovorin calcium PO on days 3-4, 10-11, 17-18, and 24-25. Patients with continuing clinical evidence of testicular leukemia undergo RT QD, 5 days a week, for approximately 2½ weeks (12 fractions total). Treatment continues for 56 days in the absence of disease progression or unacceptable toxicity. INTERIM MAINTENANCE THERAPY: Patients receive vincristine sulfate IV over 1 minute on days 1, 15, 29, and 43; intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium PO or IV on days 2-3, 17-18, 31-32, and 45-46; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. Treatment continues for 63 days in the absence of disease progression or unacceptable toxicity. DELAYED INTENSIFICATION THERAPY: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO BID or IV on days 1-7 and 15-21; doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4 and 43; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO QD on days 29-42; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; methotrexate IT on days 1, 29, and 36; and leucovorin calcium PO on days 3-4, 31-32 and 38-39. MAINTENANCE THERAPY: Patients with CNS3 disease undergo RT QD, 5 days a week, for 2 weeks (10 fractions total). Patients receive vincristine sulfate IV over 1 minute on day 1; prednisone PO BID or IV on days 1-5 (may receive methylprednisolone IV if PO not tolerated); methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO QD on days 1-84; and methotrexate IT on day 1 (also day 29 of courses 1-4 for CNS3 patients who did not undergo RT). Treatment repeats every 12 weeks for 2 years (females) or 3 years (males) in the absence of disease progression or unacceptable toxicities. After completion of study treatment, patients are followed up periodically for 10 years.

Acute Myeloid Leukemia, Leukemia Cutis, Myeloid Neoplasm, Myeloid Sarcoma

A Phase III Randomized Trial for Patients With De Novo AML Using Bortezomib and Sorafenib (NSC# 681239, NSC# 724772) for Patients With High Allelic Ratio FLT3/ITD

PRIMARY OBJECTIVES: I. To compare event-free survival (EFS) and overall survival (OS) in patients with de novo acute myeloid leukemia (AML) without high allelic ratio fms-like tyrosine kinase (FLT3)/internal tandem duplications (ITD)+ mutations who are randomized to standard therapy versus bortezomib/standard combination therapy. II. To determine the feasibility of combining bortezomib with standard chemotherapy in patients with de novo AML. III. To compare the OS and EFS of high-risk patients treated with intensive Induction II with historical controls from AAML03P1 and AAML0531. IV. To determine the feasibility of administering sorafenib (sorafenib tosylate) with standard chemotherapy and in a one year maintenance phase in patients with de novo high allelic ratio FLT3/ITD+ AML. SECONDARY OBJECTIVES: I. To assess the anti-leukemic activity of sorafenib in patients with de novo high allelic ratio FLT3/ITD+ AML. II. To compare the percentage of patients converting from positive minimal residual disease (MRD) to negative MRD after Intensive Induction II with historical controls from AAML03P1 and AAML0531. III. To compare OS, disease-free survival (DFS), cumulative incidence of relapse, and treatment-related mortality from end of Intensification I between patients allocated to best allogenic donor stem cell transplant (SCT) and comparable patients on AAML0531 who did not receive allogenic donor SCT. IV. To compare OS, DFS, cumulative incidence of relapse, treatment-related mortality, and severe toxicity between patients allocated to matched family donor SCT on AAML1031 and AAML0531. V. To assess the health-related quality of life (HRQOL) of patients treated with chemotherapy and stem cell transplant (SCT) for AML. VI. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen. VII. To obtain sorafenib and metabolite steady state pharmacokinetics and pharmacokinetic-pharmacodynamic data in subjects with FLT3/ITD receiving sorafenib. VIII. To compare the changes in shortening fraction/ejection fraction over time between patients treated with and without dexrazoxane. IX. To refine the use of minimal-residual disease (MRD) detection with 4-color flow cytometry. X. To evaluate the prognostic significance of molecular MRD and its contribution to risk identification with multidimensional flow cytometry (MDF)-based MRD in patients with translocations amenable to quantitative real time (RT)-polymerase chain reaction (PCR) (e.g., t\[8;21\], inv\[16\], t\[9;11\], Wilms tumor 1 \[WT1\] expression). XI. To determine the leukemic involvement of the hematopoietic early progenitor cell and its role in defining response to therapy. XII. To define the leukemic stem cell population in patients with AML. XIII. To determine the prevalence and prognostic significance of molecular abnormalities of WT1, runt-related transcription factor (RUNX)1, mixed-lineage leukemia (MLL)-partial tandem duplication (PTD), tet methylcytosine dioxygenase 2 (TET2), Cbl proto-oncogene, E3 ubiquitin protein ligase (c-CBL), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and other novel AML-associated genes in pediatric AML. XIV. Correlate the expression of cluster of differentiation (CD)74 antigen as well as proteasome beta 5-subunit (PSMB5) gene expression and mutation with response to bortezomib. XV. To evaluate the changes in protein expression and unfolded protein response (UPR) in patients with AML. XVI. To determine the expression level of wild-type FLT3, and correlate with outcome and in vitro sensitivity to FLT3 inhibition. XVII. To collect biology specimens at diagnosis, treatment time points, and relapse for future biology studies XVIII. To create a pediatric-specific algorithm to predict the occurrence of grade 2-4 acute graft-versus-host disease (GVHD) prior to its clinical manifestations using a combination of pre-transplant clinical variables and serum GVHD biomarker concentrations in the first weeks after SCT. OUTLINE: This is a dose-escalation study of sorafenib tosylate. Patients are randomized to Arm A or B or offered treatment on 1 of 6 arms. (Arms A and B are closed to new patient enrollment as of 02/04/2016) Arm A: INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and ADE chemotherapy comprising cytarabine intravenously (IV) over 1-30 minutes on days 1-10; daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5; and etoposide IV over 1-2 hours on days 1-5. INDUCTION II: Patients with low risk (LR) receive cytarabine IT and ADE chemotherapy as in Induction I. Patients with high risk (HR) receive cytarabine IT on day 1 and MA chemotherapy comprising high-dose cytarabine IV over 1-3 hours on days 1-4, and mitoxantrone IV over 15-30 minutes on days 3-6. Patients who achieve complete remission (CR) proceed to Intensification I (beginning on day 37). Patients with refractory disease are off protocol therapy. INTENSIFICATION I: Patients receive cytarabine IT on day 1 and AE chemotherapy comprising high-dose cytarabine IV over 1-3 hours, and etoposide IV over 1-2 hours on days 1-5. Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 34. Patients with refractory disease are off protocol therapy. INTENSIFICATION II: Patients with LR receive cytarabine IT on day 1 and MA chemotherapy as in Induction II. Patients with HR and no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. Arm B: INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Induction I, Arm A. Patients also receive bortezomib IV over 3-5 seconds on days 1, 4, and 8. INDUCTION II: Patients with LR receive cytarabine IT, ADE chemotherapy, and bortezomib as in Induction I. Patients with HR receive cytarabine IT and MA chemotherapy as in Induction II, Arm A (HR patients) and bortezomib IV on days 1, 4, and 8. INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and bortezomib IV on days 1, 4, and 8. Patients who achieve CR proceed to Intensification II or stem cell transplantation (SCT) beginning on day 34. Patients with refractory disease are off protocol therapy. INTENSIFICATION II: Patients with LR receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and bortezomib IV on days 1, 4, and 8. Patients with HR and no donor for SCT receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9 and asparaginase intramuscularly (IM) on days 2 and 9. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. ARM C (COHORT 1): INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36. INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year. ARM C (COHORT 2): INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I and sorafenib tosylate PO at the time of known HR FLT3/ITD+ (including in Induction I and concurrently with chemotherapy). INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36. INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year. ARM C (COHORT 3): INDUCTION I: Patients receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I and sorafenib tosylate PO on days 11-28. INDUCTION II: Patients receive cytarabine IT on day 1, cytarabine IV over 1-30 minutes on days 1-8, daunorubicin hydrochloride IV over 1-15 minutes on days 1, 3, and 5, etoposide IV over 1-2 hours on days 1-5, and sorafenib tosylate PO on days 9-36. INTENSIFICATION I: Patients receive cytarabine IT and AE chemotherapy in Arm A, Intensification II, and sorafenib tosylate PO on daily on days 6-28. INTENSIFICATION II: Patients receive cytarabine IT on day 1, MA chemotherapy as in Arm A, Induction II (HR patients), and sorafenib tosylate PO on days 7-34. STEM CELL TRANSPLANTATION (SCT) (HR patients with matched family \[MFD\] or unrelated donor): CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes once daily on days -5 to -2 and busulfan IV over 2 hours 4 times daily on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic SCT within 36 to 48 hours after the last dose of busulfan. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO beginning on day -2 and continuing until day 98 (matched sibling donor) or day 180 (with taper) (other related/unrelated donors or cord blood) and methotrexate IV on days 1, 3, and 6 (matched sibling/cord blood donors) or days 1, 3, 6, and 11 (other related/unrelated donors). Patients with unrelated donors also receive antithymocyte globulin IV over 6-8 hours on days -3 to -1. MAINTENANCE: Patients receive sorafenib tosylate PO starting on day 40-100 after completion of intensification II or SCT for one year. ARM D: INDUCTION I: Patients with unknown FLT3/ITD status prior to study enrollment receive cytarabine IT and ADE chemotherapy as in Arm A, Induction I. If patients are determined to be HR FLT3/ITD+ no later than the end of Induction I they will be eligible to participate in Arm C. After completion of study therapy, patients are followed up monthly for 6 months, every 2 months for 6 months, every 4 months for 1 year, every 6 months for 1 year, and then yearly thereafter.

Adult T Acute Lymphoblastic Leukemia, Ann Arbor Stage II Adult Lymphoblastic Lymphoma, Ann Arbor Stage II Childhood Lymphoblastic Lymphoma, Ann Arbor Stage III Adult Lymphoblastic Lymphoma, Ann Arbor Stage III Childhood Lymphoblastic Lymphoma, Ann Arbor Stage IV Adult Lymphoblastic Lymphoma, Ann Arbor Stage IV Childhood Lymphoblastic Lymphoma, Childhood T Acute Lymphoblastic Leukemia

A Phase III Randomized Trial Investigating Bortezomib (NSC# 681239) on a Modified Augmented BFM (ABFM) Backbone in Newly Diagnosed T-Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LLy)

PRIMARY OBJECTIVES: I. To compare event-free survival (EFS) in patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LLy) who are randomized to a modified augmented Berlin-Frankfurt-Munster (ABFM) backbone versus bortezomib plus the modified ABFM backbone. SECONDARY OBJECTIVES: I. To determine the safety and feasibility of modifying standard therapy for T-ALL and T-LLy based on the results of UKALL 2003, which includes a dexamethasone-based induction, additional doses of pegaspargase (PEG-ASP) during induction and delayed intensification (DI), and dexamethasone pulses during maintenance therapy. II. To determine if prophylactic (presymptomatic) cranial radiation therapy (CRT) can be safely and effectively eliminated in the 85-90% of T-ALL patients classified as standard or intermediate risk. III. To determine the proportion of end of consolidation (EOC) minimal residual disease (MRD) \>= 0.1% T-ALL patients who become MRD negative (undetectable by flow cytometry) after intensification of chemotherapy, using three high risk (HR) BFM blocks, and to compare EFS between the patients who become MRD negative after the three HR BFM blocks and continue on chemotherapy with those who continue to have detectable MRD and are eligible for other treatment strategies, including hematopoietic stem cell transplant (HSCT). IV. To compare the EFS between very high risk (induction failure) T-LLy patients treated with HR BFM intensification blocks who have partial or complete response (PR or CR) with those who do not respond (NR). CORRELATIVE OBJECTIVES: I. To investigate the prognostic significance of day 29 bone marrow (BM) MRD in T-LLy patients. II. To determine if protein expression patterns can predict bortezomib response and drug resistance in T-ALL. III. To analyze and target relevant signaling pathways in T-ALL blasts, focusing on early T cell precursor (ETP) acute lymphoblastic leukemia (ALL). OUTLINE: Patients are randomized to 1 of 2 treatment arms. Patients are risk assigned based on data from end of induction and/or consolidation therapy; this then modifies the subsequent therapy received. T-ALL Risk Group Definitions: Standard Risk (SR): CNS1*, lumbar puncture prior to steroid therapy (not steroid pretreated), Day 29 (end of induction) bone marrow M1, Day 29 bone marrow minimal residual disease (MRD) \<=0.01%, no testicular leukemia at diagnosis. Intermediate Risk (IR): Not SR or VHR. Very High Risk (VHR): M3 marrow at Day 29 and/or end of consolidation (EOC) MRD \>=0.1%. *CNS2 and CNS3 cannot be SR and are assigned to IR or VHR based on marrow response. T-LL Risk Group Definitions: Standard Risk (SR): CNS1*, MRD at diagnosis \<1% in bone marrow, lumbar puncture prior to steroid therapy (not steroid pretreated), Day 29 (end of induction) complete response (CR) or partial response (PR). Intermediate Risk (IR): Not SR or VHR. Very High Risk (VHR): Stable Disease (SD)/No response (NR) at Day 29 (End of Induction). *CNS2 and CNS3 cannot be SR and are assigned to IR or VHR based on radiographic response. ARM A INDUCTION: Patients receive cytarabine intrathecally (IT) at time of diagnostic lumbar puncture (if within 72 hours from start of protocol therapy) OR day 1; vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, and 22; dexamethasone orally (PO) twice daily (BID) on days 1-28 (no taper); daunorubicin hydrochloride IV over 1-15 minutes on days 1, 8, 15, and 22; pegaspargase IV over 1-2 hours on days 4 and 18; and methotrexate IT on days 8 and 29 (and on days 15 and 22 for central nervous system 3 involvement \[CNS3\] T-ALL patients). ARM A CONSOLIDATION: Beginning on day 36 from Induction, patients receive methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 T-ALL or CNS3 T-LLy patients); cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42; pegaspargase IV over 1-2 hours on days 15 and 43; and vincristine sulfate IV on days 15, 22, 43, and 50. Patients with persistent testicular disease undergo radiation therapy. Patients are then assigned to subsequent therapy according to risk assignment. Patients with standard risk (SR) disease receive Interim Maintenance with Capizzi methotrexate (CMTX); patients with intermediate risk (IR) disease receive Interim Maintenance with high-dose methotrexate (HDMTX), Delayed Intensification, and then Interim Maintenance with CMTX; and patients with very high risk (VHR) disease receive 3 HR Intensification Blocks, Delayed Intensification, and then Interim Maintenance with CMTX. ARM A CMTX INTERIM MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 11, 21, 31, and 41; methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. The next course (based on risk assignment) begins on day 57 or when blood counts recover (whichever occurs later). ARM A DELAYED INTENSIFICATION: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 43, and 50; dexamethasone PO BID or IV on days 1-7 and 15-21; doxorubicin hydrochloride IV over 15 minutes on days, 1, 8, and 15; pegaspargase IV over 1-2 hours on days 4, 18, and 43; methotrexate IT on days 1, 29, and 36; cyclophosphamide IV over 30-60 minutes on day 29; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and thioguanine PO on days 29-42. The next course (based on risk assignment) begins on day 64 or when blood counts recover (whichever occurs later). ARM A HDMTX INTERIM MAINTENANCE: Patients receive high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium IV or PO on days 3-4, 17-18, 31-32, and 45-46; vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. The next course (based on randomization assignment) begins on day 57 or when blood counts recover (whichever occurs later). ARM A INTENSIFICATION BLOCK I: Patients receive dexamethasone IV or PO BID on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium IV or PO on days 3-4; vincristine sulfate IV on days 1 and 6; cyclophosphamide IV over 1-6 hours on days 2-4; high-dose cytarabine IV over 3 hours every 12 hours on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. The next course (Intensification Block II) begins on day 22 or when blood counts recover (whichever occurs later). ARM A INTENSIFICATION BLOCK II: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium PO or IV on days 3-4; vincristine sulfate IV on days 1 and 6; ifosfamide IV over 1 hour every 12 hours on days 2-4; daunorubicin hydrochloride IV over 30 minutes on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 1 as in Intensification Block I. The next course (Intensification Block III) begins on day 22 or when blood counts recover (whichever occurs later). ARM A INTENSIFICATION BLOCK III: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose cytarabine IV over 3 hours every 12 hours on days 1-2; etoposide IV over 1-2 hours every 12 hours on days 3-5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 5 as in Intensification Block I. The next course (based on randomization) begins on day 22 or when blood counts recover (whichever occurs later). ARM A MAINTENANCE THERAPY: All patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 29 for SR patients during the first 4 cycles); methotrexate IT on day 1 (and day 29 during the first 4 cycles for SR patients and during the first 2 cycles for IR patients). Patients with CNS1-3VHR and CNS2 VHR, and CNS3 IR disease also undergo cranial radiation therapy during the first 4 weeks (cycle 1). Treatment in female patients with T-ALL and patients with T-LLY repeats every 12 weeks for up to 2 years from the start of Interim Maintenance (week 119). Treatment in male patients with T-ALL repeats every 12 weeks for up to 3 years from the start of Interim Maintenance (week 171). ARM B INDUCTION: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11(1.3 mg/m\^2 per dose); and cytarabine, vincristine sulfate, dexamethasone, daunorubicin hydrochloride, pegaspargase, and methotrexate as in Induction Arm A. ARM B CONSOLIDATION: Beginning on day 36 from Induction, patients receive methotrexate IT on days 1, 8, 15, and 22 (days 1 and 8 only for CNS3 T-ALL or CNS3 T-LLy patients); cyclophosphamide IV over 30-60 minutes on days 1 and 29; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39; mercaptopurine PO once daily (QD) on days 1-14 and 29-42; pegaspargase IV over 1-2 hours on days 15 and 43; and vincristine sulfate IV on days 15, 22, 43, and 50. Patients with persistent testicular disease undergo radiation therapy. Patients are then assigned to subsequent therapy according to risk assignment. Patients with standard risk (SR) disease receive Interim Maintenance with Capizzi methotrexate (CMTX); patients with intermediate risk (IR) disease receive Interim Maintenance with high-dose methotrexate (HDMTX), Delayed Intensification, and then Interim Maintenance with CMTX; and patients with very high risk (VHR) disease receive 3 HR Intensification Blocks, Delayed Intensification, and then Interim Maintenance with CMTX. ARM B CMTX INTERIM MAINTENANCE: Patients receive vincristine sulfate IV over 1 minute on days 1, 11, 21, 31, and 41; methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted) on days 1, 11, 21, 31, and 41; pegaspargase IV over 1-2 hours on days 2 and 22; and methotrexate IT on days 1 and 31. The next course (based on risk assignment) begins on day 57 or when blood counts recover (whichever occurs later). ARM B DELAYED INTENSIFICATION: Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 15, and 18 (1.3 mg/m\^2 per dose); and vincristine sulfate, dexamethasone, doxorubicin hydrochloride, pegaspargase, methotrexate, cyclophosphamide, cytarabine, and thioguanine as in Delayed Intensification Arm A. The next course (based on risk assignment) begins on day 64 or when blood counts recover (whichever occurs later). ARM B HDMTX INTERIM MAINTENANCE: Patients receive high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43; leucovorin calcium IV or PO on days 3-4, 17-18, 31-32, and 45-46; vincristine sulfate IV on days 1, 15, 29, and 43; mercaptopurine PO QD on days 1-56; and methotrexate IT on days 1 and 29. The next course (based on randomization assignment) begins on day 57 or when blood counts recover (whichever occurs later). ARM B INTENSIFICATION BLOCK I: Patients receive dexamethasone IV or PO BID on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium IV or PO on days 3-4; vincristine sulfate IV on days 1 and 6; cyclophosphamide IV over 1-6 hours on days 2-4; high-dose cytarabine IV over 3 hours every 12 hours on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on day 1. The next course (Intensification Block II) begins on day 22 or when blood counts recover (whichever occurs later). ARM B INTENSIFICATION BLOCK II: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose methotrexate IV over 24 hours on day 1; leucovorin calcium PO or IV on days 3-4; vincristine sulfate IV on days 1 and 6; ifosfamide IV over 1 hour every 12 hours on days 2-4; daunorubicin hydrochloride IV over 30 minutes on day 5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 1 as in Intensification Block I. The next course (Intensification Block III) begins on day 22 or when blood counts recover (whichever occurs later). ARM B INTENSIFICATION BLOCK III: Patients receive dexamethasone PO BID or IV on days 1-5; high-dose cytarabine IV over 3 hours every 12 hours on days 1-2; etoposide IV over 1-2 hours every 12 hours on days 3-5; pegaspargase IV over 1-2 hours on day 6; and triple IT therapy on day 5 as in Intensification Block I. The next course (based on randomization) begins on day 22 or when blood counts recover (whichever occurs later). ARM B MAINTENANCE THERAPY: All patients receive vincristine sulfate IV over 1 minute on days 1, 29, and 57; dexamethasone PO BID or IV on days 1-5, 29-33, and 57-61; mercaptopurine PO on days 1-84; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 29 for SR patients during the first 4 cycles); methotrexate IT on day 1 (and day 29 during the first 4 cycles for SR patients and during the first 2 cycles for IR patients). Patients with CNS1-3VHR and CNS2 VHR, and CNS3 IR disease also undergo cranial radiation therapy during the first 4 weeks (cycle 1). Treatment in female patients with T-ALL and patients with T-LLY repeats every 12 weeks for up to 2 years from the start of Interim Maintenance (week 119). Treatment in male patients with T-ALL repeats every 12 weeks for up to 3 years from the start of Interim Maintenance (week 171). All treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically for up to 10 years.

Localized Extraskeletal Ewing Sarcoma, Peripheral Primitive Neuroectodermal Tumor of Bone, Peripheral Primitive Neuroectodermal Tumor of Soft Tissues

A Phase III Randomized Trial of Adding Vincristine-Topotecan-Cyclophosphamide to Standard Chemotherapy in Initial Treatment of Non-Metastatic Ewing Sarcoma

PRIMARY OBJECTIVES: l. Test the effect of the combination of vincristine (vincristine sulfate), cyclophosphamide, and topotecan (topotecan hydrochloride) (VTC) added to the standard 5-drug interval-compressed chemotherapy backbone on event-free and overall survival of children and young adults with Ewing sarcoma. CORRELATIVE SCIENCE OBJECTIVES: I. To evaluate initial volumetric tumor size as a prognostic factor for event free survival (EFS) in patients with localized Ewing tumors. II. To evaluate histologic response as a prognostic factor for EFS in patients with localized Ewing tumors. III. To continue evaluation of biologic markers both as related to prognosis and as eventual therapeutic targets via encouraging concurrent enrollment on a Ewing sarcoma specimen-collection study. IV. To evaluate imaging response by fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) as a prognostic factor for EFS. V. To evaluate the effects of the type of local therapy on EFS and overall survival. VI. To evaluate the effect of local surgical margins in conjunction with histologic response on EFS in patients with localized Ewing tumors. VII. To evaluate the effect of local therapy modality (surgery, radiotherapy, or a combination) as well as the type of surgical reconstruction on musculoskeletal complications. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM A: INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9. ARM B: INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19. Patients could undergo surgery alone after recovery from week 12 chemotherapy if the primary tumor could be completely resected with negative margins and with reasonable functional result. Patients with inadequate margins after surgery were to receive radiotherapy in addition. Patients with lesions in surgically difficult sites such as the spine, skull, and periacetabular pelvis, patients with a poor response to induction chemotherapy, or those patients in whom surgery would result in unacceptable functional results were recommended to receive radiation and not surgery. Radiotherapy was to be administered during weeks 1-7 of consolidation therapy or after recovery from surgery for patients with positive margins. Patients who received planned pre-operative radiation and had positive surgical margins were to receive additional radiotherapy. After completion of study therapy, patients are followed up every 3 months for 3 years and then every 6 months for 2 years.

Acute Promyelocytic Leukemia With t(15;17)(q24.1;q21.2); PML-RARA

A Phase III Study for Patients With Newly Diagnosed Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide and All-Trans Retinoic Acid

PRIMARY OBJECTIVES: I. To eliminate exposure to conventional chemotherapy (including anthracyclines), for patients with standard risk acute promyelocytic leukemia (APL), through use of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) (tretinoin) based therapy while achieving an event free survival (EFS) that is not inferior compared to historical controls. II. To significantly reduce exposure to conventional chemotherapy, and in particular, anthracycline exposure, for patients with high risk APL, through use of ATO and ATRA based therapy while achieving an event free survival that is not inferior compared to historical controls. EXPLORATORY OBJECTIVES: I. To analyze the clinical impact of FMS-like tyrosine kinase 3 (FLT3) mutations in pediatric APL. II. To correlate clinical outcomes with the kinetics of reduction in promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) transcript level by quantitative real-time (RT)-polymerase chain reaction (PCR) (RQ-PCR) in bone marrow and peripheral blood samples from diagnosis to time points during therapy. III. To monitor incidence of coagulopathy complications, utilizing standardized conventional supportive care, and correlate with a battery of coagulation testing. IV. To evaluate the neurocognitive outcomes of patients treated on this protocol using patient-completed, performance-based measures of neuropsychological functioning and parent questionnaire report. OUTLINE: INDUCTION THERAPY: Patients with standard and high risk APL receive tretinoin orally (PO) twice daily (BID) and arsenic trioxide intravenously (IV) over 2-4 hours on days 1-28. High risk APL patients also receive dexamethasone PO or IV BID on days 1-14 and idarubicin IV over 15 minutes on days 1, 3, 5, and 7. Patients achieving hematologic complete remission (hCR)/hematologic complete remission with incomplete blood count recovery (hCRi) may go on to consolidation therapy. Patients who do not achieve hCR/hCRi may continue treatment with tretinoin and arsenic trioxide for up to 70 days. CONSOLIDATION THERAPY: Patients receive tretinoin PO BID on days 1-14 and 29-42 and arsenic trioxide IV over 2-4 hours on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 56 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive tretinoin PO BID on days 1-14 and arsenic trioxide IV over 2-4 hours on days 1-5, 8-12, 15-19, and 22-26. MINIMAL RESIDUAL DISEASE (MRD) CONSOLIDATION THERAPY: Patients who have APL in the bone marrow after 2 courses of consolidation therapy receive MRD consolidation therapy prior to continuing onto consolidation course 3. Patients receive cytarabine IV over 1-3 hours every 12 hours on days 1-4; mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6; and tretinoin PO BID on days 1-14. If there are no APL cells in the bone marrow after completion of MRD consolidation therapy, patients continue on to consolidation course 3. After completion of study treatment, patients are followed up monthly for 12 months, every 3 months for 36 months, every 6 months for 48 months, and then annually for 2 years.

Ann Arbor Stage III Hodgkin Lymphoma, Ann Arbor Stage III Lymphocyte-Depleted Classic Hodgkin Lymphoma, Ann Arbor Stage III Mixed Cellularity Classic Hodgkin Lymphoma, Ann Arbor Stage III Nodular Sclerosis Classic Hodgkin Lymphoma, Ann Arbor Stage IV Hodgkin Lymphoma, Ann Arbor Stage IV Lymphocyte-Depleted Classic Hodgkin Lymphoma, Ann Arbor Stage IV Mixed Cellularity Classic Hodgkin Lymphoma, Ann Arbor Stage IV Nodular Sclerosis Classic Hodgkin Lymphoma, Classic Hodgkin Lymphoma, Lymphocyte-Rich Classic Hodgkin Lymphoma

A Phase III, Randomized Study of Nivolumab (Opdivo) Plus AVD or Brentuximab Vedotin (Adcetris) Plus AVD in Patients (Age >/= 12 Years) With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

PRIMARY OBJECTIVE: I. To compare the progression-free survival (PFS) in patients with newly diagnosed advanced stage classical Hodgkin lymphoma randomized to N-AVD (nivolumab, doxorubicin hydrochloride \[doxorubicin\], vinblastine sulfate \[vinblastine\], dacarbazine) versus that obtained with BV-AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine). SECONDARY OBJECTIVES: I. To compare overall survival (OS) in patients randomized to N-AVD versus BV-AVD. II. To compare event-free survival (EFS) in patients randomized to N-AVD versus BV-AVD. III. To compare the metabolic complete response (CR) rate at the end of treatment in patients randomized to N-AVD versus BV-AVD. IV. To compare the physician-reported treatment-related adverse event rates between arms stratified by age groups. V. To compare patient-reported symptoms using selected Patient Reported Outcome Common Toxicity Criteria for Adverse Events (PRO-CTCAE) items between arms stratified by age groups. VI. To compare the safety and tolerability of N-AVD versus that of BV-AVD. QUALITY OF LIFE OBJECTIVE: I. To compare between arms patient-reported fatigue, neuropathy and health-related quality of life over time (baseline, beginning of cycle 3, 4-8 weeks after the last dose of protocol therapy \[following last dose of study drug or radiation therapy, whichever is later\], and 1 and 3 years after randomization) using the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), and the PROMIS Global, respectively. BANKING OBJECTIVES: I. To bank specimens for future correlative studies. II. To bank positron emission tomography (PET)-computed tomography (CT) images for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV, dacarbazine IV, and nivolumab IV over 30 minutes on days 1 and 15. Patients may receive pegfilgrastim subcutaneously (SC) on days 2 and 16, or filgrastim SC or IV on days 6-10 and 21-25. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at the discretion of the treating physician. Patients also undergo peripheral blood specimen collection and CT, PET/CT and/or magnetic resonance imaging (MRI) on study. ARM II: Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, dacarbazine IV, and brentuximab vedotin IV over 30 minutes on days 1 and 15. Patients may receive pegfilgrastim SC on days 2 and 16, or filgrastim SC or IV on days 6-10 and 21-25. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at the discretion of the treating physician. Patients also undergo peripheral blood specimen collection and CT, PET/CT and MRI on study. After completion of study treatment and prior to disease progression, patients are followed up every 3 months for the first year, every 6 months for years 2 and 3, then annually until 10 years after registration. Patients are followed up at the time of progression and then annually until 10 years after registration. Patients who receive radiation therapy are followed up at 8-12 weeks after completion of radiation therapy.

Systemic Lupus Erythematosus

A Phase III, Randomized, Double-blind, Parallel-group, Placebo Controlled Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of IV Anifrolumab in Pediatric Participants 5 to < 18 Years of Age With Moderate to Severe Active Systemic Lupus Erythematosus (SLE) While on Background Standard of Care Therapy

This study aims to characterize the pharmacokinetics, pharmacodynamics, efficacy, and safety of Anifrolumab solution for infusion compared with placebo solution for infusion in pediatric participants with severe active systemic lupus erythematosus who are on background standard of care therapy. The study duration for a participant will be approximately 116 weeks, which includes: * Screening period of up to 30 days. * Part A consists of a four-week, single-blind, placebo-controlled, randomised, pharmacokinetic period. * Part B is a double-blind, placebo-controlled, randomised, safety/efficacy period lasting 48 weeks (for rollover participants from Part A) or 52 weeks (for de novo participants). * Part C is a 52-week open-label extension period. * Part D is a safety follow-up period. One safety visit at 12 weeks post last dose.

Ganglioneuroblastoma, Nodular, Neuroblastoma

A Pilot Study of Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide in the Post-Consolidation Setting for High-Risk Neuroblastoma

PRIMARY OBJECTIVE: I. To determine the feasibility of administering dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the frontline Post-Consolidation setting in patients with high-risk neuroblastoma who have undergone Induction and Consolidation therapy with tandem high-dose chemotherapy with stem cell rescue (ASCT). SECONDARY OBJECTIVES: I. To describe the toxicity profile of dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the Post-Consolidation setting. II. To describe the event-free survival and overall survival of patients who receive dinutuximab in combination with irinotecan and temozolomide, GM-CSF, and isotretinoin in the Post-Consolidation setting. EXPLORATORY OBJECTIVES: I. To describe the toxicity profiles associated with chemo-immunotherapy in the Post-Consolidation setting according to the type of prior therapy. II. To describe response to chemo-immunotherapy in the Post-Consolidation setting using the revised International Neuroblastoma Risk Classification (INRC) in patients with evaluable or measurable disease at study entry. III. To characterize immune and cytokine profiles in patients receiving Post-Consolidation chemo-immunotherapy. IV. To bank serial blood samples to investigate the relationship between factors related to the tumor, host, and immune environment and clinical outcomes in patients treated with chemo-immunotherapy. OUTLINE: Patients receive temozolomide orally (PO) or via enteral tube daily and irinotecan intravenously (IV) over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim subcutaneously (SC) or IV over 2 hours daily on days 6-12, and isotretinoin PO twice daily (BID) on days 8-21. Patients undergo multigated acquisition scan (MUGA) during screening. Patients also undergo magnetic resonance imaging (MRI), or computed tomography (CT), iobenguane I-123 (123I-MIBG), or fludeoxyglucose F-18-positron emission tomography (FDG-PET), bone marrow (BM) aspiration, and BM biopsy on study. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months.

Subject Presenting Wheeze, COPD, Asthma

A Pilot Study to Assess Aevice Medical Device for Detection of Wheeze in Pediatric Subjects and Use for Remote Auscultation

Cardiomyopathy

A Prospective and Retrospective Registry and Biomarker Study to Evaluate the Natural History of Pediatric Patients With Cardiomyopathy Due to MYBPC3 Mutations

• 650-209-8092
• mpollman@tenayathera.com

Dermatitis, Atopic

A Prospective Observational Study of Patients Receiving DUPIXENT® for Atopic Dermatitis

This is a prospective observational study conducted to (1) characterize the patients who receive DUPIXENT® for AD in a real world setting with respect to their medical history, socio-demographic and disease characteristics, and prior and concomitant treatments of AD; (2) characterize real world use patterns of DUPIXENT® for AD (eg, most commonly used regimens by line of therapy, reason for initiation of new treatments, concomitant therapies, treatment durations and reasons for discontinuation and/or switching); (3) assess the long-term effectiveness of DUPIXENT® in AD patients in a real world setting; (4) assess comorbid atopic conditions, patterns of use and effects of treatment in comorbid atopic conditions in patients who receive DUPIXENT® for AD; and (5) collect safety data on study participants

Embryonal Rhabdomyosarcoma, Fusion-Negative Alveolar Rhabdomyosarcoma, Spindle Cell/Sclerosing Rhabdomyosarcoma

A Prospective Phase 3 Study of Patients With Newly Diagnosed Very Low-Risk and Low-Risk Fusion Negative Rhabdomyosarcoma

PRIMARY OBJECTIVES: I. To evaluate the failure free survival (FFS) of patients with very low-risk (VLR) rhabdomyosarcoma (RMS) (fusion negative \[FN\], stage 1, clinical group \[CG\] I, MYOD1 wildtype \[WT\], TP53 \[WT\]) when treated with 24 weeks of vincristine and dactinomycin (VA). II. To evaluate the FFS of patients with low-risk (LR) RMS (FN, stage 1 CG II, or stage 2 CG I/II or CG III \[orbit only\], MYOD1 WT, TP53 WT) when treated with 12 weeks of vincristine, dactinomycin and cyclophosphamide (VAC) followed by 12 weeks of VA. SECONDARY OBJECTIVES: I. To evaluate the overall survival (OS) of patients with VLR RMS treated with 24 weeks of VA. II. To evaluate the OS of patients with LR RMS treated with 12 weeks of VAC followed by 12 weeks of VA. III. To demonstrate the feasibility of central molecular risk stratification of patients with newly diagnosed RMS in the context of a prospective clinical trial. EXPLORATORY OBJECTIVES: I. To collect blood and tissue samples for banking at baseline, during treatment, at the end of therapy, and at the time of progression to bank for future research. II. To describe the methylation array profile of patients with fusion negative, low-risk rhabdomyosarcoma. III. To describe the outcomes of patients with VLR or LR RMS and MYOD1 or TP53 mutations treated with intensified therapy. OUTLINE: Patients are assigned to 1 of 2 regimens based on clinical features. Patients with positive mutation status are transitioned to a third regimen, Regimen M. REGIMEN VA: Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). REGIMEN VAC/VA: Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Patients may also undergo radiation therapy at cycle 5. REGIMEN M: Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), bone scan, positron emission tomography (PET) scan and tumor biopsy throughout the study.

Embryonal Rhabdomyosarcoma, Fusion-Negative Alveolar Rhabdomyosarcoma, Spindle Cell/Sclerosing Rhabdomyosarcoma

A Prospective Phase 3 Study of Patients With Newly Diagnosed Very Low-Risk and Low-Risk Fusion Negative Rhabdomyosarcoma

PRIMARY OBJECTIVES: I. To evaluate the failure free survival (FFS) of patients with very low-risk (VLR) rhabdomyosarcoma (RMS) (fusion negative \[FN\], stage 1, clinical group \[CG\] I, MYOD1 wildtype \[WT\], TP53 \[WT\]) when treated with 24 weeks of vincristine and dactinomycin (VA). II. To evaluate the FFS of patients with low-risk (LR) RMS (FN, stage 1 CG II, or stage 2 CG I/II or CG III \[orbit only\], MYOD1 WT, TP53 WT) when treated with 12 weeks of vincristine, dactinomycin and cyclophosphamide (VAC) followed by 12 weeks of VA. SECONDARY OBJECTIVES: I. To evaluate the overall survival (OS) of patients with VLR RMS treated with 24 weeks of VA. II. To evaluate the OS of patients with LR RMS treated with 12 weeks of VAC followed by 12 weeks of VA. III. To demonstrate the feasibility of central molecular risk stratification of patients with newly diagnosed RMS in the context of a prospective clinical trial. EXPLORATORY OBJECTIVES: I. To collect blood and tissue samples for banking at baseline, during treatment, at the end of therapy, and at the time of progression to bank for future research. II. To describe the methylation array profile of patients with fusion negative, low-risk rhabdomyosarcoma. III. To describe the outcomes of patients with VLR or LR RMS and MYOD1 or TP53 mutations treated with intensified therapy. OUTLINE: Patients are assigned to 1 of 2 regimens based on clinical features. Patients with positive mutation status are transitioned to a third regimen, Regimen M. REGIMEN VA: Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). REGIMEN VAC/VA: Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Patients may also undergo radiation therapy at cycle 5. REGIMEN M: Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), bone scan, positron emission tomography (PET) scan and tumor biopsy throughout the study.

Spinal Muscular Atrophy (SMA)

A Prospective, Long-Term Registry of Patients With a Diagnosis of Spinal Muscular Atrophy (SMA)

This is a prospective, multi center, multinational, non-interventional observational study. All patients will be managed according to the clinical site's normal clinical practice, i.e., the diagnostic and clinical treatment/practice process that a clinician chooses according to their clinical judgement for an SMA patient. Clinical care will not be driven by the protocol. No additional visits or investigations will be performed beyond normal clinical practice. Patients will be followed for 15 years from enrolment or until death, whichever is sooner.

• 1-888-669-6682
• novartis.email@novartis.com

Spinal Muscular Atrophy (SMA)

A Prospective, Long-Term Registry of Patients With a Diagnosis of Spinal Muscular Atrophy (SMA)

This is a prospective, multi center, multinational, non-interventional observational study. All patients will be managed according to the clinical site's normal clinical practice, i.e., the diagnostic and clinical treatment/practice process that a clinician chooses according to their clinical judgement for an SMA patient. Clinical care will not be driven by the protocol. No additional visits or investigations will be performed beyond normal clinical practice. Patients will be followed for 15 years from enrolment or until death, whichever is sooner.

• 1-888-669-6682
• novartis.email@novartis.com

Short Bowel Syndrome

A Prospective, Multi-center Registry for Patients With Short Bowel Syndrome

Bile Acid Synthesis Disorders

A Prospective, Observational, Non-Interventional, Post-Marketing, Patient Registry to Collect Data on Routine Clinical Care in Patients Treated With Cholbam® (Cholic Acid)

No experimental intervention is involved. Patients in the Registry undergo clinical assessments and receive care as determined by the patient's treating physician.

Chondral Defect, Osteochondritis Dissecans (OCD), Articular Cartilage Defect, Articular Cartilage Disorder of Knee

A Prospective, Open-label, Randomized, Concurrent Active-controlled, Longitudinal, Multicenter, Phase 3 Clinical Study of the Safety and Efficacy of MACI in Patients Aged 10 to 17 Years With Symptomatic Chondral or Osteochondral Defects of the Knee

This is a 2-year prospective, multicenter, randomized, open-label, parallel group clinical trial; a total of 45 patients, ages 10 to 17 years, will be randomized to receive a 1-time treatment with MACI or microfracture (2:1, 30 MACI:15 microfracture). After meeting screening criteria at the initial visit, all patients will have a screening arthroscopy to further assess study eligibility. During the screening arthroscopy, patients will be further evaluated against entry criteria. Cartilage lesion size will be measured prior to any cartilage repair procedure and randomization. All patients who meet the eligibility criteria and are considered suitable for treatment in the study will have a cartilage biopsy taken prior to randomization to study treatment. Eligible patients will be randomized during the screening arthroscopy procedure to receive either MACI or microfracture treatment. Patients randomized to microfracture will undergo the procedure during the screening arthroscopy. All biopsied tissue will be sent to the Vericel manufacturing facility in Cambridge, Massachusetts, where the sample will be processed to isolate the autologous chondrocytes. Cells from patients randomized to the MACI group will be used in the preparation of the MACI implant; cells from patients randomized to the microfracture group will be cryopreserved. Patients randomized to treatment with MACI will return within 12 weeks of the screening arthroscopy to undergo the chondrocyte implantation procedure via arthrotomy. Patients are to follow a recommended postoperative rehabilitation program and compliance with the rehabilitation schedule will be monitored. Patients will be followed post-study treatment for 2 years (104 Weeks).

• 484-387-2257
• mchkolnik@vcel.com

Chondral Defect, Osteochondritis Dissecans (OCD), Articular Cartilage Defect, Articular Cartilage Disorder of Knee

A Prospective, Open-label, Randomized, Concurrent Active-controlled, Longitudinal, Multicenter, Phase 3 Clinical Study of the Safety and Efficacy of MACI in Patients Aged 10 to 17 Years With Symptomatic Chondral or Osteochondral Defects of the Knee

This is a 2-year prospective, multicenter, randomized, open-label, parallel group clinical trial; a total of 45 patients, ages 10 to 17 years, will be randomized to receive a 1-time treatment with MACI or microfracture (2:1, 30 MACI:15 microfracture). After meeting screening criteria at the initial visit, all patients will have a screening arthroscopy to further assess study eligibility. During the screening arthroscopy, patients will be further evaluated against entry criteria. Cartilage lesion size will be measured prior to any cartilage repair procedure and randomization. All patients who meet the eligibility criteria and are considered suitable for treatment in the study will have a cartilage biopsy taken prior to randomization to study treatment. Eligible patients will be randomized during the screening arthroscopy procedure to receive either MACI or microfracture treatment. Patients randomized to microfracture will undergo the procedure during the screening arthroscopy. All biopsied tissue will be sent to the Vericel manufacturing facility in Cambridge, Massachusetts, where the sample will be processed to isolate the autologous chondrocytes. Cells from patients randomized to the MACI group will be used in the preparation of the MACI implant; cells from patients randomized to the microfracture group will be cryopreserved. Patients randomized to treatment with MACI will return within 12 weeks of the screening arthroscopy to undergo the chondrocyte implantation procedure via arthrotomy. Patients are to follow a recommended postoperative rehabilitation program and compliance with the rehabilitation schedule will be monitored. Patients will be followed post-study treatment for 2 years (104 Weeks).

• 484-387-2257
• mchkolnik@vcel.com

HIV/AIDS

A Randomized Controlled Trial of Women Involved in Supporting Health (WISH), a Peer-Led Intervention to Improve Postpartum Retention in HIV Care

Despite significant progress in the reduction of perinatal transmission of HIV, there has been less attention to retaining women living with HIV (WLH) in care in the postpartum period. Retention in care particularly affects black and Hispanic women as they are disproportionately affected by the HIV epidemic in the United States (U.S.). In preliminary work, the investigators used HIV surveillance data from the Philadelphia Department of Public Health to examine the HIV care continuum of 561 women, 78% of whom were black, during pregnancy and up to two years postpartum (2005-2011). Only 38% of women received HIV care within 3 months after delivery, and retention remained poor at 1 (39%) and 2 (25%) years postpartum. Poor maternal retention in care also occurs in Mississippi, Georgia, and New York, demonstrating that this break in the HIV care continuum is widespread. Retaining WLH in care positively impacts their well-being and health postpartum and for years to come, which promotes not only their health but that of their newborns. Therefore, the long-term goal of this study is to decrease HIV disparities by increasing WLH's retention in care in the postpartum period. Presently, there are a limited number of evidence-based interventions aimed at improving retention in care for WLH. Through a critical review of research literature, the investigators found that interventions to improve retention in care have been implemented in low-resource countries, but studies in high-resource countries are lacking. In sub-Saharan Africa, the use of peers has resulted in significantly higher maternal retention and viral suppression compared to standard of care. Peers are WLH who remained engaged in HIV care postpartum, and provide education and support to WLH in the prenatal and postpartum periods. The investigators also conducted a series of qualitative interviews with WLH in the U.S. to evaluate factors contributing to poor retention in care postpartum, and to assess the acceptability and feasibility of a peer intervention in meeting women's needs. The results showed that women's primary motivation to engage in prenatal care is to keep their infant healthy, but that many of them experience significant life challenges that impede their ability to engage in care postpartum. However, they expressed great interest in receiving support from a peer to motivate sustained engagement in care postpartum. The investigators propose to test the efficacy of a theory-driven peer intervention, based on the integrated model of health behavior. The peer intervention, Women Involved in Supporting Health (WISH), is designed to increase self-efficacy, social support, self-regulatory behaviors, and outcome expectancy in order to improve retention in care and viral suppression postpartum. The intervention will consist of three face-to-face prenatal sessions, starting in early third trimester, and two face-to-face postpartum sessions scheduled up to three months postpartum. The prenatal sessions focus on knowledge that will address barriers to outcome expectancies and self-efficacy, and the postpartum sessions build on outcome expectancy and knowledge to develop skills tailored to adherence to antiretroviral therapy and engagement in HIV care. Between the sessions, the peer and the WLH will communicate via text messages, phone calls and/or video chat. The randomized controlled trial (RCT) will take place across Center for AIDS Research sites in Philadelphia, the District of Columbia, Atlanta, and Birmingham, where HIV infection rates remain disproportionally high among black and Hispanic women. A total of 260 pregnant WLH will be randomized to either WISH adherence or an attention-matched WISH parenting control group. The impact of this research will be the development of the first evidence-based peer intervention to address the pressing need to improve postpartum retention in HIV care and viral suppression of WLH in the U.S.

Lugano Classification Limited Stage Hodgkin Lymphoma AJCC v8

A Randomized Phase 3 Interim Response Adapted Trial Comparing Standard Therapy With Immuno-oncology Therapy for Children and Adults With Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma

PRIMARY OBJECTIVES: I. To compare the progression-free survival (PFS) of a standard chemotherapy approach versus an immunotherapy (IO) approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage classic Hodgkin lymphoma (cHL) who have a rapid early response (RER) as determined by position emission tomography post cycle 2 (PET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy. II. To compare the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) plus involved site radiation therapy (ISRT) in patients with newly diagnosed early stage cHL who have a slow early response (SER) as determined by PET2 after 2 cycles of ABVD chemotherapy. SECONDARY OBJECTIVES: I. To demonstrate non-inferiority of overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients who have a RER as determined by PET2 after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy. II. To evaluate the overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients who have a SER as determined by PET2 after 2 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy. III. To demonstrate non-inferiority of overall survival (OS) at 12 years of IO therapy versus standard therapy in early stage cHL patients. IV. To evaluate in patients with newly diagnosed early stage cHL the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) in the overall cohort, in the favorable risk cohort, and in the unfavorable risk cohort. V. To evaluate the event-free survival (EFS) at 12 years of patients undergoing standard chemotherapy versus an IO therapy approach (brentuximab vedotin and nivolumab). VI. To compare the physician-reported treatment-related adverse event (AE) rates between a standard chemotherapy approach and an IO therapy approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage cHL. VII. To compare patient-reported adverse events using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), stratified by age groups, therapeutic arms, and receipt of radiation therapy (RT) over time. VIII. To evaluate changes in patient-reported fatigue, cognitive functioning, and health-related quality of life (HRQoL), e.g., emotional, physical, and role functioning, by treatment arm, using validated adult and pediatric measurement systems. IX. To evaluate self-reported late morbidities (e.g., cardiovascular, pulmonary and endocrine) over time for children, adolescents and adults undergoing standard chemotherapy versus an IO therapy approach (brentuximab vedotin and nivolumab) with and without RT using measures from the St. Jude Lifetime Cohort Study (SJLIFE). X. To evaluate fludeoxyglucose F-18 (FDG)-position emission tomography (PET) measurements of metabolic tumor burden (MTV and total lesion glycolysis \[TLG\]) at PET at baseline (PET1) as a predictive marker of PFS. XI. To evaluate the associations between race/ethnicity and key outcomes including early response to therapy, PFS and OS. EXPLORATORY OBJECTIVES: I. To evaluate the PFS of a standard chemotherapy approach versus an IO therapy approach (brentuximab vedotin and nivolumab) in patients with newly diagnosed early stage cHL across different age groups (ages 5-11 years, 12-21 years, 22-39 years, 40-60 years). II. To bank specimens for future correlative studies. III. To assess concordance and discordance of rapid central review and local institutional review of FDG PET 5-point score (5-PS; previously referred to as Deauville score) at baseline PET1, interim PET2 and end of systemic therapy PET-end of systemic therapy (EST) SER. IV. To assess the association between PFS and the quantitative FDG-PET/computed tomography (CT) parameters (PET MTV, TLG, delta-standardized uptake value \[SUV\] and PET SUV-based quantitative surrogates \[qPET\] of visual qualitative 5-PS) on measurements by automated measurements using convolutional neural networks (CNNs) through artificial-intelligence (AI) machine learning in the entire population. V. To assess the agreement between quantitative FDG-PET/CT parameters obtained using AI and those based on measurements by a trained imaging physician. VI. To compare patient-reported adverse events (via pediatric \[Ped\]-PRO-CTCAE and PRO-CTCAE) to provider adverse event reporting. VII. To evaluate the association between self-reported race/ethnicity and social determinants of health. VIII. To evaluate the associations between race/ethnicity and post-progression/post-relapse overall survival. IX. To evaluate the completion rates of PRO and health-related quality of life (HRQoL) contact forms at 1 year off treatment for the first 450 eligible patients. X. To collect contact information from participants for future re-contact. OUTLINE: Patients are stratified by risk status (favorable versus unfavorable) and then all patients receive the ABVD regimen (doxorubicin hydrochloride intravenously \[IV\] over 3-15 minutes, bleomycin sulfate IV over at least 10 minutes, vinblastine sulfate IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients then undergo FDG-PET/CT or magnetic resonance imaging (MRI) and are identified as RER or SER. Patients with a favorable risk status and RER are randomized to Arm A or Arm B. Patients with a favorable risk status and SER are randomized to Arm C or Arm D. Patients with an unfavorable risk status and RER are randomized to Arm E or Arm F. Patients with an unfavorable risk status and SER are randomized to Arm G or Arm H. ARM A (RER, FAVORABLE): Patients receive ABVD IV for an additional 2 cycles on study. Each cycle lasts 28 days and ABVD is administered on days 1 and 15 of each cycle in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM B (RER, FAVORABLE): Patients receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 30 minutes once during each treatment cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM C (SER, FAVORABLE): Patients receive either the eBEACOPP regimen (doxorubicin hydrochloride IV over 3-15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on day 1, etoposide or etoposide phosphate IV over 2-4 hours on days 1-3, prednisone or prednisolone orally \[PO\] twice daily \[BID\] on days 1-14, procarbazine hydrochloride PO on days 1-7, bleomycin sulfate IV over at least 10 minutes on day 8, and vincristine sulfate IV on day 8 of each cycle) or the eBPDac regimen (doxorubicin hydrochloride IV 3-15 minutes on day 1, cyclophosphamide IV 30-60 minutes on day 1, etoposide or etoposide phosphate IV over 2-4 hours on days 1-3, prednisone or prednisolone PO BID on days 1-14, dacarbazine IV over 15-60 minutes on days 2 \& 3, bleomycin sulfate IV over at least 10 minutes on day 4, 5, 6, 7, or 8, vincristine sulfate IV on day 4, 5, 6, 7, or 8 of each cycle). Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Subsequently, patients undergo ISRT. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM D (SER, FAVORABLE): Patients receive brentuximab vedotin IV and nivolumab IV as in arm B followed by ISRT. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM E (RER, UNFAVORABLE): Patients receive AVD regimen (doxorubicin hydrochloride IV over 3-15 minutes, vinblastine IV, and dacarbazine IV over 15-60 minutes) on days 1 and 15 of each treatment cycle. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM F (RER, UNFAVORABLE): Patients receive treatment as in arm B. Patients also undergo FDG-PET, PET, PET-CT, PET-MRI, CT, and/or MRI throughout the trial. Patients may also undergo blood sample collection on trial. ARM G (SER, UNFAVORABLE): Patients receive treatment and imaging, and may undergo blood sample collection as in arm C. ARM H (SER, UNFAVORABLE): Patients receive treatment and imaging, and may undergo blood sample collection as in arm B. After completion of study treatment, patients are followed up every 3 months for the first year, then every 6 months for the second and third year, then annually until 12 years from date of registration.

Ann Arbor Stage IIB Hodgkin Lymphoma, Ann Arbor Stage IIIB Hodgkin Lymphoma, Ann Arbor Stage IVA Hodgkin Lymphoma, Ann Arbor Stage IVB Hodgkin Lymphoma, Childhood Hodgkin Lymphoma, Classic Hodgkin Lymphoma

A Randomized Phase 3 Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (cHL) in Children and Young Adults

PRIMARY OBJECTIVE: I. To assess the event free survival (EFS) of a novel regimen incorporating brentuximab vedotin (Bv; Adcetris) in the chemotherapy backbone of doxorubicin hydrochloride (doxorubicin) (Adriamycin), vincristine sulfate (vincristine), etoposide, prednisone and cyclophosphamide (Bv-AVEPC) in newly diagnosed high-risk classical Hodgkin lymphoma (cHL) compared to those treated with Adriamycin, bleomycin sulfate, vincristine sulfate, etoposide, prednisone, and cyclophosphamide (ABVE-PC). SECONDARY OBJECTIVES: I. To determine whether children/young adults with high-risk cHL treated with Bv-AVEPC have a higher rate of early response (determined by fludeoxyglucose F 18 \[FDG\]-positron emission tomography \[PET\]) and a reduction in protocol directed radiation therapy (RT) compared to those treated with ABVE-PC. II. To compare the rate of neuropathy (\>= grade 3) among patients treated on the Bv-AVEPC (experimental arm) to patients treated on the ABVE-PC (standard arm). EXPLORATORY OBJECTIVES: I. To validate and compare the Childhood Hodgkin International Prognostic Score (CHIPS) to conventional Ann Arbor stage (stages II B with bulk, III B, IV A or B) in predicting outcome in high-risk childhood cHL. II. To determine the incidence of preferentially expressed antigen in melanoma (PRAME) and testis-specific antigens in Epstein-Barr virus (EBV)- cHL tumors and the incidence of EBV antigens (Epstein-Barr nuclear antigen 1 \[EBNA1\], Epstein-Barr virus latent membrane protein 1 \[LMP1\], large multifunctional peptidase 2 \[LMP2\]) in EBV+ cHL tumors, with the goal of developing strategies to integrate cellular therapy into treatment for newly diagnosed high-risk cHL. (Biology) III. To incorporate qualitative visual FDG-PET into response-directed treatment algorithms and explore quantitative FDG-PET and computed tomography (CT) definitions of tumor burden and response for incorporation into next generation pediatric cHL risk-stratification schemes, exploring the extension of these algorithms to young adults. (Imaging) IV. To evaluate the reduction in normal tissue irradiation associated with the current treatment approach compared to the volume of historic involved field radiation therapy (IFRT) fields. (Radiation Therapy) V. To evaluate EFS and patterns of relapse following protocol-specified RT utilization and treatment volumes. (Radiation Therapy) VI. To characterize the extent of chemotherapy induced peripheral neuropathy (CIPN), as reported by patients and parent proxies, through serial administration of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-NTX). (Patient Reported Outcomes \[PRO\] of Peripheral Neuropathy and Health-Related Quality of Life) VII. To describe the Health-Related Quality of Life (HRQL) consequences of peripheral neuropathy over time by correlating total neuropathy scale scores with the individual items with the Child Health Ratings Inventories (CHRIs)-Global scale (e.g., physical health, pain, emotional functioning). (PRO of Peripheral Neuropathy and Health-Related Quality of Life) VIII. To perform a cross validation of the FACT-GOG-NTX with the Total Neuropathy Score-Pediatric Vincristine (TNS-PV) to determine the performance of both measures with the use of brentuximab vedotin in a limited institutional approach in children and adolescents with cHL. (PRO of Peripheral Neuropathy and Health-Related Quality of Life) IX. To assess the resource use and cost implications of Bv in combination with chemotherapy and radiotherapy (RT) for newly diagnosed high-risk cHL in children and young adults. (Economic) X. To estimate the risk of relapse among rapidly responding lesions (RRL) subjects that have at least one lesion that is Deauville 3 at PET 2. (Follow-up of Deauville score 3 lesions on FDG-PET imaging \[confirmed by central imaging review\]) XI. To characterize the pharmacokinetics of brentuximab vedotin in children \< 13 years of age. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I (ABVE-PC): Patients receive doxorubicin hydrochloride intravenously (IV) over on days 1-2, bleomycin sulfate IV or subcutaneously (SC) on days 1 and 8, vincristine sulfate IV on days 1 and 8, etoposide IV on days 1-3, prednisone orally (PO) twice daily (BID) or methylprednisolone IV on days 1-7, and cyclophosphamide IV on days 1 and 2. ARM II (Bv-AVEPC): Patients receive brentuximab vedotin IV on day 1. Patients also receive doxorubicin hydrochloride, etoposide, prednisone or methylprednisolone, and cyclophosphamide as in Arm I and vincristine sulfate IV on day 8. In both arms, treatment repeats every 21 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte simulating factor (GCSF) or equivalent is given on both arms. After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 30, 36, and 48 months.

Alveolar Rhabdomyosarcoma, Botryoid-Type Embryonal Rhabdomyosarcoma, Embryonal Rhabdomyosarcoma, Rhabdomyosarcoma, Sclerosing Rhabdomyosarcoma, Spindle Cell Rhabdomyosarcoma

A Randomized Phase 3 Study of Vincristine, Dactinomycin, Cyclophosphamide (VAC) Alternating With Vincristine and Irinotecan (VI) Versus VAC/VI Plus Temsirolimus (TORI, Torisel, NSC# 683864) in Patients With Intermediate Risk (IR) Rhabdomyosarcoma (RMS)

PRIMARY OBJECTIVE: I. To compare the event-free survival (EFS) of patients with intermediate-risk (IR) rhabdomyosarcoma (RMS) treated with surgery, radiotherapy, and vincristine (vincristine sulfate), dactinomycin, and cyclophosphamide (VAC) alternating with vincristine and irinotecan (irinotecan hydrochloride) (VI) (VAC/VI) with maintenance to that of patients treated with surgery, radiotherapy and VAC/VI plus temsirolimus with maintenance. SECONDARY OBJECTIVE: I. To compare the overall survival (OS) of patients with IR RMS treated with surgery, radiotherapy, and VAC alternating with VI with maintenance to that of patients treated with surgery, radiotherapy and VAC/VI plus temsirolimus with maintenance. EXPLORATORY OBJECTIVES: I. To compare the outcome of patients based on their FOXO1 fusion gene partner, by evaluating PAX3 versus (vs) PAX7 in all patients found to be FOXO1 fusion positive. II. To compare the outcome of patients based on their \[F18\]-fluorodeoxy-D-glucose-positron emission tomography (FDG-PET) response at week 9 (positive or negative), as assessed by Deauville criteria (5-point). III. To estimate the frequency of patients with circulating tumor deoxyribonucleic acid (DNA) (ctDNA) at diagnosis and subsequent time-points, and explore whether tumor-specific somatic variants are detectable in the ctDNA. IV. To compare the outcome of patients (VAC/VI with or without temsirolimus) who have received maintenance therapy on ARST1431 to those who received VAC/VI on ARST0531. OUTLINE: FEASIBILITY PHASE (THE FEASIBILITY PHASE IS COMPLETE, EFFECTIVE WITH AMENDMENT #1A): (\< 21 years old): This is a dose-escalation study of temsirolimus. Patients receive vincristine sulfate intravenously (IV) over 1 minute on day 1 of weeks 1-13, 16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, cyclophosphamide IV over 60 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 10, 16, 19, 25, 31, and 37, and temsirolimus IV over 30-60 minutes on days 1, 8, and 15. Patients also undergo radiation therapy (RT) beginning week 13 for up to 6.5 weeks. Courses with temsirolimus repeat every 21 days for 12 weeks in the absence of disease progression or unacceptable toxicity. EFFICACY PHASE: Patients are randomized to Regimen A or B. Patients with disease that is ARMS FOXO1 fusion negative (stage I, group I/II, stage 1, group III \[orbit\] or stage II, group I/II) are assigned to Regimen C. REGIMEN A (VAC/VI): Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks 1-13, 16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, cyclophosphamide IV over 60 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 10, 16, 19, 25, 31, and 37. Patients also undergo primary site RT beginning at week 13 or metastatic site RT beginning at week 43 for up to 6.5 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients then receive vinorelbine IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide orally (PO) once daily (QD) on days 1-28. Cycles repeats every 28 days for 24 weeks in the absence of disease progression or unacceptable toxicity. REGIMEN B (VAC/VI TEMSIROLIMUS): Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks 1-13, 16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, cyclophosphamide IV over 60 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 10, 16, 19, 25, 31, and 37 and temsirolimus IV over 30-60 minutes on day 1 of weeks 1-12 and 21-42. Patients also undergo RT as in Regimen A. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients then receive vinorelbine IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide PO QD on days 1-28. Cycles repeats every 28 days for 24 weeks in the absence of disease progression or unacceptable toxicity. MAINTENANCE PHASE (Patients in Regimen A or Regimen B): Patients receive vinorelbine IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 6 cycles. REGIMEN C (FOXO1 FUSION NEGATIVE): Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks 1-10 and 13-22, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, and 22, cyclophosphamide IV over 60 minutes on day 1 of weeks 1, 4, 7, and 10. Patients undergo RT beginning at week 13 for up to 6.5 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 2 years, every 6 months for 1 year, and then annually for up to 10 years.

Primary Mediastinal Large B-Cell Lymphoma

A Randomized Phase 3 Trial of Nivolumab (NSC# 748726) in Combination With Chemo-Immunotherapy for the Treatment of Newly Diagnosed Primary Mediastinal B-Cell Lymphoma

PRIMARY OBJECTIVE: I. To determine if nivolumab + chemo-immunotherapy results in a superior long term progression-free survival (PFS) (events defined as disease progression confirmed by central review or death) when compared with chemo-immunotherapy alone in patients with newly diagnosed primary mediastinal B-cell lymphoma. SECONDARY OBJECTIVES: I. To compare the rates of "efficacy-related event-free survival (EFS)" (eEFS) (events defined as progression, change in therapy due to finding that led to concern about efficacy, biopsy + disease after 6 cycles of therapy, or death) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL. II. To compare the rates of "therapy-related EFS" (tEFS) (events defined as relapse/progression, change in therapy for any reason, biopsy + disease after 6 cycles of therapy, secondary malignancy \[SMN\] or death) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL. III. To compare the rates of overall survival (OS) between chemo-immunotherapy alone and chemo-immunotherapy + nivolumab in patients with newly diagnosed PMBCL. IV. To establish the rate of a positive positron emission tomography (PET)-computed tomography (CT) (defined as Deauville score 4 or 5) at the completion of 6 cycles of nivolumab + rituximab (R)- cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/dose-adjusted (DA)-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH)-R and R-CHOP/DA-EPOCH-R in patients with newly diagnosed PMBCL and evaluate the prognostic significance of such a finding. EXPLORATORY OBJECTIVES: I. To bank radiology images for further studies. II. To bank specimens for future correlative studies. III. Characterize the immune profile of patients treated with nivolumab + chemo-immunotherapy to identify markers predictive of response. IV. Define the rate of complete response at the completion of initial planned therapy. OUTLINE: Patients are randomly assigned to backbone therapy or backbone therapy + nivolumab within each of 6 strata. The strata are determined by physician's choice of backbone (DA-EPOCH-R versus \[vs.\] R-CHOP vs. R-CHOP + RT) and whether or not the patient had 1 prior cycle of therapy. ARM A (DA-EPOCH-R): Patients receive prednisone or prednisolone orally (PO) once daily (QD) on days 1-5 and rituximab intravenously (IV) or rituximab and hyaluronidase human subcutaneously (SC) over 5 minutes on day 1 or 5. Patients also receive etoposide phosphate, doxorubicin hydrochloride, and vincristine sulfate IV over 96 hours on days 1-4 and cyclophosphamide IV over 30-60 minutes on day 5. Beginning 24-72 hours after completing cyclophosphamide, patients receive filgrastim or pegylated filgrastim SC daily until absolute neutrophil count (ANC) is \>= 500/uL after the expected nadir. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) during screening and as clinically indicated and alumbar puncture (LP) for cerebral spinal fluid (CSF) collection optionally during screening. Patients also undergo computed tomography (CT) or positron emission tomography (PET)/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study. ARM B (DA-EPOCH-R + NIVOLUMAB): Patients receive treatment as in Arm A. Patients also receive nivolumab IV over 30 minutes on day 1. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study. ARM C (R-CHOP): Patients receive prednisone or prednisolone PO QD on days 1-5 and rituximab IV or rituximab and hyaluronidase human SC over 5 minutes on day 1 or 5. Patients also receive cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV over 1-15 minutes or up to 60 minutes, and vincristine sulfate IV over 1 or up to 60 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles (5 if the patient had 1 prior cycle of treatment) in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study. ARM D (R-CHOP + NIVOLUMAB): Patients receive treatment as in Arm C. Patients also receive nivolumab IV over 30 minutes on day 1. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study. ARM E (R-CHOP + RADIOTHERAPY): Patients receive treatment as in Arm C. Within 6-8 weeks after completion of chemotherapy, patients undergo radiation therapy over 25 fractions. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study. ARM F (R-CHOP + RADIOTHERAPY + NIVOLUMAB): Patients receive treatment as in Arm D. Within 6-8 weeks after completion of chemotherapy, patients undergo radiation therapy over 25 fractions. Patients undergo ECHO during screening and as clinically indicated and LP for CSF collection optionally during screening. Patients also undergo CT or PET/CT throughout the trial. Additionally, patients undergo bone marrow biopsy and aspiration optionally during screening and as clinically indicated on study. Patients undergo blood sample collection on study. After completion of study treatment, patients are followed up every 3 months for year 1, every 6 months for years 2-3, and annually thereafter.

Alveolar Rhabdomyosarcoma, Botryoid-Type Embryonal Rhabdomyosarcoma, Embryonal Rhabdomyosarcoma, Metastatic Embryonal Rhabdomyosarcoma, Metastatic Rhabdomyosarcoma, Solid Alveolar Rhabdomyosarcoma, Spindle Cell Rhabdomyosarcoma, Spindle Cell/Sclerosing Rhabdomyosarcoma

A Randomized Phase 3 Trial of Vinorelbine, Dactinomycin, and Cyclophosphamide (VINO-AC) Plus Maintenance Chemotherapy With Vinorelbine and Oral Cyclophosphamide (VINO-CPO) vs Vincristine, Dactinomycin and Cyclophosphamide (VAC) Plus VINO-CPO Maintenance in Patients With High Risk Rhabdomyosarcoma (HR-RMS)

PRIMARY OBJECTIVE: I. To compare event-free survival (EFS) of patients with high-risk rhabdomyosarcoma (HR-RMS) treated with vinorelbine, dactinomycin and cyclophosphamide (VINO-AC) followed by 24 weeks of vinorelbine and oral cyclophosphamide (VINO-CPO) maintenance therapy to that of patients treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by 24 weeks of VINO-CPO maintenance therapy. SECONDARY OBJECTIVES: I. To assess the safety and feasibility of administering VINO-AC in newly diagnosed patients with HR-RMS. II. To describe the toxicity experience of patients with HR-RMS treated with VINO-AC compared to VAC. III. To compare overall survival (OS) of patients with HR-RMS treated with VINO AC followed by 24 weeks of VINO-CPO maintenance therapy to that of patients treated with VAC followed by 24 weeks of VINO-CPO maintenance therapy. IV. To compare objective radiologic response rates at week 12 between patients with HR-RMS treated with VINO-AC to those treated with VAC. V. To determine whether the addition of 24 weeks of VINO-CPO maintenance therapy improves EFS in patients with HR-RMS when compared to historical controls. VI. To determine the association between circulating tumor-derived deoxyribonucleic acid (ctDNA) levels at diagnosis and during initial chemotherapy and event-free survival (EFS) in patients with HR RMS. VII. To prospectively validate the prognostic impact of genomic variants in HR RMS. EXPLORATORY OBJECTIVE: I. To collect serial blood samples and tumor tissue for banking at baseline, during treatment, at the end of therapy, and at the time of progression for future tumor and liquid biopsy studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive vincristine sulfate intravenously (IV) on days 1, 8 and 15 of cycles 1-4, 7, 8, 11, and 12, and day 1 of cycles 5, 6, 9, 10, 13, and 14. Patients also receive dactinomycin IV over 1-15 minutes or IV push (IVP) over 1-5 minutes on day 1 of cycles 1-5, 8-10, and 11-14, and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40. ARM B: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8, vincristine sulfate IV on day 15, dactinomycin IV over 1-15 minutes or IVP over 1-5 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40. MAINTENANCE: All patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide orally (PO) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients in both arms undergo computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), x-ray imaging, and/or bone scan, as well as blood sample collection throughout the trial. Patients may also undergo bone marrow aspiration and/or biopsy as clinically indicated After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for years 2-3, and every 6 months for years 4-5.

B Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, B Acute Lymphoblastic Leukemia, BCR-ABL1-Like, Lymphoblastic Lymphoma, Mixed Phenotype Acute Leukemia, T Acute Lymphoblastic Leukemia

A Randomized Trial of Levocarnitine Prophylaxis to Prevent Asparaginase-Associated Hepatotoxicity in Adolescents and Young Adults Receiving Acute Lymphoblastic Leukemia Therapy

PRIMARY OBJECTIVE: I. To determine in a randomized manner whether the addition of levocarnitine prophylaxis to asparaginase-containing regimens will decrease the incidence of conjugated hyperbilirubinemia (\> 3 mg/dL) during ALL induction therapy for adolescents and young adults (adolescents and young adults \[AYAs\], age 15-39 years). SECONDARY OBJECTIVES: I. To examine the impact of levocarnitine prophylaxis on differences in the incidence of grade \>= 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations during ALL Induction. II. To compare rates of minimal residual disease (MRD) positivity at end of Induction and describe MRD+ by end of consolidation (EOC) in those receiving ALL induction chemotherapy with and without levocarnitine. EXPLORATORY OBJECTIVES: I. To compare rates of toxicity and associated dose reductions for chemotherapy administered with and without concomitant levocarnitine supplementation. II. To compare across study arms the peak levels during Induction of conjugated and total bilirubin, AST, ALT, and duration of conjugated hyperbilirubinemia from onset \> 3 mg/dL to =\< 3 mg/dL. III. To describe the efficacy of levocarnitine prophylaxis to reduce the incidence and/or severity of early patient-reported chemotherapy-induced peripheral neuropathy. IV. To describe the three-year event-free and overall survival (EFS/OS) in those treated with and without levocarnitine prophylaxis. V. To examine the association of age with asparaginase activity and asparaginase-associated hepatotoxicity during induction. VI. To examine the association of body-mass-index (BMI) percentile (or absolute BMI for young adults) with asparaginase activity and asparaginase-associated hepatotoxicity during induction. VII. To describe adherence by self-report and pill-count to oral levocarnitine in patients randomized to the intervention arm. VIII. To examine the association of plasma levels of carnitine and related markers with the efficacy of levocarnitine supplementation. IX. To determine the impact of inherited genetic variation on hepatoxicity and levocarnitine efficacy. OUTLINE: Patients are randomized to 1 of 2 arms (arm A vs. B). ARM A: Patients receive levocarnitine orally (PO) or intravenously (IV) as a bolus over 2 to 3 minutes or by infusion (over 10 to 30 minutes or per institutional standard) starting prior to standard of care induction chemotherapy with pegaspargase or calaspargase pegol and continued through the earlier of the last day of Induction phase (i.e., day prior to start of next phase) or Induction day 35. Patients may also undergo blood sample collection during screening and on study. ARM B: Patients receive standard of care induction chemotherapy with pegaspargase or calaspargase pegol on study. Patients may also undergo blood sample collection during screening and on study. ARM C (RESCUE): Patients in Arms A and B who develop conjugated hyperbilirubinemia \> 3 mg/dL during induction may receive levocarnitine rescue PO or IV as a bolus dose over 2 to 3 minutes or by infusion (over 10 to 30 minutes or per institutional standard) until resolution of conjugated hyperbilirubinemia =\< 3 mg/dL (or start of consolidation or the next treatment phase, whichever occurs first).

Aortic Stenosis, Coronary Artery Disease, Coronary Stenosis

A Randomized, Comparative Effectiveness Study of Staged Complete Revascularization With Percutaneous Coronary Intervention to Treat Coronary Artery Disease vs Medical Management Alone in Patients With Symptomatic Aortic Valve Stenosis Undergoing Elective Transfemoral Transcatheter Aortic Valve Replacement: The COMPLETE TAVR Study

• 604-875-4111
• brobinson@cci-cic.org

Necrotizing Enterocolitis

A Randomized, Double Blind, Parallel-group, Placebo Controlled Study to Evaluate the Efficacy and Safety of IBP-9414 in Premature Infants 500-1500g Birth Weight in the Prevention of Necrotizing Enterocolitis - The Connection Study

Necrotizing Enterocolitis

A Randomized, Double Blind, Parallel-group, Placebo Controlled Study to Evaluate the Efficacy and Safety of IBP-9414 in Premature Infants 500-1500g Birth Weight in the Prevention of Necrotizing Enterocolitis - The Connection Study

Cardiomyopathy, Hypertrophic

A Randomized, Double-blind, Placebo-controlled Clinical Study to Evaluate Mavacamten in Adolescents (Age 12 Years to < 18 Years) With Symptomatic Obstructive Hypertrophic Cardiomyopathy

• 855-907-3286
• Clinical.Trials@bms.com

Clostridium Difficile, Clostridium Difficile Infections, Clostridium Difficile Infection Recurrence, Clostridioides Difficile Infection, Clostridioides Difficile Infection Recurrence, CDI, C. Diff Infection, Recurrent Clostridium Difficile Infection, C.Difficile Diarrhea, Diarrhea Infectious

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of VE303 for Prevention of Recurrent Clostridioides Difficile Infection

• 857-706-1427
• Consortium02-ctinquiries@vedantabio.com

Seizures, Lennox Gastaut Syndrome

A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of Carisbamate (YKP509) As Adjunctive Treatment for Seizures Associated with Lennox-Gastaut Syndrome in Children and Adults, with Optional Open-Label Extension

The secondary objectives are: * To evaluate the efficacy of carisbamate (YKP509) as adjunctive treatment in reducing the total number of seizures compared with placebo in pediatric and adult subjects diagnosed with Lennox Gastaut Syndrome (LGS) * Evaluate the safety, tolerability of carisbamate in the LGS population * Evaluate steady-state pharmacokinetics of carisbamate in subjects with Lennox Gastaut.

• 201-421-3810
• bremes@sklsi.com

Ulcerative Colitis

A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Budesonide Extended-release Tablets n Pediatric Subjects Aged 5 to 17 Years With Active, Mild to Moderate Ulcerative Colitis

• 9082428287
• sandra.narain@bauschhealth.com

Ulcerative Colitis

A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Budesonide Extended-release Tablets n Pediatric Subjects Aged 5 to 17 Years With Active, Mild to Moderate Ulcerative Colitis

• 9082428287
• sandra.narain@bauschhealth.com

Focal Segmental Glomerulosclerosis

A Randomized, Multicenter, Double-blind, Parallel, Active-control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS

This is a randomized, multicenter, double-blind, parallel, active-control study. Approximately 300 patients aged 8 to 75 years (inclusive) will be enrolled in the study. The study will be conducted in approximately 300 study centers, globally. The investigational drug (sparsentan) is a dual-acting angiotensin receptor blocker and endothelin receptor antagonist. The active control is irbesartan. Patients who meet eligibility criteria will require washout from renin-angiotensin-aldosterone system (RAAS) blockers, if applicable prior to their first dose of study drug. Patients will be randomly assigned in a 1:1 ratio to receive either sparsentan or active control (irbesartan). After completing the double-blind portion of the study, patients may participate in the open-label extension for treatment with sparsentan if they meet eligibility criteria. Primary completion date represents the anticipated completion date of the double-blind portion of the study. Study completion date represents the anticipated completion date of the open-label extension portion of the study.

Acute Myeloid Leukemia (AML), Cancer

A Randomized, Open Label Phase 3 Study Evaluating Safety and Efficacy of Venetoclax in Combination With Azacitidine After Allogeneic Stem Cell Transplantation in Subjects With Acute Myeloid Leukemia (AML) (VIALE-T)

Desmoid Fibromatosis, Recurrent Desmoid Fibromatosis, Unresectable Desmoid Fibromatosis

A Safety, Pharmacokinetic and Efficacy Study of a y-Secretase Inhibitor, Nirogacestat (PF-03084014), in Children and Adolescents With Progressive, Surgically Unresectable Desmoid Tumors

PRIMARY OBJECTIVES: I. To estimate the 2-year progression-free survival (PFS) rate in patients with progressive, surgically unresectable desmoid tumor treated with nirogacestat. II. To describe the toxicities of nirogacestat in children and adolescents with desmoid tumor. III. To characterize the pharmacokinetics (PK) of nirogacestat in children and adolescents. SECONDARY OBJECTIVE: I. To determine the objective tumor response rate (ORR) of nirogacestat in children and adolescents with progressive, surgically unresectable desmoid tumor. EXPLORATORY OBJECTIVES: I. To collect blood, archival tumor samples and on-study/post-treatment tumor samples (if available) from patients enrolled on this trial to correlate various CTNNB1 and APC gene mutations and genomic signatures with tumor response and PFS. II. To explore the effect of nirogacestat on immune cells and immunoglobulin levels in the peripheral blood. III. To collect blood samples for banking at baseline, during treatment, and at the time of progression for future research. IV. To compare assessment of tumor response using Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria, and T2 and volumetric changes using magnetic resonance imaging (MRI). V. To utilize a tool developed to specifically assess patient reported outcomes (PROs) in adult patients with desmoid tumor (GOunder/DTRF DEsmoid Symptom/Impact Scale \[GODDESS\]) and the Patient Reported Outcomes Measurement Information System (PROMIS) to explore the relationship between PROs and tumor response and PFS. OUTLINE: Patients receive nirogacestat orally (PO) twice daily (BID) on days 1-28. Cycles repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) and computed tomography (CT) or MRI on study. Patients may also undergo x-ray imaging and blood sample collection on study. After completion of study treatment, patients are followed up at 30 days.

Aortic Stenosis

ACURATE IDE: Transcatheter Replacement of Stenotic Aortic Valve Through Implantation of ACURATE in Subjects InDicatEd for TAVR

Subjects will be enrolled at up to 85 centers in the United States, Canada, Europe, and Australia. There will be up to 2,820 subjects in ACURATE IDE. The ACURATE IDE study cohorts include the following. * Main Randomized Cohort: A prospective, multicenter, 1:1 randomized controlled trial (RCT; ACURATE versus a commercially available balloon-expandable SAPIEN 3™ Transcatheter Heart Valve or future iteration \[SAPIEN 3; Edwards Lifesciences LLC, Irvine, CA, USA\] or a commercially available self-expanding CoreValve® Transcatheter Aortic Valve Replacement System, CoreValve® Evolut™ R Recapturable TAVR System, EVOLUT™ PRO System, or future iteration \[CoreValve; Medtronic, Inc., Dublin, Ireland\]). There will be up to 1,500 subjects in the RCT. * Roll-In Cohort: A non-randomized roll-in phase with the test device. Centers that do not have implantation experience with the ACURATE neo™ Aortic Bioprosthesis (transfemoral delivery; Boston Scientific Corporation, Marlborough, MA, USA) will perform at least 2 roll-in cases before commencing treatment in the randomized cohort. Centers with prior experience with ACURATE are not required to do roll-in cases. Data from roll-in subjects will be summarized separately from the randomized cohort and will not be included in the primary endpoint analysis. * 4D CT Imaging Substudy: Selected centers with the ability to perform high quality 4D computer tomography (CT) scans will include subjects in a 4D CT Imaging Substudy to assess the prevalence of reduced leaflet mobility and hypoattenuated leaflet thickening (HALT) and the relationship, if any, to clinical events. Subjects will be randomized to test (ACURATE) and control device. * ACURATE Prime™ XL Nested Registry: A non-randomized, nested registry cohort of subjects who will receive the ACURATE Prime™ Transfemoral Aortic Valve System XL (ACURATE Prime XL Nested Registry). Participating centers will be a subset of United States centers that have enrolled subjects in ACURATE IDE. Data from subjects in this nested registry will be summarized separately from the randomized and roll-in cohorts. * ACURATE Extended Durability Study: An additional 1:1 randomized study (ACURATE versus a commercially available balloon-expandable SAPIEN 3™ Transcatheter Heart Valve or future iteration \[SAPIEN 3; Edwards Lifesciences LLC, Irvine, CA, USA\] or a commercially available self-expanding CoreValve® Transcatheter Aortic Valve Replacement System, CoreValve® Evolut™ R Recapturable TAVR System, EVOLUT™ PRO System, or future iteration \[CoreValve; Medtronic, Inc., Dublin, Ireland\]) including only subjects considered to be at low surgical risk. Subjects will receive ACURATE neo2 (S, M, or L valve sizes) or ACURATE Prime XL. Data from subjects in the Extended Durability Study will be summarized separately from other cohorts. * ACURATE Continued Access Study (CAS): An additional cohort of subjects receiving ACURATE neo2 (S, M, and L valve sizes) or ACURATE Prime XL. Data from subjects in the ACURATE CAS will be summarized separately from other cohorts and will be used to further assess performance and safety. All subjects implanted will be followed at baseline, peri- and post-procedure, at discharge or 7 days post-procedure (whichever comes first), 30 days, 6 months, and then annually for up to 10 years post-procedure. Enrolled subjects who do not have a study device implanted will be assessed through 1-year post-procedure for safety/adverse events.

Sickle Cell Disease

An Adaptive, Randomized, Placebo-controlled, Double-blind, Multi-center Study of Oral Etavopivat, a Pyruvate Kinase Activator in Patients With Sickle Cell Disease (HIBISCUS)

Etavopivat is designed to activate PKR and thereby modulate RBC metabolism by impacting two critical pathways in RBCs. The etavopivat clinical development program will investigate whether decreasing 2,3-DPG may help oxygen bind to hemoglobin (i.e. increasing oxygen affinity), and thereby increase ATP and impact RBC function. This study is a randomized, placebo-controlled, double-blind, multicenter Phase 2/3 study of patients age 12 to 65 years (inclusive), with sickle cell disease. There is one planned interim analyses in this study design. Initially, patients will be randomized at 1:1:1 to one of two dose levels of etavopivat or placebo. At the first interim analysis, one of the two etavopivat dose levels will be selected for the Phase 3 portion of the study, in which patients will be randomized at 1:1 to the selected etavopivat dose or placebo. Efficacy on hemoglobin will be evaluated at conclusion of the double-blind treatment period. Following completion of 52 weeks of double-blind treatment, patients may enter a 112-week etavopivat open-label extension period.

• (+1) 866-867-7178
• clinicaltrials@novonordisk.com

Lysosomal Acid Lipase Deficiency, Cholesterol Ester Storage Disease, Wolman Disease, Acid Cholesteryl Ester Hydrolase Deficiency, Type 2, Acid Lipase Deficiency, LIPA Deficiency, LAL-Deficiency

An Observational Disease and Clinical Outcomes Registry of Patients With Lysosomal Acid Lipase (LAL) Deficiency

Lysosomal Acid Lipase (LAL) Deficiency is a rare autosomal recessive lysosomal storage disorder (LSD) that is caused by a marked decrease of lysosomal acid lipase (LAL), the enzyme that breaks down cholesteryl esters and triglycerides in the lysosomes. Lysosomal Acid Lipase Deficiency presenting in infants (historically called Wolman Disease) is a medical emergency with rapid disease progression over a period of weeks that is typically fatal within the first 6 months of life. More commonly, LAL Deficiency presents in children and adults and this presentation has been historically called Cholesteryl Ester Storage Disease (CESD). In general, data on the prevalence of LAL Deficiency are limited, and the overall prevalence of the disease in the population is unclear. For all presentations, LAL Deficiency is associated with significant morbidity and mortality. Deficient LAL enzyme activity results in the lysosomal accumulation of cholesteryl esters and triglycerides. In the liver, this accumulation leads to hepatomegaly, increased hepatic fat content, transaminase elevation signaling chronic liver injury, and progression to fibrosis, cirrhosis, and complications of end stage liver disease. In the spleen, LAL Deficiency results in splenomegaly, anemia, and thrombocytopenia. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. Dyslipidemia is common with elevated low density lipoprotein (LDL) and triglycerides and low high density lipoprotein (HDL), associated with increased liver fat content and transaminase elevations. In addition to liver disease, patients with LAL Deficiency experience increased risk for cardiovascular disease and accelerated atherosclerosis. The LAL Deficiency Registry is a global registry, established to help improve care for patients through improved understanding of the disease and long-term effectiveness of therapeutic interventions including sebelipase alfa. As with other registries, which are becoming increasingly valuable for collecting information in large, heterogeneous, 'real world' populations, the LAL Deficiency Registry aims to provide evidence to help support patient care and inform clinical practice. This Registry is also being conducted, in part, to fulfill post-marketing commitments and requirements agreed to by the Sponsor as a condition for sebelipase alfa approval in the EU and the USA.

• 1-855-752-2356
• clinicaltrials@alexion.com

Alagille Syndrome

An Open Label Study to Evaluate the Long-term Safety and Efficacy of Odevixibat (A4250) in Patients With Alagille Syndrome (ASSERT-EXT)

This Phase 3, open-label, multi-center extension study will have two groups of participants: Cohort 1 (participants who participated in Study A4250-012 \[NCT04674761; ASSERT\] and meet the entry criteria for this study) and Cohort 2 (infants under 12 months of age) with ALGS. The study will consist of 2 or 3 periods: 1. A 'Treatment period' of 72 weeks (cohort 1) or 12 weeks (cohort 2). Participants will visit the clinic every 4 to 12 weeks and will receive a dose of 120 μg/kg odevixibat daily. 2. An 'Optional extension period' where participants who wish to continue receiving odevixibat after the 'treatment period' will have the opportunity to remain on treatment with visits every 16 weeks until the drug is commercially available. The optional extension is available provided continued use is supported by the risk-benefit profile, the participant has not been previously withdrawn or discontinued from the study, and the study is not terminated by the Sponsor. 3. A 'Safety follow-up period' of 4 weeks (cohort 1) or 2 weeks (cohort 2). The Safety Follow-up Period will not occur for those who remain on treatment in the optional extension period. Participants will need to complete an e-diary and questionnaires throughout the study (cohort 1 only). Participants will undergo blood samplings, urine collections (cohort 1 only), physical examinations, and clinical evaluations. They may continue some other medications, but the details need to be recorded.

• See e mail
• clinical.trials@ipsen.com

Autism

An Open-Label Extension Study of CM-AT for the Treatment of Children With Autism With All Levels of Fecal Chymotrypsin

Autism is clearly a significant cause of disability in the pediatric population. Treatment is based on the observation that many children with autism do not digest protein. CM-AT is a proprietary enzyme that is designed as a granulated powder taken three times daily.

Progressive Familial Intrahepatic Cholestasis (PFIC)

An Open-label Extension Study to Evaluate the Long-term Safety and Efficacy of Maralixibat in the Treatment of Subjects with Progressive Familial Intrahepatic Cholestasis (PFIC)

The study will be conducted at multiple sites in North America, Europe, Asia, and South America.

Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia

An Open-Label Feasibility Study to Assess the Safety and Pharmacokinetics of Enasidenib in Pediatric Patients With Relapsed/Refractory Acute Myeloid Leukemia (R/R-AML) With an Isocitrate Dehydrogenase-2 (IDH2) Mutation

PRIMARY OBJECTIVES: I. To determine the safety of treatment with enasidenib mesylate (enasidenib) administered at continuous daily oral dosing for a 28-day cycle up to 12 cycles in pediatric patients with IDH2-mutant relapsed/refractory (R/R)-acute myeloid leukemia (AML). II. To characterize the plasma pharmacokinetic (PK) profile of enasidenib in pediatric patients with IDH2-mutant R/R-AML. SECONDARY OBJECTIVES: I. To investigate the pharmacodynamic (PD) relationship of oncogenic metabolite 2-hydroxyglutarate (2-HG) to enasidenib treatment in pediatric patients with IDH2-mutant R/R-AML. II. To describe the clinical activity of enasidenib in pediatric patients with IDH2-mutant R/R-AML. OUTLINE: Patients receive enasidenib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and/or biopsy and collection of blood on study. After completion of study treatment, patients are followed up at 30 days, then periodically up to 1 year.

Bone Cancer

An Open-Label Phase 2 Study of Maintenance Therapy With OST31-164 After Resection of Recurrent Osteosarcoma

This is a Phase 2, open-label, multicenter, single-arm study in patients (12-39 years) with a recent history of pulmonary recurrent osteosarcoma that has been completely resected. Planned enrollment is a maximum of 45 patients who will receive OST31-164 as a single agent every 3 weeks for 48 weeks with 4 doses constituting 1 treatment cycle (12 weeks per cycle). Each patient will receive treatment at a dose of 1x109 CFU until week 48 or until disease progression, unacceptable toxicity, or the patient meets any other treatment discontinuation criteria. Following treatment discontinuation, all patients will enter a 3-year survival follow-up period. Exploratory evaluation of immune response will be conducted. If available, tissue from the recent resection will be sent to the COG Biobank for future genomic and pathologic analysis by the COG.

Acute Lymphocytic Leukaemia, Acute Myeloid Leukaemia Refractory, Myelodysplastic Syndromes, Blastic Plasmacytoid Dendritic Cell Neoplasia

An Open-label, First-in-human, Dose-escalation/Expansion Study of SAR443579 Administered as Single Agent by Intravenous Infusion in Adult and Pediatric Participants With Relapsed or Refractory Acute Myeloid Leukemia (R/R AML), B-cell Acute Lymphoblastic Leukemia (B-ALL), High Risk-myelodysplasia (HR-MDS), or Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Study duration per participant is 2.5 years.

• 800-633-1610
• Contact-US@sanofi.com

Central Precocious Puberty

An Open-Label, Single-Arm, Multi-Center, Phase 3 Study on the Efficacy, Safety, and Pharmacokinetics of Debio 4326, a Triptorelin 12-month Formulation, in Pediatric Participants Who Are Receiving Gonadotropin-Releasing Hormone Agonist Therapy for Central Precocious Puberty

• +41 21 321 01 11
• clinicaltrials@debiopharm.com

Heart Transplant Infection, Kidney Transplant Infection, Liver Transplant Infection, CMV

Assessment of CMV-specific T Cell Responses by Flow Cytometry With Intracellular Cytokine Staining to Predict CMV Infection Risk in Pediatric Solid Organ Transplant Recipients

Hematologic Disorder, Bleeding Disorder, Connective Tissue Disorder, Hemophilia, Thrombosis, Von Willebrand Diseases, Thrombophilia, Rare Bleeding Disorder, Platelet Disorder, Factor IX Deficiency, Factor VIII Deficiency, Thalassemia, Sickle Cell Disease

ATHN Transcends: A Natural History Cohort Study of the Safety, Effectiveness, and Practice of Treatment in People With Non-Neoplastic Hematologic Disorders

This is a longitudinal, natural history observational cohort study being conducted at approximately 150 ATHN-affiliated sites. Participants will be followed for a minimum of 15 years. Harmonized data elements will be collected at the time of enrollment, quarterly, annually, and ad hoc. Base data will be collected for all participants. Specific data will be collected for participants enrolled in cohort-specific Arms and Modules. Each participant will be assigned to a single cohort: Hemophilia, Von Willebrand Disease, Congenital Platelet Disorders, Rare Disorders, Bleeding Not Otherwise Specified (NOS), Thrombosis/Thrombophilia, or Non-Neoplastic Hematologic Conditions. Study Arms and study Modules may be developed to provision disease and/or disease specific insights related to stakeholders, including but not limited to pharmaceutical companies, ATHN, and Hemophilia Treatment Centers (HTCs). Arms may branch off into product-specific data collection via Modules to be collected during the study, in conjunction with planned study assessments. ATHN Transcends Principal Investigators Tammuella Chrisentery-Singleton, MD Ochsner Clinic Foundation American Thrombosis and Hemostasis Network Michael Recht, MD, PhD, MBA Yale University School of Medicine National Bleeding Disorders Foundation PUPs Arm: Principal Investigator: Shannon Carpenter, MD, MS University of Missouri Kansas City School of Medicine Children's Mercy Hospital ALTUVIIO Module: Co-Principal Investigators Shannon Carpenter, MD, MS University of Missouri Kansas City School of Medicine Children's Mercy Hospital Co-Principal Investigator Julie Jaffray, MD University of California San Diego Rady Children's Hospital San Diego INHIBIT Module: Co-Principal Investigators: Nicoletta Machin DO, MS Assistant Professor, Division of Hematology/Oncology Hemophilia Center of Western Pennsylvania University of Pittsburgh Medical Center Hemophilia Natural History Arm: Co-Principal Investigators: Tyler Buckner, MD, MSc Hemophilia and Thrombosis Center University of Colorado Anschutz Medical Campus Michael Recht, MD, PhD, MBA Yale University School of Medicine National Bleeding Disorders Foundation Rebinyn Module Co-Principal Investigators: Lauren Amos, MD Children's Mercy Hospital, Kansas City Guy Young, MD University of Southern California Children's Hospital Los Angeles Hemophilia Gene Therapy Outcomes Arm: Co-Principal Investigators: Janice M. Staber, MD Iowa Hemophilia and Thrombosis Center University of Iowa Stead Family Children's Hospital Ulrike M. Reiss, MD Hemophilia Treatment Center St. Jude's Children's Research Hospital Severe VWD Natural History Arm: Co-Principal Investigators: Robert F. Sidonio, Jr., MD, MSc Aflac Cancer and Blood Disorders Center, Hemophilia of Georgia Center for Bleeding and Clotting Disorders Angela C. Weyand, MD C.S. Mott Children's Hospital, University of Michigan Medical School, Ann Arbor Congenital Platelet Disorders Natural History Arm: Principal Investigator Sanjay Ahuja, MD Rainbow Babies \& Children's Hospital, Case Western Reserve University Glanzmann Thrombasthenia Module: Co-Principal Investigators: Divya Citla-Sridhar, MD University of Arkansas for Medical Sciences Arkansas Children's Hospital Meera Chitlur, MD Children's Hospital of Michigan Hemophilia Cohort This cohort includes three Arms and five Modules: Previously Untreated Patients (PUPs) Arm This is a pediatric focused Arm of PUPs with hemophilia A or B. ALTUVIIIO® Module The purpose is to investigate the safety and effectiveness of ALTUVIIIO® in PUPs with hemophilia A. INHIBIT Module This is an observational study assessing inhibitor formation in children with severe hemophilia A. Hemophilia Natural History Arm This Arm is investigating the safety, effectiveness, and practice of treatment for people with hemophilia. Hemlibra® Module All participants treated with Hemlibra® are eligible to participate. Rebinyn® Module The Rebinyn® Module is a prospective study in hemophilia B participants without inhibitors. Hemophilia Gene Therapy Outcomes Arm This Arm is investigating the safety and effectiveness of gene therapy in people with hemophilia. HEMGENIX® Module This is an observational study to characterize the effectiveness and safety of HEMGENIX® in participants with hemophilia B. Congenital Platelet Disorders (CPD) Natural History Arm: The CPD Arm is investigating the safety and efficacy of hemostatic therapies in the prevention or treatment of bleeding events in adult and pediatric participants with inherited congenital platelet disorders. Glanzmann Thrombasthenia (GT) Module: This Module is a study of bleeding symptoms, treatments, and treatment outcomes in patients with Glanzmann thrombasthenia. Von Willebrand Disease Cohort No arms or modules open at this time. Rare Disorders Cohort No arms or modules open at this time. Bleeding NOS No arms or modules open at this time. Thrombosis/Thrombophilia No arms or modules open at this time. Non-Neoplastic Hematologic Conditions No arms or modules open at this time.

• 800-360-2846
• cfedor@athn.org

Chronic Kidney Diseases, Bone Loss

Bone in CKD Alkali Response Pilot Trial (BICARb)

Chronic kidney disease is associated with bone loss and fractures in both children and adults, but bone protective therapies that are both proven and safe to use across the life-course in CKD are lacking. In this study, the investigators will conduct a pilot, double-blinded, randomized, placebo-controlled trial in 15 children and 88 adults evaluating the skeletal effects of potassium alkali therapy. These data will form the basis for a larger U01 proposal to determine the efficacy of potassium citrate on mitigating the effects of CKD on bone.

• 718-655-1120
• kreidy@montefiore.org

Acute Myeloid Leukemia, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Clinical Stage IV Esophageal Adenocarcinoma AJCC v8, Clinical Stage IV Gastric Cancer AJCC v8, Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8, Fallopian Tube Carcinoma, Hormone Receptor-Positive Breast Carcinoma, Invasive Breast Carcinoma, Lung Non-Small Cell Carcinoma, Lung Small Cell Carcinoma, Malignant Solid Neoplasm, Melanoma, Metastatic Prostate Carcinoma, Multiple Myeloma, Ovarian Carcinoma, Ovarian High Grade Serous Adenocarcinoma, Primary Peritoneal Carcinoma, Stage III Fallopian Tube Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Stage III Ovarian Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IV Fallopian Tube Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IV Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8, Triple-Negative Breast Carcinoma

Cancer Moonshot Biobank Research Protocol

PRIMARY OBJECTIVE: I. To support current and future investigations into drug resistance and sensitivity and other National Cancer Institute (NCI)-sponsored cancer research initiatives through the procurement and distribution of multiple longitudinal biospecimens and associated data from a diverse group of cancer patients who are undergoing standard of care treatment at NCI Community Oncology Research Program (NCORP) sites and other National Clinical Trials Network (NCTN) sites. SECONDARY OBJECTIVES: I. To provide a service of value to study participants and their medical providers through the performance of molecular profiling assays on tumor samples in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory and reporting of results to physicians and patients that they may opt to use in clinical management, including analysis of data for acquired resistance mechanisms. II. To enable the development of patient-derived models such as cell lines and xenografts for cancer researchers through the provision of biospecimens from up to 20% of study participants to the NCI's Patient Derived Models Repository (PDMR), a national resource available to investigators. III. To develop and implement robust approaches in patient and provider engagement to improve understanding of biobanking and its relationship to cancer research and increase representation of minority and underserved study participants in cancer research. IV. To develop increased capabilities in United States (U.S.) community hospitals and clinics for contribution to cancer research through biobanking activities. V. To enable secondary research generated from the project through deposition of data in public repositories such as Cancer Research Data Commons (CRDC), The Cancer Imaging Archive (TCIA) and database of Genotypes and Phenotypes (dbGAP), including clinical, radiology and pathology data with an emphasis on treatment response and outcome data. VI. To provide residual biospecimens and associated data from the project to the cancer research community. OUTLINE: Patients undergo collection of tissue samples during baseline and at time of disease progression and collection of blood samples throughout the study, including at time of disease progression. Patients with hematological malignancies also undergo collection of bone marrow and cerebral spinal fluid at the same time points. Archival blood and tissue, as well as bone marrow of patients with hematological malignancies, is also collected, if available. Additionally, patients may undergo computed tomography (CT), positron emission tomography (PET)/CT and/or magnetic resonance imaging (MRI) throughout the study, and may undergo paracentesis on study. Patient medical records are reviewed, and data is collected for at least 5 years.

Acute Myeloid Leukemia, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Clinical Stage IV Esophageal Adenocarcinoma AJCC v8, Clinical Stage IV Gastric Cancer AJCC v8, Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8, Fallopian Tube Carcinoma, Hormone Receptor-Positive Breast Carcinoma, Invasive Breast Carcinoma, Lung Non-Small Cell Carcinoma, Lung Small Cell Carcinoma, Malignant Solid Neoplasm, Melanoma, Metastatic Prostate Carcinoma, Multiple Myeloma, Ovarian Carcinoma, Ovarian High Grade Serous Adenocarcinoma, Primary Peritoneal Carcinoma, Stage III Fallopian Tube Cancer AJCC v8, Stage III Lung Cancer AJCC v8, Stage III Ovarian Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IV Fallopian Tube Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IV Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8, Triple-Negative Breast Carcinoma

Cancer Moonshot Biobank Research Protocol

PRIMARY OBJECTIVE: I. To support current and future investigations into drug resistance and sensitivity and other National Cancer Institute (NCI)-sponsored cancer research initiatives through the procurement and distribution of multiple longitudinal biospecimens and associated data from a diverse group of cancer patients who are undergoing standard of care treatment at NCI Community Oncology Research Program (NCORP) sites and other National Clinical Trials Network (NCTN) sites. SECONDARY OBJECTIVES: I. To provide a service of value to study participants and their medical providers through the performance of molecular profiling assays on tumor samples in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory and reporting of results to physicians and patients that they may opt to use in clinical management, including analysis of data for acquired resistance mechanisms. II. To enable the development of patient-derived models such as cell lines and xenografts for cancer researchers through the provision of biospecimens from up to 20% of study participants to the NCI's Patient Derived Models Repository (PDMR), a national resource available to investigators. III. To develop and implement robust approaches in patient and provider engagement to improve understanding of biobanking and its relationship to cancer research and increase representation of minority and underserved study participants in cancer research. IV. To develop increased capabilities in United States (U.S.) community hospitals and clinics for contribution to cancer research through biobanking activities. V. To enable secondary research generated from the project through deposition of data in public repositories such as Cancer Research Data Commons (CRDC), The Cancer Imaging Archive (TCIA) and database of Genotypes and Phenotypes (dbGAP), including clinical, radiology and pathology data with an emphasis on treatment response and outcome data. VI. To provide residual biospecimens and associated data from the project to the cancer research community. OUTLINE: Patients undergo collection of tissue samples during baseline and at time of disease progression and collection of blood samples throughout the study, including at time of disease progression. Patients with hematological malignancies also undergo collection of bone marrow and cerebral spinal fluid at the same time points. Archival blood and tissue, as well as bone marrow of patients with hematological malignancies, is also collected, if available. Additionally, patients may undergo computed tomography (CT), positron emission tomography (PET)/CT and/or magnetic resonance imaging (MRI) throughout the study, and may undergo paracentesis on study. Patient medical records are reviewed, and data is collected for at least 5 years.

Autism Spectrum Disorder

Cannabidivarin (CBDV) vs. Placebo in Children With Autism Spectrum Disorder (ASD)

There is a clear unmet need for new therapeutics to treat irritability in children with ASD that do not have the metabolic and weight adverse event profiles of the currently approved treatments. Cannabidivarin (CBDV) is a nonpsychoactive phytocannabinoid and a safe variant of Cannabidiol (CBD). It has no appreciable tetrahydrocannabinol (THC) \[less than 0.01%\], has been shown to have no impact on weight or metabolism, and improves both social and cognitive functioning in animal models of idiopathic and syndromal autism (Fragile X, Rett Syndrome, Angelman Syndrome). The CDC currently estimates 1 in 59 children have ASD. ASD is characterized by deficits in social communication, irritability, repetitive behaviors, impulsivity, temper tantrums, and high caregiver burden. Currently, the only FDA-approved medications for symptoms of ASD are aripiprazole and risperidone, both of which are indicated for irritability in pediatric ASD. These medications are effective but are associated with considerable side effects with long term treatment in this chronic developmental disorder, including weight gain, metabolic syndrome and the risk of type 2 diabetes, prolactin elevation and growth of breast tissue, extrapyramidal symptoms and the risk of tardive dyskinesia. The anticonvulsant divalproex sodium (valproate/VPA) also significantly reduces irritability and repetitive behaviors in individuals with ASD. Although VPA is efficacious for pediatric epilepsy and some symptoms of ASD, it also has significant side effects, including weight gain, sedation and nausea. CBDV, like VPA, is effective in the treatment of pediatric epilepsy, and ASD mouse models demonstrate potential mechanisms for treatment with CBDV, including potential therapeutic effects on repetitive behaviors, irritability, sociability, and quality of life, and the capacity to reduce inflammation. This study aims to examine the efficacy and safety of cannabidivarin (CBDV) with a primary aim of studying its effect on irritability in children with ASD. STUDY DESIGN: This is a 12-week randomized, double-blind study of CBDV vs. placebo in 100 child and adolescent subjects aged 5 to 18 years with a diagnosis of ASD.

• 914-315-4236
• casara.ferretti@einsteinmed.edu

Chronic Kidney Disease

Chronic Kidney Disease in Children Prospective Cohort Study (CKiD)

Since its inception in 2003, the scientific aims of CKiD have been to determine the risk factors for decline in kidney function and to define how progressive decline in kidney function impacts biomarkers of risk factors for cardiovascular disease; neurocognitive function and behavior; and growth failure and its associated morbidity. The goals have been extended to understand the impact of childhood CKD on: the risk factors for decline in kidney function in childhood and young adulthood; the development of cardiovascular disease in adolescence and young adulthood; the trajectories of markers of metabolic bone disease and the relationship to cardiovascular endpoints; and the social function, neurocognitive function and emotional well-being of adolescents and young adults and the relationship to successful transfer to adult nephrology care.

• 215-590-2449
• FurthS@email.chop.edu

Bronchiolitis

Comparison of Conventional Non-Invasive Ventilation and Neurally-Adjusted Ventilatory Assistance (NAVA) Non-Invasive Ventilation for the Treatment of Bronchiolitis

Bronchiolitis is a common diagnosis in pediatric hospitals and critical care units. Viral infection in younger patients often results in increased work of breathing, hypoxemia, impaired ventilation, and increased secretion burden. In some cases, treatment of severe respiratory failure includes intubation and mechanical ventilation. Current practice for patients with bronchiolitis who require hospital admission is to initially provide non-invasive ventilation to improve the patient's respiratory mechanics. This non-invasive respiratory support can range from simple nasal cannula, to high-flow nasal cannula, to non-invasive positive pressure ventilation. The high-flow nasal cannula (HFNC) provides warm, humidified, oxygen-enriched air. Therapy commonly is prescribed with a prescribed fraction of inhaled oxygen (FiO2) delivered at 1-2 L/kg/min. This helps to improve oxygenation as the high rate of flow can "wash-out" carbon dioxide in the upper airways and thus reduce the volume of dead space ventilation. Non-invasive ventilation (NIV) essentially provides a similar method of support as invasive ventilation without the use of endotracheal tube. Prescribed airway support is instead delivered non-invasively through a specialized nasal cannula or for larger children an occlusive facemask of appropriate size. The ventilator provides positive-end expiratory pressure (PEEP) with a prescribed delivery rate of a set inspiratory pressure (positive inspiratory pressure, or pressure control). This ventilator support enables the delivery of a set FiO2, helps maintain open airways to reduce atelectasis and allow for improved oxygenation with better V/Q matching, and improves work of breathing. The ventilator analyzes the flow generated by the patient's inspiratory effort and attempts to provide the prescribed positive inspiratory pressure at the time of the patient's own effort. One of the major drawbacks of non-invasive ventilation for young pediatric patients with bronchiolitis is the difficulty in achieving synchrony between patient effort and ventilator-delivered positive inspiratory pressure. This is secondary to the large air leak given the non-invasive apparatus and the low inspiratory flows generated by this patient population. Thus, the ventilator and patient are often dyssynchronous which may actually increase work of breathing and agitation while impeding on the ventilatory support provided. Neurally-Adjusted Ventilatory Assistance (NAVA) attempts to mitigate the harms of ventilator/patient dyssynchrony. This modality utilizes a specialized catheter placed into the esophagus, often via a nasogastric route, which has the capability of monitoring the electrical activity of the patient's diaphragm. This catheter can also be utilized to deliver feeds similarly to a basic nasogastric tube. The NAVA catheter monitors both the activation of the patient's diaphragm (indicating patient respiratory effort) and the strength of this activation in, referred to as the electrical activity of the diaphragm (Edi) and measured in millivolts (µV). Both human and animal studies have positively correlated the peak Edi values with work-of-breathing and demonstrated higher Edi values when respiratory pathology is present . Based on the Edi tracing, the ventilator can then deliver positive inspiratory pressure that is synchronous with both the patient's respiratory effort and proportional to the strength of this effort through a multiplier referred to as the NAVA level on the ventilator. This modality has been shown to improve patient agitation levels, reduce the need for sedating medications, and enhance synchrony in non-invasive ventilation modes. The current practice model of the investigators entails that patients with bronchiolitis who require more than 1.5 L/kg of HFNC or require non-invasive ventilation, whether via a conventional or NAVA modality, are managed in the Pediatric Intensive Care Unit (PICU). Both modalities for non-invasive ventilation (conventional and NAVA) are used routinely. Patient respiratory status is aggregated into a value known as the Respiratory Severity Score (RSS) which accounts for respiratory rate, dyspnea, retractions, and auscultatory findings adjusted for the age of the patient. The RSS value is a validated assessment tool with good interobserver reliability between Medical Doctors (MDs), Registered Nurses (RNs), and Respiratory Therapists (RTs). It is calculated on a 4-hour basis for all patients with bronchiolitis in the investigator's PICU and helps determine clinical improvement or deterioration and better guide decisions to increase or decrease support. While multiple physiologic studies demonstrate a reduced work of breathing with invasive NAVA ventilation, the majority of pediatric studies focused on non-invasive NAVA ventilation were designed to determine improvements in patient/ventilator synchronization. The investigators' project aims are two-fold. The study team hypothesizes that Edi levels and RSS scores will positively correlate for patients with bronchiolitis, allowing for another metric to gauge clinical status. The investigators also hypothesizes that the improved synchronization on NAVA-NIV may improve respiratory status as measured by RSS scores and Edi levels, reduce further escalations in respiratory support, shorten the length of non-invasive ventilation required, and reduce intubation rates. This improvement will be more substantial when transitioning from HFNC to NAVA-NIV compared to transitioning to conventional-NIV.

• 2017459825
• jweingar@montefiore.edu

Asthma

Effect of IL-4RαR576 Polymorphism on Response to Dupilumab in Asthma, a Genotype-stratified, Randomized, Placebo- Controlled Trial

This is a double-blind, randomized, placebo-controlled parallel-group phase 4 clinical trial. Patients will be genotyped and categorized as those with: 1) the wild type allele (Q576/Q576), 2) heterozygous allele (Q576/R576), or 3) homozygous mutant allele (R576/R576); the genotype associated with more severe disease. After a run-in period of 2-12 weeks to determine asthma control, subjects who fulfill all inclusion/exclusion criteria will be randomized to receive either subcutaneous Dupilumab or placebo (1:1 randomization allocation ratio). This study addresses fundamental mechanisms by which the IL-4Rα-R576 variant drives the TH2/TH17 disease endotype and the influence of this variant on response to Dupilumab therapy. It brings together individuals with deep clinical and scientific expertise in allergic diseases, including epidemiology, genetics, inflammation, and tolerance mechanisms to investigate, in a coordinated strategy, the hypothesis that the IL-4Rα-R576 variant drives TH2/TH17 cell inflammation by subverting allergen-specific iTreg cells into TH17 cells. Asthmatics bearing this endotype will be particularly likely to favorably respond to Dupilumab therapy by virtue of its prevention of iTreg cell reprogramming into TH17-like cells, potentially leading to their long-term stability and potential for sustained immune tolerance.

• 857-218-5336
• Wanda.Phipatanakul@childrens.harvard.edu

Lupus Nephritis

Efficacy & Safety of Pharmacokinetically-Driven Dosing of Mycophenolate Mofetil for the Treatment of Pediatric Proliferative Lupus Nephritis- A Double-Blind Placebo Controlled Clinical Trial

Subjects will be randomized 1:1 to receive blinded treatment with MMFPK or MMFBSA for up to 53 weeks. The primary endpoint, clinical remission of LN, is measured at the end of Part 1 at week 26. Subjects in the MMFBSA arm who have only partial renal response (PRR) at the end of Part 1 will newly receive MMFPK upon entering Part 2 of the study (week 26 - 53). Subjects with complete renal responses (CRR) at the end of Part 1 will continue the same dosing regimen of MMF (MMFBSA or MMFPK) in Part 2 as was given in Part 1 of the study. Subjects in the MMFPK arm with PRR at the end of Part 1 will enter Part 2 and continue in the MMFPK arm. Subjects who are LN non-responders by the end of Part 1 at week 26 will be considered treatment failures and discontinued from the study intervention. All subjects who are discontinued from the study intervention for reasons of efficacy or safety will receive LN treatment and monitoring as per the treating physician's decision. However, these subjects will be asked to participate in study visits at weeks 26 and 53/End of Study.

• 513-803-2118
• plumm@cchmc.org

Bronchiolitis Acute Viral

Eliminating Monitor Overuse (EMO) Hybrid Effectiveness-Deimplementation Trial

• 267-426-2901
• bonafide@chop.edu

Malignant Neoplasm

EROS: Engendering Reproductive Health Within Oncologic Survivorship

PRIMARY OBJECTIVES: I. To evaluate the success of the implementation of reproductive health programming (Didactics, Engendering Reproductive Health Within Oncologic Survivorship \[EROS\] Reproductive Health Assessment and EROS Trial Algorithm) among reproductive aged females (15-55) with cancer. SECONDARY OBJECTIVES: I. To assess the degree of discrepancy between patients and their clinicians in estimates of significance of the reproductive health goals for the patient. II. To evaluate baseline and follow-up reproductive health assessments for trends in reproductive health choices relating to oncofertility, oncocontraception and pregnancy over the 2-year study period. III. To identify clinical and demographic factors that predict the adequacy of reproductive health care management. TERTIARY OBJECTIVES: I. To perform a longitudinal study following endocrine markers of fertility in a cohort of the first 200 registered EROS trial patients who agree to participate. II. To perform a longitudinal study of sexual function using the Patient-Reported Outcomes Measurement Information System (PROMIS) sexual function survey in all subjects participating in the EROS Trial. OUTLINE: Participating institutions are randomized to 1 of 2 arms. Patients are assigned to a study arm depending on the institutional assignment. ARM A: Patients undergo usual standard practice related to reproductive health. ARM B: Patients undergo reproductive health program comprising didactics, reproductive health assessment and navigating algorithm, and network development. After completion of study intervention, patients are followed up periodically.

Medulloblastoma, Medulloblastoma, Non-WNT/Non-SHH

Evaluation of Digoxin for Relapsed Non-WNT, Non-SHH Medulloblastoma

• 813-745-6250
• Jessica.Crimella@moffitt.org

Asthma in Children

Evaluation of the Asthma Management Program to Promote Activity for Students in Schools (Asthma-PASS)

Investigators will conduct a cluster-randomized controlled trial with 416 children ages 5-11 years with persistent or uncontrolled asthma from 26 Bronx schools. Schools will be randomly assigned to either (1) the Asthma-PASS intervention or an asthma management (AM) comparison group. Both groups will participate in an existing classroom-based daily activity program. Enrollment will occur over 4 consecutive school years with 6-8 schools joining the study each year. The investigators will assess the effectiveness of Asthma-PASS in reducing asthma morbidity, and improving PA as well as additional clinical and functional outcomes. The investigators will also identify potential mediators and moderators of the intervention effect. They will evaluate the process of intervention implementation by applying the RE-AIM framework.

Rhabdomyosarcoma

Evolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma

• 813-745-6250
• Jessica.Crimella@moffitt.org

Osteosarcoma

Functional Outcomes in Patients Who Undergo Upfront Surgical Resection for High-Grade Osteosarcoma of the Extremity: A Pilot Study

This prospective, non-randomized pilot study will assess patient-reported functional outcomes of upfront surgical resection in patients with newly diagnosed, biopsy-proven, localized osteosarcoma of the extremity or the pelvis. Following biopsy, all patients will undergo wide excision of the tumor followed by systemic multi-agent cytotoxic chemotherapy consisting of a regimen at least equivalent to the standard of care of high dose Methotrexate, Doxorubicin, and Cisplatin (MAP). Patients and/or their parent/guardian will be administered PROMIS (Patient-Reported Outcomes Measurement Information System) questionnaires, while surgeons will be administered the Musculoskeletal Tumor Society (MSTS) questionnaire at various timepoints through the first year post-surgery.

• 718-741-2356
• rzylber@montefiore.org

DiGeorge Syndrome, 22q11.2 Deletion Syndrome

Genetic Modifiers of 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome is a disorder caused by the deletion of a small piece of chromosome 22. Most people with this disorder are missing a sequence of about 3 million DNA building blocks on chromosome 22 within each cell. This disorder affects many areas of the body. People with 22q11.2 deletion syndrome may have heart defects, immune deficiency, kidney abnormalities, hearing loss, and cleft palate or other facial deformities. Many children experience developmental delays and learning disabilities, and they have an increased risk of developing mental illnesses, including schizophrenia, depression, anxiety, and bipolar disorder. All people with 22q11.2 deletion syndrome are missing the same sequence of DNA, but the severity of this disorder varies widely; some people are diagnosed with multiple health and developmental problems, while others experience very few symptoms. In some people, the symptoms may be so minimal that they are not even aware they have 22q11.2 deletion syndrome. This study will examine genetic material-either from blood or saliva-among people with 22q11.2 deletion syndrome. Participants will attend one study visit and undergo either blood or saliva collection. By analyzing the DNA sequences of participants, the study will aim to identify any genetic variations that may affect the severity of 22q11.2 deletion syndrome.

• 914-329-4653
• bernice.morrow@einsteinmed.edu

Congenital Heart Disease

Implementing Models for Mechanical Circulatory Support Presurgical Assessment in Congenital Heart Disease Treatment

Congenital heart disease (CHD) remains the most common type of major congenital malformation and the leading cause of mortality from birth defects \[1-4\]. Advances in effective treatment for these lesions have significantly extended the lifespan of affected patients, especially for the most complex subtypes of disease. However, these patients are at higher risk of heart failure (HF) secondary to longer life expectancy. This includes patients with a systemic right ventricle and a single ventricle circulation palliated by a Fontan procedure \[5, 6\]. HF has been documented in up to 30% of patients with a systemic right ventricle and 40% of patients who have had a Fontan procedure \[7\]. Ventricular assist devices (VAD) are implanted in patients with HF to improve cardiac output and prolong life. VAD remains underutilized in patients with CHD and HF in part due to the highly variable anatomy in this population. This is true despite outcomes having been shown to be the same for VAD placement in patients with and without CHD \[8-10\]. In the absence of VAD placement, however, wait list mortality for patients with CHD is higher than for those patients without CHD \[11, 12\]. Advances in imaging techniques have allowed early diagnosis of CHD as well as anatomic assessment prior to surgical procedures. Given the significant yet often subtle anatomic differences between CHD patients, it is a substantial challenge to thoroughly depict all of the components of a complex patient's cardiac anatomy in a two-dimensional imaging dataset. An innovative technology that is being used with more enthusiasm in the medical field, is three-dimensional (3D) printing. The investigator and the research team have previously reported on the best technique that should be used to create 3D printed cardiac models from MRI and the subtypes of complex CHD's for which 3D printing should be utilized \[13-16\]. 3D printing allows creation of patient specific physical anatomic models from a patient's own imaging data. These models provide a physical guide to patient-specific anatomic features that often make VAD and cannula placement challenging in patients with CHD \[17\]. Factors such as complex cardiac anatomic malformations, heavy trabeculations or a severely dilated ventricle can distort the usual anatomic landmarks used to identify the best position for cannula placement. The primary goal is to establish the utility of this advanced imaging technique, which provides a much more comprehensive understanding of complex congenital cardiac anatomy. The investigator hypothesizes that 3D printed models will allow more informed preoperative planning with a clearer understanding of the best site for inflow and outflow cannula and VAD placement leading to better surgical preparedness, less operating room time and improved patient outcomes. AIM 1: To assess if a 3D printed cardiac model improves perceived visualization of VAD and cannula placement sites in CHD-HF patients as compared to 2D imaging. The study will prospectively enroll CHD-HF patients at multiple centers and randomize to Group A (3D printed models will be used for pre-VAD planning) or Group B (no model-controls). For both Groups, all of the cardiothoracic surgeons at the participating center will complete a questionnaire after reviewing 2D imaging data. For Group A, a survey will also be administered after reviewing a patient specific 3D model. The primary outcome measure will be better perceived visualization of cannula and VAD sites. The investigator hypothesizes that the 3D model will more clearly demonstrate sites of cannula and VAD placement as compared to 2D imaging. AIM 2: To determine if perioperative factors and outcomes improve in CHD-HF patients with use of a 3D printed model versus traditional imaging in VAD placement planning. Clinical characteristics will be collected at time of enrollment including primary diagnosis and indication for VAD. After VAD placement, information regarding the intraoperative and postoperative course will be collected including surgical cardiopulmonary bypass time (CPB) and need for cannula repositioning. Longer CPB increases morbidity and mortality and is associated with intensive care readmission in patients after LVAD placement \[18-20\]. The primary measures of improvement will be CPB. The investigator hypothesizes that the improved preoperative planning using 3D models will lead to a decrease in CPB time. The skill with which patient specific CHD anatomy for pre-procedural planning is assessed must be improved, especially for the most complex patients. To confirm the clinical benefit of 3D printed models in pre-surgical planning and justify their use in routine care, multicenter clinical trials must be conducted. As an expert in the field of 3D imaging in cardiac disease, the investigator is well poised to lead this body of research. The goal is to become well versed in conducting high quality multicenter studies and to become facile in survey tool design through this K23 proposal. The investigator will then design a prospective multicenter study for an independent R01 proposal focused on assessing the utility of 3D models in pre-procedural planning for all complex congenital heart diseases. Investigating and reporting on these findings will result in a paradigm shift in what one considers "standard of care" for advanced imaging offered to our most complex CHD patients.

• 212-305-8509
• kf2549@cumc.columbia.edu

Congenital Heart Disease

Implementing Models for Mechanical Circulatory Support Presurgical Assessment in Congenital Heart Disease Treatment

Congenital heart disease (CHD) remains the most common type of major congenital malformation and the leading cause of mortality from birth defects \[1-4\]. Advances in effective treatment for these lesions have significantly extended the lifespan of affected patients, especially for the most complex subtypes of disease. However, these patients are at higher risk of heart failure (HF) secondary to longer life expectancy. This includes patients with a systemic right ventricle and a single ventricle circulation palliated by a Fontan procedure \[5, 6\]. HF has been documented in up to 30% of patients with a systemic right ventricle and 40% of patients who have had a Fontan procedure \[7\]. Ventricular assist devices (VAD) are implanted in patients with HF to improve cardiac output and prolong life. VAD remains underutilized in patients with CHD and HF in part due to the highly variable anatomy in this population. This is true despite outcomes having been shown to be the same for VAD placement in patients with and without CHD \[8-10\]. In the absence of VAD placement, however, wait list mortality for patients with CHD is higher than for those patients without CHD \[11, 12\]. Advances in imaging techniques have allowed early diagnosis of CHD as well as anatomic assessment prior to surgical procedures. Given the significant yet often subtle anatomic differences between CHD patients, it is a substantial challenge to thoroughly depict all of the components of a complex patient's cardiac anatomy in a two-dimensional imaging dataset. An innovative technology that is being used with more enthusiasm in the medical field, is three-dimensional (3D) printing. The investigator and the research team have previously reported on the best technique that should be used to create 3D printed cardiac models from MRI and the subtypes of complex CHD's for which 3D printing should be utilized \[13-16\]. 3D printing allows creation of patient specific physical anatomic models from a patient's own imaging data. These models provide a physical guide to patient-specific anatomic features that often make VAD and cannula placement challenging in patients with CHD \[17\]. Factors such as complex cardiac anatomic malformations, heavy trabeculations or a severely dilated ventricle can distort the usual anatomic landmarks used to identify the best position for cannula placement. The primary goal is to establish the utility of this advanced imaging technique, which provides a much more comprehensive understanding of complex congenital cardiac anatomy. The investigator hypothesizes that 3D printed models will allow more informed preoperative planning with a clearer understanding of the best site for inflow and outflow cannula and VAD placement leading to better surgical preparedness, less operating room time and improved patient outcomes. AIM 1: To assess if a 3D printed cardiac model improves perceived visualization of VAD and cannula placement sites in CHD-HF patients as compared to 2D imaging. The study will prospectively enroll CHD-HF patients at multiple centers and randomize to Group A (3D printed models will be used for pre-VAD planning) or Group B (no model-controls). For both Groups, all of the cardiothoracic surgeons at the participating center will complete a questionnaire after reviewing 2D imaging data. For Group A, a survey will also be administered after reviewing a patient specific 3D model. The primary outcome measure will be better perceived visualization of cannula and VAD sites. The investigator hypothesizes that the 3D model will more clearly demonstrate sites of cannula and VAD placement as compared to 2D imaging. AIM 2: To determine if perioperative factors and outcomes improve in CHD-HF patients with use of a 3D printed model versus traditional imaging in VAD placement planning. Clinical characteristics will be collected at time of enrollment including primary diagnosis and indication for VAD. After VAD placement, information regarding the intraoperative and postoperative course will be collected including surgical cardiopulmonary bypass time (CPB) and need for cannula repositioning. Longer CPB increases morbidity and mortality and is associated with intensive care readmission in patients after LVAD placement \[18-20\]. The primary measures of improvement will be CPB. The investigator hypothesizes that the improved preoperative planning using 3D models will lead to a decrease in CPB time. The skill with which patient specific CHD anatomy for pre-procedural planning is assessed must be improved, especially for the most complex patients. To confirm the clinical benefit of 3D printed models in pre-surgical planning and justify their use in routine care, multicenter clinical trials must be conducted. As an expert in the field of 3D imaging in cardiac disease, the investigator is well poised to lead this body of research. The goal is to become well versed in conducting high quality multicenter studies and to become facile in survey tool design through this K23 proposal. The investigator will then design a prospective multicenter study for an independent R01 proposal focused on assessing the utility of 3D models in pre-procedural planning for all complex congenital heart diseases. Investigating and reporting on these findings will result in a paradigm shift in what one considers "standard of care" for advanced imaging offered to our most complex CHD patients.

• 212-305-8509
• kf2549@cumc.columbia.edu

Acute Lymphoblastic Leukemia, B Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia, T Acute Lymphoblastic Leukemia

International Phase 3 Trial in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Testing Imatinib in Combination With Two Different Cytotoxic Chemotherapy Backbones

PRIMARY OBJECTIVE: I. To compare disease-free survival (DFS) of standard risk (SR) pediatric Philadelphia chromosome (Ph)+ acute lymphoblastic leukemia (ALL) treated with continuous imatinib mesylate (imatinib) combined with either a high-risk Children's Oncology Group (COG) ALL chemotherapy backbone or the more intensive European (Es)PhALL chemotherapy backbone. SECONDARY OBJECTIVES: I. To compare DFS of SR pediatric Ph+ and ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. II. To determine the feasibility of administration of imatinib after allogeneic hematopoietic stem cell transplantation (HSCT) in high risk (HR) Ph+ ALL patients. III. To determine event-free survival (EFS) of HR pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib. IV. To compare rates of grade 3 or higher infections in standard risk (SR) Ph+ ALL patients between the two randomized arms. V. To evaluate EFS and overall survival (OS) of all eligible Ph+ALL patients enrolled on the study. VI. To evaluate OS in SR Ph+ ALL patients. VII. To evaluate OS in HR Ph+ ALL patients. VIII. To evaluate EFS and OS of all eligible ABL-class fusion positive ALL patients enrolled on the study. EXPLORATORY OBJECTIVES: I. To describe the toxicities associated with post-HSCT administration of imatinib in HR Ph+ALL patients. II. To evaluate the long-term toxicities in SR Ph+ ALL patients treated with chemotherapy plus imatinib (no transplant), overall and between both randomized arms. III. To determine prognostic significance of minimal residual disease (MRD) in Ph+ ALL at various time points during therapy. IIIa. To evaluate MRD in HR patients just prior to HSCT and then at regular intervals post-HSCT and explore the association of these measurements with long-term outcome. IIIb. To evaluate concordance of MRD assessments made by IGH-T cell receptor (TCR) polymerase chain reaction (PCR) assay and next generation sequencing (NGS) assays. IV. To determine and validate if IKZF1 deletions alone (IKZF1del) or with other transcription factor deletions (ie, IKZF1 plus subtype \[IKZF1plus\]) or other identified genetic lesions predict poor outcomes in Ph+/ABL-class Ph-like ALL in patients treated on AALL1631. V. To determine the frequency and prognostic significance of p190 and p210 BCR::ABL1 fusion variants in pediatric Ph+ ALL/ABL-class Ph-like ALL. VI. To measure adherence to oral chemotherapeutic agents (imatinib, 6-mercaptopurine and methotrexate) during the maintenance phase in SR Ph+ ALL patients. VIa. To identify factors associated with poor adherence. VIb. To determine association between relapse risk and adherence to each oral chemotherapeutic agent (separately and combined). VII. To measure adherence to imatinib after allogeneic HSCT in HR Ph+ ALL patients and identify factors associated with poor adherence. VIII. To compare DFS of SR ABL-class fusion positive ALL patients treated with continuous imatinib combined with either a high-risk COG-ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone. IX. To determine the potential therapeutic impact of major secondary events via pharmacologic inhibitor screens in existing/engineered cell models of Ph+ and ABL-class Ph-like ALL harboring secondary events and to test the in vivo activity of the most compelling candidate compounds from pilot studies using patient-derived xenograft (PDX) models established from Ph+ and ABL-class Ph-like ALL samples collected from patients treated on AALL1631. X. To decipher the molecular and cellular heterogeneity of chronic myelogenous leukemia (CML)-like versus typical Ph+ ALL via single-cell genomics and functional assays and investigate CML-like phenotypes via single-cell ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) sequencing to identify distinct transcriptomic and mutational profiles that will provide novel opportunities for diagnostic and therapeutic interventions. OUTLINE: INDUCTION IA PART 1: Patients receive induction IA according to standard of care on days 1-14. INDUCTION IA PART 2: Patients receive imatinib mesylate orally (PO) once daily (QD) or twice daily (BID) on days 15-33, prednisolone PO twice daily (BID) or methylprednisolone intravenously (IV) on days 15-28, vincristine sulfate IV over 1 minute on days 15 and 22, daunorubicin hydrochloride IV over 1-15 minutes on days 15 and 22, and methotrexate intrathecally (IT) on day 29. INDUCTION IB: Patients receive imatinib mesylate PO QD or BID on days 1-35, cyclophosphamide IV over 30-60 minutes on days 1 and 28, mercaptopurine PO on days 1-28, cytarabine IV or subcutaneously (SC) on days 3-6, 10-13, 17-20, and 24-27, and methotrexate IT on days 10 and 24. POST-INDUCTION THERAPY: Patients classified as standard risk are randomized to 1 of 2 arms. Patients with high risk are assigned to Arm C. ARM A: CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, vincristine sulfate IV over 1 minute on days 1 and 6, dexamethasone PO BID or IV on days 1-5, cyclophosphamide IV over 30-60 minutes on days 2-4, leucovorin calcium or levoleucovorin PO or IV on days 3 and 4, high dose cytarabine IV over 3 hours and pegaspargase or calaspargase pegol IV over 1-2 hours on day 5, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate PO QD or BID on days 1-21, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 1, high dose methotrexate IV over 24 hours on day 1, dexamethasone PO BID or IV on days 1-5, vincristine sulfate IV over 1 minute on days 1 and 6, ifosfamide IV over 1 hour on days 2-4, leucovorin calcium or levoleucovorin PO or IV on days 3 and 4, dexrazoxane hydrochloride IV over 15 minutes and daunorubicin hydrochloride IV over 1-15 minutes on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate PO QD or BID on days 1-21, high dose cytarabine IV over 3 hours on days 1-3, dexamethasone PO BID or IV on days 1-5, etoposide IV over 1-2 hours on days 3-5, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT on day 5, pegaspargase or calaspargase pegol IV over 1-2 hours on day 6, and filgrastim SC or IV on days 7-11 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 1 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 8, 15, 22, and 29, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 1 PART 2: Patients receive imatinib mesylate PO QD on days 36-63, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 38-41 and 45-48, and methotrexate IT on days 38 and 45in the absence of disease progression or unexpected toxicity. INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate PO on days 1, 8, 15, and 22, and mercaptopurine PO on days 1-28 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 2 PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-35, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 8, 15, 22, and 29, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 8 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION 2 PART 2: Patients receive imatinib mesylate PO QD on days 36-49, cyclophosphamide IV over 30-60 minutes on day 36, thioguanine PO on days 36-49, cytarabine IV over 1-30 minutes or SC on days 36-39 and 43-46, and methotrexate IT on days 36 and 43 in the absence of disease progression or unexpected toxicity. MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, methotrexate PO once weekly (QW) and IT on days 1 and 43 of cycles 1, 2, and 3, and mercaptopurine PO on days 1-84. Cycles with imatinib mesylate and mercaptopurine repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity. ARM B: INTERIM MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-63, vincristine sulfate IV over 1 minute and high dose methotrexate IV over 24 hours on days 1, 15, 29, and 43, leucovorin calcium or levoleucovorin PO or IV on days 3-4, 17-18, 31-32, and 45-46, mercaptopurine PO on days 1-56, and methotrexate IT on days 1 and 29 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION PART 1: Patients receive imatinib mesylate PO QD or BID on days 1-28, methotrexate IT on day 1, dexamethasone PO BID or IV on days 1-7 and 15-21, vincristine sulfate IV over 1 minute, dexrazoxane hydrochloride IV over 15 minutes, and doxorubicin IV over 3-15 minutes on days 1, 8, and 15, and pegaspargase or calaspargase pegol IV over 1-2 hours or IM on day 4 in the absence of disease progression or unexpected toxicity. DELAYED INTENSIFICATION PART 2: Patients receive imatinib mesylate PO QD on days 29-56, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days 29-42, cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39, methotrexate IT on days 29 and 36, vincristine sulfate IV over 1 minute on days 43 and 50, and pegaspargase or calaspargase pegol IV over 1-2 hours on day 43 in the absence of disease progression or unexpected toxicity. INTERIM MAINTENANCE WITH CAPIZZI METHOTREXATE: Patients receive imatinib mesylate PO QD or BID on days 1-56, vincristine sulfate IV over 1 minute and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and pegaspargase or calaspargase pegol IV over 1-2 hours on days 2 and 23 in the absence of disease progression or unexpected toxicity. MAINTENANCE: Patients receive imatinib mesylate PO QD or BID on days 1-84, vincristine sulfate IV over 1 minute on days 1, 29, and 57, prednisolone PO BID (or methylprednisolone IV for cycle 1 and 2) on days 1-5, 29-33, and 57-61, mercaptopurine PO on days 1-84, methotrexate PO QW, and methotrexate IT on day 1 (and day 29 for cycle 1 and 2). Cycles repeat every 84 days for up to 104 weeks from the start of Induction IA in the absence of disease progression or unexpected toxicity. ARM C: CONSOLIDATION BLOCK 1: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, vincristine sulfate, dexamethasone, leucovorin calcium or levoleucovorin, high dose cytarabine, and pegaspargase or calaspargase pegol as in Arm A Consolidation Block 1, and filgrastim SC or IV on day 7 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 2: Patients receive imatinib mesylate, methotrexate, cytarabine, therapeutic hydrocortisone, high dose methotrexate, dexamethasone, vincristine sulfate, ifosfamide, leucovorin calcium or levoleucovorin, dexrazoxane hydrochloride, daunorubicin hydrochloride, pegaspargase or calaspargase pegol, and filgrastim as Arm A Consolidation Block 2 in the absence of disease progression or unexpected toxicity. CONSOLIDATION BLOCK 3: Patients receive imatinib mesylate, dexamethasone, etoposide, methotrexate, cytarabine, therapeutic hydrocortisone, pegaspargase or calaspargase pegol, and filgrastim as in Arm A Consolidation Block 3, and high dose cytarabine IV over 3 hours on days 1-2 in the absence of disease progression or unexpected toxicity. HSCT: Patients undergo HSCT on day 0. Patients who do not proceed to HSCT receive Delayed Intensification 1, Interim Maintenance, Delayed Intensification 2, and Maintenance as in Arm A. POST-HSCT: Patients receive imatinib mesylate PO QD or BID starting on days 56-365 in the in the absence of disease progression or unexpected toxicity. After completion of study treatment, patients are followed up every year for 3 years.

Aortic Valve Disease, Aortic Valve Insufficiency, Aortic Regurgitation

J-Valve TF Early Feasibility Study

The EFS is a prospective, single arm, multi-center, interventional study that will enroll up to 25 subjects in up to 15 centers in the United States and/or Canada and report the primary endpoint of all-cause death or disabling stroke at 30 days.

Central Nervous System Neoplasm, Infantile Fibrosarcoma, Recurrent Acute Leukemia, Refractory Acute Leukemia, Solid Neoplasm

Larotrectinib (LOXO-101, NSC# 788607) for Previously Untreated TRK Fusion Pediatric Solid Tumors and TRK Fusion Relapsed Pediatric Acute Leukemias

PRIMARY OBJECTIVE: I. To determine the objective response rate (ORR) of children with infantile fibrosarcoma (IFS) treated with neoadjuvant larotrectinib prior to local control. SECONDARY OBJECTIVES: I. To determine event-free survival (EFS), overall survival (OS), and duration of response (DoR) of children with IFS treated with neoadjuvant larotrectinib prior to local control. II. To determine the ORR, EFS, OS, and DoR of children with newly diagnosed TRK fusion solid tumors other than IFS treated with neoadjuvant larotrectinib prior to local control. III. To describe the toxicity of larotrectinib in children with solid tumors and acute leukemia. IV. To determine the percentage of patients with TRK fusion solid tumors with detectable circulating tumor deoxyribonucleic acid (DNA) at baseline and after 2 weeks, 4 weeks, 24 weeks of treatment, at the time of discontinuation of larotrectinib therapy, and at progression. EXPLORATORY OBJECTIVES: I. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors other than IFS treated with adjuvant larotrectinib following upfront surgery with positive margins after neoadjuvant larotrectinib. II. To determine the EFS, OS, and DoR of children with TRK fusion solid tumors who experience a complete response to larotrectinib and subsequently discontinue larotrectinib therapy. III. To determine the remission induction rate for patients with recurrent/refractory TRK fusion leukemia when treated with larotrectinib. IV. To evaluate the surgical morbidity and extent of resection of initially unresectable tumors in patients with TRK fusion solid tumors who undergo surgical resection following neoadjuvant larotrectinib. V. To evaluate mechanisms of response and resistance to larotrectinib in children with TRK fusion cancers. VI. To evaluate the morphologic features of TRK fusion solid tumors at time of initial biopsy to further define criteria for pathologic diagnosis of these tumors. VII. To evaluate immunohistochemistry for pan-TRK as a screening method for TRK fusion tumors and in resection specimens following neoadjuvant treatment with larotrectinib. VIII. To evaluate the histologic response to larotrectinib in resection specimens following neoadjuvant treatment. IX. To evaluate circulating tumor DNA for the detection of the emergence of resistance mutations and recurrence in patients with TRK fusion solid tumors treated with larotrectinib. X. To evaluate the ratio of cerebrospinal fluid (CSF) to concurrent plasma concentrations of larotrectinib in patients with leukemia. XI. To evaluate the change in neurocognitive/behavioral functioning over time between baseline and 5 years post-diagnosis of patients treated on this protocol using parent-reported adaptive functioning (Adaptive Behavior Assessment System \[ABAS\]-III General Adaptive Composite), executive function (Behavior Rating Inventory of Executive Function Scales-Preschool Version \[BRIEF-P\] or BRIEF-2 Global Executive Composite Score), psychosocial functioning (Behavior Assessment System for Children \[BASC\]-3 Internalizing, Externalizing and Behavioral Symptoms Indices) and quality of life (Pediatric Quality of Life Inventory \[PedsQL\] Total score). OUTLINE: Patients receive larotrectinib orally (PO) or by nasogastric (NG) or gastric tube (G-tube) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity. Patients whose tumors shrink sufficiently while taking larotrectinib may undergo surgical resection of their tumor while on study. After completion of study treatment, patients are followed up at 3, 6, 12, 18, 24, 30, 36, and 48 months and annually thereafter for up to 5 years from the date of study entry.

Langerhans Cell Histiocytosis

LCH-IV, International Collaborative Treatment Protocol for Children and Adolescents With Langerhans Cell Histiocytosis

The international efforts of the past 20 years have shown that combination therapy with vinblastine and prednisone is an effective therapy for Multi-system (MS)-LCH. The previous prospective trial LCH-III confirmed this regimen as a standard regimen for MS-LCH in patients with and without risk organ involvement. It also showed that prolonged treatment in the latter group (treatment duration of 12 vs. 6 months) is superior in preventing disease reactivations. The results of this trial are encouraging and serve as a basis for the LCH-IV study design.Due to the complexity of the disease presentations and outcomes, the LCH-IV study seeks to tailor treatment based on features at presentation and on response to treatment, leading to seven strata: * Stratum I: First-line treatment for MS-LCH patients (Group 1) and patients with Single system (SS)-LCH with multifocal bone or "Central Nervous System (CNS)-risk" lesions (Group 2) * Stratum II: Second-line treatment for non-risk patients (patients without risk organ involvement who fail first-line therapy or have a reactivation after completion of first-line therapy) * Stratum III: Salvage treatment for risk LCH (patients with dysfunction of risk organs who fail first-line therapy) * Stratum IV: Stem cell transplantation for risk LCH (patients with dysfunction of risk organs who fail first-line therapy) * Stratum V: Monitoring and treatment of isolated tumorous and neurodegenerative CNS-LCH * Stratum VI: Natural history and management of "other" SS-LCH (patients who do not need systemic therapy at the time of diagnosis) * Stratum VII: Long-term Follow up (all patients irrespective of previous therapy will be followed for reactivation or permanent consequences once complete disease resolution has been achieved and the respective protocol treatment completed)

• 901-595-0362
• Heidi.clough@stjude.org

Neoplasms

Long-Term Follow-Up (LTFU) of Participants Treated With ADP Adoptive Cell Therapies

Participants who received a ADP adoptive cell therapy will be enrolled in this non-therapeutic, multi-center, long term follow-up (LTFU) study and will be followed for up to 15 years post-infusion of lentiviral vector-based adoptive cell therapy. Participants will be monitored for safety following last adoptive cell therapy infusion.

• 215-825-9260
• patients@adaptimmune.com

Neoplasms

Long-Term Follow-Up (LTFU) of Participants Treated With ADP Adoptive Cell Therapies

Participants who received a ADP adoptive cell therapy will be enrolled in this non-therapeutic, multi-center, long term follow-up (LTFU) study and will be followed for up to 15 years post-infusion of lentiviral vector-based adoptive cell therapy. Participants will be monitored for safety following last adoptive cell therapy infusion.

• 215-825-9260
• patients@adaptimmune.com

Primary Immunodeficiency Diseases (PID)

Long-term Safety and Tolerability of TAK-881 in Subjects With Primary Immunodeficiency Diseases (PIDD)

The study consists of two Epochs: Epoch 1 and Epoch 2. In Epoch 1 eligible participants will have the opportunity to receive TAK-881 for a minimum of 6 months. After 6 months in study TAK-881-3002, the results of the anti-rHuPH20 binding antibody assay from either study TAK-881-3001 (NCT05755035) or study TAK-881-3002 (Epoch 1) will be used to determine the next steps in the study: * Epoch 1: Participants with an anti-rHuPH20 antibody titer less than \[\<\] 1:160 will complete the EOS visit on the day of the first non-investigational product (IP) infusion following Study Visit Week 25. * Epoch 2: Participants with an anti-rHuPH20 antibody titer greater than or equal to \[\>=\] 1:160 at any time point during Study TAK-881-3001 (NCT05755035) and/or study TAK-881-3002 (Epoch 1), will continue with an additional two years of TAK-881 treatment and undergo safety follow-up and will complete the EOS visit on the day of the first non-IP infusion following study Visit Week 121.

• +1-877-825-3327
• medinfoUS@takeda.com

Neoplasms

Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered NY-ESO-1-Specific (c259) T Cells, Alone or in Combination With Other Agents, in HLA-A2+ Participants With NY-ESO-1 and/or LAGE-1a Positive Solid Tumors (IGNYTE-ESO)

New York esophageal antigen-1 (NY-ESO-1) and LAGE-1a antigens are tumor-associated proteins that have been found in several tumor types. Clinical trials using adoptively transferred T cells directed against NY-ESO-1/LAGE-1a have shown objective responses. Letetresgene autoleucel (lete-cel, GSK3377794) is the first generation of NY-ESO-1 specific T-cell receptor engineered T cells. This is a master protocol investigating T-cell therapies. It will initially consist of a core protocol with two independent substudies investigating Letetresgene autoleucel in previously untreated (1L) Human Leukocyte Antigen (HLA)-A*02+ participants with NY-ESO-1+ advanced (metastatic or unresectable) synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS) (Substudy 1) and Letetresgene autoleucel as second line or higher (2L+) treatment in HLA-A*02+ participants with NY-ESO-1+ advanced (metastatic or unresectable) SS or MRCLS who have progressed following treatment with anthracycline based chemotherapy (Substudy 2).

Recurrent, Refractory, or High Risk Leukemias, Matched Targeted Therapy

Matched Targeted Therapy (MTT) Recommendation for Patients With Recurrent, Refractory, or High Risk Leukemias and Myelodysplastic Syndrome

Our tissues and organs are made up of cells. Cancer occurs when the molecules that normally control cell growth are damaged. The damage results in unchecked cell growth which causes a tumor, a collection of cancer cells. The damage is referred to as an alteration. There are different types of cancer-causing alterations. Genes are the part of cells that contain the instructions which tell our cells how to make the right proteins to grow and work. Genes are composed of Deoxyribonucleic Acid (DNA) letters that spell out these instructions. By participating in this study, the participant's leukemia cells will be tested for cancer causing alterations. This testing is called leukemia profiling. The leukemia profiling will be performed using bone marrow or blood that has already been obtained during a clinical test. Alternately, the profiling may be done on leukemia cells that are planned to be obtained as part of routine clinical care. This study will determine whether it is possible to use profiling results to determine a matched targeted therapy for patients with leukemia. It will describe the range of mutations found in patients with leukemia with this type of profiling, and describe the clinical outcomes of patients who receive a matched targeted therapy.

Osteosarcoma, Ewing Sarcoma

Metformin as Maintenance Therapy in Patients With Bone Sarcoma and High Risk of Relapse

MATERIALS \& METHODS The study is divided in two groups 1. Group 1-Localized osteosarcoma that have reported a post neoadjuvant chemotherapy primary tumor necrosis ≤ 60% Metformin will be administrated for 3 years maximum or until progression disease or if G3 or G4 toxicity is verified. 37 patients as total population are necessary to evaluate a 3 yrs increase of EFS from 35% ( historical data Tsuda Y ) to 60%, 2. Group 2 Osteosarcoma and Ewing sarcoma patients in Complete Remission after the first relapse.Metformin will be administrated for 3 years or until progression . The Event Free Survival of this second group will be calculated at 1 yr with the aim of an increase of EFS from 20%(historical data) to 45% STATISTICAL ANALYSIS AND SAMPLE SIZE Sample size was calculated by the Expected Total Study Length minimization criteria to ensure a potency parameter of 80 % and point if there is a benefit in use Metformin compared to the historical control. EFS will be estimated by Kaplan-Meier and the standard error will be used to calculate the interim analysis Z-factor as well as the final statistical analysis. The final statistical analysis will be performed * Group 1 after 3 years after last patient enrollment * Group 2 at 1 year from the last patient enrollment : EFS at 1 year OBJECTIVE 1. Evaluate the event free survival (EFS) in osteosarcoma and Ewing sarcoma patients with high risk of relapse compared to the historical control. 2. Evaluate Metformin's toxicity as maintenance therapy.

• +39(051)6366668
• alessandra.longhi@ior.it

Sickle Cell Disease

Minimizing Toxicity in HLA-identical Sibling Donor Transplantation for Children With Sickle Cell Disease

This is a prospective, multicenter phase II study of HLA-identical sibling donor HSCT in 30 pediatric patients with SCD using nonmyeloablative conditioning with alemtuzumab, total-body irradiation, and sirolimus. The primary Objective of this study is to determine if the SUN regimen can decrease the incidence of grade II-IV acute graft-versus host disease (GVHD) by day +100 while maintaining similar disease-free survival compared to establish HLA-identical donor hematopoietic stem cell transplant (HSCT) regimens in children with SCD. The secondary Objective is to determine if health-related quality of life (HRQoL) for children undergoing SUN HSCT is preserved during the early post-transplant time period. To determine if the SUN regimen can decrease the number of platelet transfusions compared to established HLA-identical HSCT regimens in children with SCD. The tertiary/Exploratory Objectives: To describe other markers of toxicity (duration of neutropenia, mucositis, length of hospitalization) and indicators of a successful HSCT (HRQoL at 1 year, proportion needing additional immunosuppression during the first year, proportion able to wean sirolimus at 1 year). With protocol version 5.0, added new secondary objective to determine if the change from intravenous to subcutaneous alemtuzumab and the addition of post-HSCT G-CSF can decrease the incidence of poor donor engraftment.

• 202-476-5000
• RNickel@childrensnational.org

Hemophilia A

MOdern Treatment of Inhibitor-PositiVe PATiEnts With Haemophilia A - An International Observational Study

This study will capture different approaches in the management of persons with haemophilia A (HA) and inhibitors. HA is a serious blood coagulation disorder caused by a deficiency in FVIII that results in a failure to produce FVIII in sufficient quantities to achieve satisfactory haemostasis. Patients with HA are predisposed to recurrent bleeds into joints and soft tissues that culminate in debilitating arthropathy and long-term morbidity. HA can be effectively treated with replacement FVIII concentrates, obtained by fractionation of human plasma (pdFVIII) or using recombinant technology (rFVIII). In patients receiving FVIII replacement therapy, inhibitors can develop that neutralise the effect of treatment. Inhibitors develop in \~35% of patients who have not been previously exposed to FVIII treatment and \~1% of patients who have undergone previous FVIII treatment. Inhibitor development has major adverse implications on bleeding rates, morbidity, mortality and quality of life. Immune tolerance induction (ITI), which involves prolonged treatment with plasma-derived (pdFVIII) or recombinant FVIII (rFVIII), is the only clinically proven strategy for eradication of inhibitors and is recommended as the primary treatment option in European and US guidelines. Bypassing agents (activated recombinant factor VII \[rFVIIa\] and activated prothrombin complex concentrate \[aPCC\]) are used to manage bleeding episodes (BEs) and for prophylaxis or in surgical settings in patients with FVIII inhibitors. The bispecific factor IX (FIX) and factor X (FX) monoclonal antibody emicizumab was approved in the US in November 2017, and in Europe in February 2018. The overall objective of this study is to capture different approaches in the management of participants with HA and inhibitors, document current ITI approaches, and evaluate efficacy and safety of ITI, including the combination of FVIII and emicizumab. Patients will be assigned to 1 of 3 groups based on the treatments they receive: * Group 1 receives ITI with Nuwiq, octanate, or wilate, with aPCC or rFVIIa administered as needed * Group 2 receives ITI with Nuwiq, octanate, or wilate, in combination with emicizumab, with aPCC or rFVIIa administered as needed * Group 3 receives routine prophylaxis with emicizumab, aPCC or rFVIIa without ITI

• 404-785-1637
• robert.sidonio.jr@emory.edu

Hemophilia A

MOdern Treatment of Inhibitor-PositiVe PATiEnts With Haemophilia A - An International Observational Study

This study will capture different approaches in the management of persons with haemophilia A (HA) and inhibitors. HA is a serious blood coagulation disorder caused by a deficiency in FVIII that results in a failure to produce FVIII in sufficient quantities to achieve satisfactory haemostasis. Patients with HA are predisposed to recurrent bleeds into joints and soft tissues that culminate in debilitating arthropathy and long-term morbidity. HA can be effectively treated with replacement FVIII concentrates, obtained by fractionation of human plasma (pdFVIII) or using recombinant technology (rFVIII). In patients receiving FVIII replacement therapy, inhibitors can develop that neutralise the effect of treatment. Inhibitors develop in \~35% of patients who have not been previously exposed to FVIII treatment and \~1% of patients who have undergone previous FVIII treatment. Inhibitor development has major adverse implications on bleeding rates, morbidity, mortality and quality of life. Immune tolerance induction (ITI), which involves prolonged treatment with plasma-derived (pdFVIII) or recombinant FVIII (rFVIII), is the only clinically proven strategy for eradication of inhibitors and is recommended as the primary treatment option in European and US guidelines. Bypassing agents (activated recombinant factor VII \[rFVIIa\] and activated prothrombin complex concentrate \[aPCC\]) are used to manage bleeding episodes (BEs) and for prophylaxis or in surgical settings in patients with FVIII inhibitors. The bispecific factor IX (FIX) and factor X (FX) monoclonal antibody emicizumab was approved in the US in November 2017, and in Europe in February 2018. The overall objective of this study is to capture different approaches in the management of participants with HA and inhibitors, document current ITI approaches, and evaluate efficacy and safety of ITI, including the combination of FVIII and emicizumab. Patients will be assigned to 1 of 3 groups based on the treatments they receive: * Group 1 receives ITI with Nuwiq, octanate, or wilate, with aPCC or rFVIIa administered as needed * Group 2 receives ITI with Nuwiq, octanate, or wilate, in combination with emicizumab, with aPCC or rFVIIa administered as needed * Group 3 receives routine prophylaxis with emicizumab, aPCC or rFVIIa without ITI

• 404-785-1637
• robert.sidonio.jr@emory.edu

Advanced Malignant Solid Neoplasm, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Locally Advanced Malignant Solid Neoplasm, Malignant Female Reproductive System Neoplasm, Metastatic HER2-Negative Breast Carcinoma, Metastatic Malignant Solid Neoplasm, Recurrent Endometrial Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Malignant Female Reproductive System Neoplasm, Recurrent Malignant Solid Neoplasm, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Unresectable HER2-Negative Breast Carcinoma, Unresectable Malignant Solid Neoplasm

Molecular Analysis for Combination Therapy Choice (ComboMATCH)

PRIMARY OBJECTIVE: I. To register, allocate, and assign patients to ComboMATCH treatment trials. SECONDARY OBJECTIVES: I. To evaluate the rate of positive outcomes in defined cohorts within treatment trials of treatment combinations including targeted therapies for molecularly defined populations, and also in the subset of treatment trials where the treatments are supported by in vivo models. II. To perform quality control of the patients registered in the form of pathological confirmation of disease and sub-type to confirm diagnosis and treatment arm allocation. SECONDARY CORRELATIVE OBJECTIVES: I. Assess the concordance of the central molecular characterization of the pre-treatment biopsy samples with the genetic readouts from the Designated Laboratories (DLs) for patients enrolled on the ComboMATCH treatment trials. II. To assess how the registration diagnostic tumor mutation profile and pre-treatment biopsy profile compare to the circulating tumor-derived deoxyribonucleic acid (ctDNA) mutation profile from plasma. EXPLORATORY OBJECTIVE: I. Assess association between ComboMATCH treatment trials outcomes (positive or negative) with the type of rationale for the selected drug combinations and the type of rationale for the gene variant/combination for selection (e.g., whether the trial was based on targeted therapies for molecularly defined populations, those that were supported by in vivo models, and those that were supported by empiric clinical data). OUTLINE: REGISTRATION: Patients undergo tumor mutational screening of previously-collected tumor samples for specific, pre-defined mutations, amplifications, or translocations of interest via tumor sequencing. Patients who are 18 years or older and have biopsiable disease undergo a new biopsy for research purposes prior to initiating treatment on the ComboMATCH treatment trial. TREATMENT: Patients with mutations targeted to investigational combination therapies are assigned to 1 of 20 treatment subprotocols. EAY191-N4: Patients with RAS pathway mutant ovarian or endometrial cancer are randomized to 1 of 2 arms. ARM I: Patients receive selumetinib PO and olaparib PO on study. Patients also undergo a tumor biopsy and blood collection during screening and on study, as well as echocardiogram (ECHO) or multigated acquisition (MUGA), and computed tomography (CT) scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated. ARM II: Patients receive selumetinib PO on study. Patients who experience progression may elect to cross over to Arm I provided they have not had dose limiting toxicities to monotherapy selumetinib. Patients also undergo a tumor biopsy and blood collection during screening and on study, as well as ECHO or MUGA, and CT scans throughout the trial. Patients may undergo bone marrow aspiration or biopsy as clinically indicated. EAY191-N2: Patients with inactivating or inferred inactivating NF1 alterations, and hormone receptor positive, HER2-negative metastatic breast cancer. Patients who are fulvestrant naive are assigned to Cohort I, while patients who are fulvestrant resistant are assigned to Cohort II. COHORT I: Patients are randomized to 1 of 2 arms. ARM I:Patients receive fulvestrant intramuscularly (IM) on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles and binimetinib PO twice daily (BID) on days 15 to 28 of cycle 1 and day 1 through 28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a CT, magnetic resonance imaging (MRI), or bone scan, ECHO or MUGA, and tumor biopsy, as well as possible blood sample collection during screening and on study. ARM II: Patients receive fulvestrant IM on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who progress on fulvestrant alone may migrate to cohort II if they meet the migration eligibility criteria. Patients not willing to migrate to cohort II will have further therapy at the investigator's discretion. Patients undergo a CT, MRI, or bone scan and tumor biopsy, as well as ECHO or MUGA and possible blood sample collection during screening and on study. COHORT II: Patients receive fulvestrant IM on day 1 of each cycle and binimetinib PO BID on days 15-28 of cycle 1 and day 1 through 28 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT, MRI, or bone scan, ECHO or MUGA and tumor biopsy, as well as possible blood sample collection during screening and on study. EAY191-E4: Patients with solid tumors who previously underwent taxane therapy. Patients receive nilotinib hydrochloride monohydrate PO twice daily (BID) on days 1-28 and paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI during screening or cycle 1 day 1, every 2 cycles for 1 year, every 3 cycles for patients on study for more than 1 year, and every 4 cycles for patients on study for more than 3 years and may also undergo CT or MRI during follow-up every 3 months for 2 years and then every 6 months for 1 year if clinically indicated. Patients also undergo collection of blood samples at baseline, cycle 2 day 1, and optionally at progression as well as tumor biopsy at baseline and optionally at progression. EAY191-A3: Patients with KRAS/NRAS/BRAF mutated low-grade serous ovarian cancer (LGSOC) naive to MEK or CDK4/6 inhibitor therapy are randomized to either combination cohort 1 or monotherapy cohort 1. Patients with LGSOC who have received prior MEK inhibitor therapy are assigned to combination cohort 2. Patients with KRAS/NRAS/HRAS/non-V600E BRAF mutated pancreatic cancer are assigned to combination cohort 3. Patients with all other KRAS/NRAS/HRAS mutated tumor types (excluding LGSOC, non-small cell lung cancer, colorectal cancer, pancreatic, and melanoma) are assigned to combination cohort 4. COMBINATION COHORTS 1, 2, 3, 4: Patients receive palbociclib PO and binimetinib PO throughout the trial. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up. MONOTHERAPY COHORT 1: Patients receive binimetinib PO throughout the trial. Patients may also undergo biopsy at screening and undergo MRI, CT, bone scan, and collection of blood samples during screening, on study, and/or during follow up. EAY191-S3: Patients with an activating AKT mutation solid tumor. Patients receive paclitaxel IV on days 1, 8, and 15 and ipatasertib PO on days 1-21 of each cycle. Treatment repeats every 28 days for up to 35 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI and blood collection throughout the trial. Patients also undergo a tumor biopsy during screening and optionally during follow-up. EAY191-A6: Patients with RAS/RAF/MEK/ERK mutant biliary tract cancers are randomized to 1 of 2 arms. ARM 1: Patients receive leucovorin IV, oxaliplatin IV, and fluorouracil IV on study. Patients undergo echocardiogram (ECHO) and multigated acquisition scan (MUGA) during screening and on study, a CT with contrast, MRI, or a fludeoxyglucose F-18 positron emission tomography (FDG-PET) during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if clinically indicated. ARM 2: Patients receive binimetinib PO, leucovorin IV, oxaliplatin IV, and fluorouracil IV on study. Patients undergo ECHO and MUGA during screening and on study, a CT with contrast, MRI, or an FDG-PET during screening, collection of blood during screening and on study, and a biopsy during screening. Patients may also undergo brain MRI or CT during screening and on study, bone scans on study, and biopsy on study if clinically indicated. EAY191-E5: Patients are assigned to 1 of 2 cohorts. COHORT I: Patients who have never received a KRAS G12C inhibitor are randomized to arms A or B. ARM A: Patients receive sotorasib PO once daily (QD) on days 1-28 and panitumumab intravenously IV on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples, biopsy, and CT or MRI on study. ARM B: Patients receive sotorasib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross-over to cohort II. Patients also undergo collection of blood samples, biopsy, and CT or MRI on study. COHORT II: Patients who have received a KRAS G12C inhibitor are assigned to arm C. ARM C: Patients receive combination therapy as in Arm A. EAY191-A2: Patients are assigned to 1 of 3 cohorts. COHORT 1: PARP-inhibitor naive patients are assigned to Arm A. ARM A: Patients receive olaparib PO BID and alpelisib PO daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 5 years in the absence of disease progression, unacceptable toxicity, or bone marrow findings consistent with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients also undergo MRI, CT, and/or PET scans throughout the trial and a biopsy prior to treatment start. Patients may also undergo bone scans on study as clinically indicated. Patients have the option to also undergo blood collection throughout the trial and a second biopsy at time of disease progression. COHORT 2: PARP-inhibitor naive patients are randomized to 1 of 2 arms. ARM B: Patients receive olaparib PO BID and alpelisib PO daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 5 years in the absence of disease progression, unacceptable toxicity, or bone marrow findings consistent with MDS or AML. Patients also undergo MRI, CT, and/or PET scans throughout the trial and a biopsy prior to treatment start. Patients may also undergo bone scans on study as clinically indicated. Patients have the option to also undergo blood collection throughout the trial and a second biopsy at time of disease progression. ARM C: Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 5 years in the absence of disease progression, unacceptable toxicity, or bone marrow findings consistent with MDS or AML. Patients experiencing disease progression have the option to migrate to Cohort 3, Arm D. Patients also undergo MRI, CT, and/or PET scans throughout the trial and a biopsy prior to treatment start. Patients may also undergo bone scans on study as clinically indicated. Patients have the option to also undergo blood collection throughout the trial and a second biopsy at time of disease progression. COHORT 3: PARP-inhibitor resistant patients are assigned to Arm D. ARM D: Patients receive olaparib PO BID and alpelisib PO daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 5 years in the absence of disease progression, unacceptable toxicity, or bone marrow findings consistent with MDS or AML. Patients also undergo MRI, CT, and/or PET scans throughout the trial and a biopsy prior to treatment start. Patients may also undergo bone scans on study as clinically indicated. Patients have the option to also undergo blood collection throughout the trial and a second biopsy at time of disease progression. EAY191-N5: Patients are randomized to 1 of 2 arms. ARM I: Patients receive neratinib maleate PO QD on days 1-14 of cycle 0 in the absence of disease progression or unacceptable toxicity. Patients then receive neratinib maleate PO QD on days 1-28 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience progression may crossover to Arm II. Patients undergo ECHO or MUGA during screening and on study, and CT or MRI and collection of blood samples throughout the trial. Patients may also undergo tumor biopsy during screening and on study. ARM II: Patients receive neratinib maleate PO QD on days 1-14 of cycle 0 in the absence of disease progression or unacceptable toxicity. Patients then receive neratinib maleate PO QD on days 1-28 and palbociclib PO QD on days 1-21 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening and on study, and CT or MRI and collection of blood samples throughout the trial. Patients may also undergo tumor biopsy during screening and on study.

Head and Neck Neoplasms

Molecular and Genomic Profiling of Head and Neck Tumors to Explore Biomarkers Associated With Prognosis and Response to Therapy

Previous research by our group using genetic microarray analysis of HNSCC and normal keratinocytes has identified two distinct groups of genetic expression based on clustering patterns of a subgroup of genes. Clinical data was summarized for each group and overall, patient segregation by gene expression profiling was a better predictor of outcome than clinicopathological variables. Further analysis identified 375 genes that discriminate between the genotypic subtypes of HNSCC. Overall, our preliminary data has shown that the pattern of global gene expression in a HNSCC specimen can be used as a predictor of prognosis. We isolated subsets of genes showing the greatest patterns of divergence in gene expression. We have also identified 366 over-expressed and 246 underexpressed genes when comparing primary tumor to normal surgical margins and have identified a similar number of genes whose expression has changed when comparing primary tumor to lymph node metastasis. Combining these data sets we have identified genes which consistently increase or decrease expression during progression from normal tissue to primary tumor, and subsequently to metastatic node. We have selected several candidate genes for subsequent analysis using HNSCC tissue arrays. Through DNA microarray analysis and other techniques for looking at genetic and molecular characteristics, a more detailed knowledge of the malignant transformation process, and alterations with therapy, in these patients may be obtained. This study will seek to perform comprehensive molecular and genetic profiling to improve biomarker development in HNSCC and correlate this data with patient clinical data. Ultimately it is hoped that tumor specific genetic abnormalities may be identified which could provide targets for treatment strategies such as gene therapy, immunotherapy, or other interventions. Study Objectives: To evaluate gene expression patterns in human head and neck squamous cell carcinoma and correlate this with treatment response, both surgical and non-surgical. To identify a series of diagnostic markers in blood, urine and/or sputum for head and neck squamous cell carcinoma and study the mechanism of action of these proteins.

• 718-920-7054
• staugust@montefiore.org

Childhood Obesity, Epigenetics

Molecular Basis of Early Childhood Obesity Programming by Intrauterine Growth Restriction

Epidemiological studies of multiple cohorts suggest an increased risk for obesity, cardiovascular disease-related death and type 2 diabetes in low birth weight infants. However, the molecular mechanisms underlying developmental programming of childhood obesity remain poorly understood. Alterations in DNA methylation during fetal life have been proposed to be one of the mechanisms that regulate this phenotype. Here, the investigators address major questions about early childhood obesity programming by studying purified subpopulations of CD3+ T-cells from intrauterine growth restricted (IUGR) newborns who have an increased risk for obesity and other metabolic disorders in adult life. The investigators will correlate altered CD3+ T-cell DNA methylation profiles in cord and peripheral blood samples and functional changes in CD3+ T-cells with adiposity in childhood.

• 718-904-4105
• mfuloria@montefiore.org

Pediatric Solid Tumor

Multicenter Cohort Study to Evaluate Outcomes After Receipt of Targeted Therapy Matched to an Individualized Cancer Therapy (iCat) Recommendations in Children and Young Adults with Solid Tumors: the ICat2, GAIN Consortium Study

Patients with extra-cranial (not in the brain) solid tumors that are either difficult to diagnose or more difficult to treat are eligible to participate in this study. All enrolled patients will have targeted sequencing of tumor performed. Sequencing results will be reviewed for clinically significant findings including determination of whether any mutations exist that suggest potential for activity of a targeted therapy (iCat recommendation). Results will be returned to the patient's oncologist and follow-up data will be collected. In this prospective multi-center cohort study, the primary objective is to describe the outcomes of pediatric patients with advanced solid tumors according to whether or not they received of targeted therapy matched to an iCat recommendation. The primary clinical outcome of interest is the endpoint of overall survival (OS), with progression-free survival and response rate (RR) as key secondary clinical outcome measures. To address this hypothesis, 825 patients will enroll from an anticipated 11 participating institutions over 3 years.

Hematopoietic Cell Transplant, Solid Organ Transplant, Respiratory Viral Infection

Multi-Center Molecular Diagnosis and Host Response of Respiratory Viral Infections in Pediatric Transplant Recipients

The investigators will collect a nasal swab and blood sample from the participant when the participant is enrolled on the study and if the participant develops a RVI in the first year after transplant. The investigators will collect a blood sample 100 days after the participant's transplant.

• 866-278-5833
• referralinfo@stjude.org

Epstein-Barr Virus+ Associated Post-transplant Lymphoproliferative Disease (EBV+ PTLD), Solid Organ Transplant Complications, Lymphoproliferative Disorders, Allogeneic Hematopoietic Cell Transplant, Stem Cell Transplant Complications

Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Subjects With Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease After Failure of Rituximab or Rituximab and Chemotherapy

This is a multicenter, open-label, phase 3 study to assess the efficacy and safety of tabelecleucel for the treatment of EBV+ PTLD in the setting of SOT-R and SOT-R+C (Cohort \[C\]-SOT) or HCT after failure of rituximab (C-HCT). SOT-R further included participants: 1. who did not receive chemotherapy and did not have a documented medical reason not to receive chemotherapy (SOT-Ro) or 2. who were considered chemotherapy ineligible/inappropriate (SOT-R-Ci) Combined population (SOT-R-Ci, SOT-R+C, and HCT) and (SOT-R-Ci and SOT-R+C) who received commercial product, or a product manufactured using a comparable process version (PV) were also used for analysis of outcomes. Enrollment will be preceded by confirmation of availability of partially human leukocyte antigen (HLA) matched and restricted tabelecleucel for the participant. Study procedures and product administration will be the same for each cohort. Tabelecleucel will be administered in cycles lasting 5 weeks (35 days). During each cycle, participants will receive intravenous tabelecleucel at a dose of 2 × 10\^6 cells/kg on Days 1, 8, and 15, followed by observation through Day 35. Treatment will continue until maximal response, unacceptable toxicity, initiation of non protocol therapy, or failure of tabelecleucel with up to 2 different HLA restrictions (C-SOT) or up to 4 different HLA restrictions (C-HCT). The study includes a total of 5 years of follow-up for disease and survival status.

• 650-278-8930
• clinicalstudies@atarabio.com

Primary Immunodeficiency Diseases (PID)

Multicenter, Prospective, Open-label, Randomized, Crossover Study to Evaluate Pharmacokinetics (PK), Safety, and Tolerability of TAK-881 in Primary Immunodeficiency Diseases (PIDD)

The study consists of a screening epoch, a ramp-up epoch (if needed) and treatment epochs. Participants who have been receiving conventional subcutaneous intravenous immunoglobin G (cIGSC) or intravenous immunoglobulin G (IGIV) before the study, will enter a ramp-up epoch which will start 1, 2, 3 or 4 weeks after the last cIGSC or IGIV pre study dose before screening. Participants who have already been receiving HYQVIA treatment before the study, will directly enter the treatment epochs after screening. Participants aged greater than or equal to \[\>=\]16 years will be randomized at a 1:1 ratio to one of the following treatment sequences: either TAK-881 followed by HYQVIA or HYQVIA followed by TAK-881. Each participant aged \>=16 years will complete both crossover epochs. Pediatric participants aged 2 to less than \[\<\]16 years will complete a single arm treatment with the study drug (TAK-881 only).

Neoplasms, Arteriovenous Malformation of Central Nervous System, Trigeminal Neuralgia

Multi-Institution Registry of SRS/SBRT Procedures

The Registry is designed to help SRS/SBRT (Stereotactic Radiosurgery/Stereotactic Body Radiation Therapy) users to understand utilization of and key treatment outcomes for these treatment approaches. Some of the objectives include: Allow participants to record information about usage of SRS/SBRT in everyday practice, including patient characteristics and disease information, treatment plans and outcomes Provide participants with ready access to data for publication of their own experience and as a tool for establishing collaborations with other participating sites Facilitate quality improvement efforts for individual treatment providers Understand the effectiveness of different treatment plans for different types of lesions, diseases and treatments The Registry tracks select outcomes for each condition treated by SRS/SBRT (for example, PSA for prostate cancer); the Registry also provides individual participants the ability to add additional outcomes for each and any condition of specific interest to their institutions. The Registry is hosted by Vision Tree, Inc who is an independent vendor of electronic registries; they are responsible for HIPAA compliance, including all security mechanisms. Patients will be enrolled prospectively. Some retrospective patient data is likely to be included in order to capture both short and longer term outcomes data.

• jjenkins@therss.org

Hypoplastic Left Heart Syndrome (HLHS)

National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) - A Collaborative Initiative to Improve Care of Children With Complex Congenital Heart Disease

The purpose of this initiative is to improve care and outcomes for infants with HLHS by: 1) expanding the established NPC-QIC national registry to gather clinical care process, outcome, and developmental data on infants with HLHS between diagnosis and 12 months of age, 2) improving implementation of consensus standards, tested by teams, into everyday practice across pediatric cardiology centers, and 3) engaging parents as partners in improving care and outcomes.

• mark.timbers@cchmc.org

Mycobacterium Infections

Natural History, Genetics, Phenotype, and Treatment of Mycobacterial Infections

The nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms foundin soil and water that rarely cause disease in humans. Since exposure to these organisms is universal and disease is rare, it can be concluded that normal host defenses are almost always sufficient to prevent infection. It follows that otherwise healthy individuals who develop disease must have abnormal susceptibility or immune defects that permit infection with nontubercuolous mycobacteria. The organisms that are most commonly encountered in clinical practice include Mycobacterium avium, and M. intracellulare \[collectively known as the M. avium complex (MAC)\], M. kansasii, M. fortuitum, M. abscessus, and M. chelonae. These organisms share significant structural and biochemical similarities with their more pathogenic relative, M. tuberculosis (MTB). Recognition of host factors that predispose or lead to NTM infection may have important implications for pathogenesis and therapeutic intervention, and may be applicable to the more virulent MTB. Identification of genetic or acquired susceptibility factors may lead to recognition of endogenous pathways that can be exploited therapeutically and to possible gene identification. Over the last two decades, three important observations have been made regarding the pathogenesis of nontuberculous mycobacterial infections. 1) In patients infected with HIV, nontuberculous mycobacterial infections often occur when the CD4+ T-lymphocyte number falls below 50/mm3. This suggested that specific T cell products or activities were required for mycobacterial resistance. 2) An association was noted between pulmonary nontuberculous mycobacterial infections and a particular body habitus, predominantly in post-menopausal women (pectus excavatum, scoliosis, mitral valve prolapse). 3) Multiple defects have been found involving the interferon gamma synthesis and use pathways in patients with disseminated nontuberculous mycobacterial infection without HIV, suggesting this is a critical pathway for host defense against these organisms. We seek to better characterize the predisposition to mycobacterial infection. This study will specifically address several aspects of immune function and investigate the proposed link to body morphotype in the relevant population. By collecting this information, we hope to provide insight into disease associations, infection susceptibility, and genetic predisposition to mycobacterial infection.

• (301) 443-2163
• samantha.kreuzburg@nih.gov

Mycobacterium Infections

Natural History, Genetics, Phenotype, and Treatment of Mycobacterial Infections

The nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms foundin soil and water that rarely cause disease in humans. Since exposure to these organisms is universal and disease is rare, it can be concluded that normal host defenses are almost always sufficient to prevent infection. It follows that otherwise healthy individuals who develop disease must have abnormal susceptibility or immune defects that permit infection with nontubercuolous mycobacteria. The organisms that are most commonly encountered in clinical practice include Mycobacterium avium, and M. intracellulare \[collectively known as the M. avium complex (MAC)\], M. kansasii, M. fortuitum, M. abscessus, and M. chelonae. These organisms share significant structural and biochemical similarities with their more pathogenic relative, M. tuberculosis (MTB). Recognition of host factors that predispose or lead to NTM infection may have important implications for pathogenesis and therapeutic intervention, and may be applicable to the more virulent MTB. Identification of genetic or acquired susceptibility factors may lead to recognition of endogenous pathways that can be exploited therapeutically and to possible gene identification. Over the last two decades, three important observations have been made regarding the pathogenesis of nontuberculous mycobacterial infections. 1) In patients infected with HIV, nontuberculous mycobacterial infections often occur when the CD4+ T-lymphocyte number falls below 50/mm3. This suggested that specific T cell products or activities were required for mycobacterial resistance. 2) An association was noted between pulmonary nontuberculous mycobacterial infections and a particular body habitus, predominantly in post-menopausal women (pectus excavatum, scoliosis, mitral valve prolapse). 3) Multiple defects have been found involving the interferon gamma synthesis and use pathways in patients with disseminated nontuberculous mycobacterial infection without HIV, suggesting this is a critical pathway for host defense against these organisms. We seek to better characterize the predisposition to mycobacterial infection. This study will specifically address several aspects of immune function and investigate the proposed link to body morphotype in the relevant population. By collecting this information, we hope to provide insight into disease associations, infection susceptibility, and genetic predisposition to mycobacterial infection.

• (301) 443-2163
• samantha.kreuzburg@nih.gov

COVID-19 Infection, Hematopoietic and Lymphatic System Neoplasm, Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm

NCI COVID-19 in Cancer Patients Study (NCCAPS): A Longitudinal Natural History Study

PRIMARY OBJECTIVES: I. Characterize patient factors, such as pre-existing comorbidities, cancer type and treatment, and demographic factors, associated with short- and long-term outcomes of coronavirus 2019 (COVID-19), including symptoms, severity, and fatality, in adult and pediatric cancer patients undergoing treatment. II. Describe cancer treatment modifications made in response to COVID-19 in adult and pediatric patients, including dose adjustments, changes in symptom management, or temporary or permanent cessation. III. Evaluate the association of COVID-19 with cancer outcomes in adult patient subgroups defined by clinico-pathologic characteristics and in pediatric patients. EXPLORATORY CORRELATIVE OBJECTIVES: I. Study the immune response to COVID-19 in patients with cancer by assessing cytokines by Olink profiling and the cellular compartment of the immune system using mass cytometry (CyTOF). II. Describe coagulation abnormalities in COVID-19 cancer patients. III. Describe the development of severe acute respiratory syndrome (SARS) coronavirus 2 (SARS CoV-2) antibodies and neutralizing antibodies in cancer patients. IV. Investigate both common and rare genetic variants associated with differences in disease outcome using a case-case design to increase understanding of COVID-19 disease in cancer patients using large-scale genome-wide association studies and whole genome sequencing. V. Characterize the development and longevity of vaccine-induced immunity using serology (ligand-binding assays) and neutralizing antibodies. VI. Collect and bank research blood specimens and radiological images for future research. PATIENT-REPORTED HEALTH-RELATED QUALITY OF LIFE OBJECTIVES: I. Describe patient-reported short-and long-term physical health, defined as a composite of physical function, pain interference and intensity, and ability to participate in social roles and activities, as measured by the Patient Reported Outcomes Measurement Information System (PROMIS)-29 version (v)2.0 profile in adult cancer patients diagnosed with COVID-19. (Primary) II. Describe patient-reported short-and long-term symptoms (anxiety, depression, and dyspnea) and function (cognitive function and social isolation) in adult cancer patients diagnosed with COVID-19. (Secondary) III. Assess how patient-reported physical health (primary objective) and symptoms and function (secondary objective) in adult cancer patients vary by COVID-19 symptom burden, cancer type, cancer treatment, comorbidities, tobacco use, body mass index, and demographic characteristics. (Exploratory) PEDIATRIC COVNET COHORT OBJECTIVE (FOR PATIENTS \< 18 YEARS OLD): I. Investigate both common and rare variants associated with differences in disease outcome using a case-case design for children and adolescents, \< 18 years old to increase understanding of COVID-19 in pediatric cancer patients. OUTLINE: Patients undergo collection of medical information about COVID-19 symptoms, treatments/cancer treatments and outcomes, and results from laboratory tests and imaging scans performed as part of routine care for up to 2 years. Patients also undergo collection of blood samples at the same times they receive routine bloodwork up to 8 times for adults and up to 5 times for children. Patients who are hospitalized for COVID-19 undergo collection of blood samples at up to 6 additional times for adults and up to 3 additional times for children. Adult patients also complete quality of life questionnaire.

Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent WHO Grade 2 Glioma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory WHO Grade 2 Glioma, Wilms Tumor

NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of AG-120 (Ivosidenib) in Patients With Tumors Harboring IDH1 Mutations

PRIMARY OBJECTIVE: I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with AG-120 (ivosidenib) with advanced solid tumors (including central nervous system \[CNS\] tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in the IDH1 pathway. SECONDARY OBJECTIVES: I. To estimate the progression free survival in pediatric patients treated with AG-120 (ivosidenib) with advanced solid tumors (including CNS tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in the IDH1 pathway. II. To obtain information about the tolerability of AG-120 (ivosidenib) in children and adolescents with relapsed or refractory cancer. III. To provide preliminary estimates of the pharmacokinetics and pharmacodynamics of AG-120 (ivosidenib) in children and adolescents with relapsed or refractory cancer. EXPLORATORY OBJECTIVES: I. To evaluate other biomarkers as predictors of response to AG-120 (ivosidenib) and specifically, whether tumors that harbor different missense mutations or fusions will demonstrate differential response to AG-120 (ivosidenib) treatment. II. To explore approaches to the profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA). OUTLINE: Patients receive ivosidenib orally (PO) once daily (QD). Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Advanced Malignant Solid Neoplasm, Recurrent Childhood Ependymoma, Recurrent Childhood Malignant Germ Cell Tumor, Recurrent Childhood Medulloblastoma, Recurrent Childhood Non-Hodgkin Lymphoma, Recurrent Childhood Osteosarcoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Neuroblastoma, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdoid Tumor, Refractory Childhood Malignant Germ Cell Tumor, Refractory Childhood Osteosarcoma, Refractory Childhood Rhabdomyosarcoma, Refractory Childhood Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Wilms Tumor

NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of Erdafitinib in Patients With Tumors Harboring FGFR1/2/3/4 Alterations

PRIMARY OBJECTIVE: I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with erdafitinib with advanced solid tumors (including central nervous system \[CNS\] tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor genetic alterations in the FGFR1/2/3/4 pathway. SECONDARY OBJECTIVES: I. To estimate the progression free survival in pediatric patients treated with erdafitinib with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor genetic alterations in the FGFR1/2/3/4. II. To obtain information about the tolerability of erdafitinib in children with relapsed or refractory cancer. III. To provide preliminary estimates of the pharmacokinetics of erdafitinib in children with relapsed or refractory cancer. EXPLORATORY OBJECTIVE: I. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA). OUTLINE: Patients receive erdafitinib orally (PO) once daily (QD) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study. After completion of study treatment, patients are followed up periodically.

Advanced Malignant Solid Neoplasm, Recurrent Ependymoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Kidney Wilms Tumor, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Glioma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma

NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of LOXO-101 (Larotrectinib) in Patients With Tumors Harboring Actionable NTRK Fusions

PRIMARY OBJECTIVE: I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with larotrectinib sulfate (LOXO-101 \[larotrectinib\]) with advanced solid tumors (including central nervous system \[CNS\] tumors), non-Hodgkin lymphomas or histiocytic disorders harboring NTRK 1/2/3 fusions. SECONDARY OBJECTIVES: I. To estimate the progression free survival in pediatric patients treated with LOXO-101 (larotrectinib) with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders with NTRK 1/2/3 fusions. II. To obtain additional information about the tolerability of LOXO-101 (larotrectinib) in children with relapsed or refractory cancer. III. To provide preliminary estimates of the pharmacokinetics of LOXO-101 (larotrectinib) in children with relapsed or refractory cancer. EXPLORATORY OBJECTIVE: I. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA). OUTLINE: Patients receive larotrectinib sulfate orally (PO) or via nasogastric (NG)- or gastric (G)-tube twice per day (BID) on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a computed tomography (CT) scan, magnetic resonance imaging (MRI), an x-ray, bone scan, and/or iobenguane (MIBG) scintigraphy during screening and on study. Patients also undergo bone marrow aspiration and/or biopsy during screening and may undergo blood sample collection on study. After completion of study treatment, patients are followed up at 30 days, then periodically thereafter.

Hematopoietic and Lymphatic System Neoplasm, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Histiocytic and Dendritic Cell Neoplasm, Recurrent Langerhans Cell Histiocytosis, Recurrent Lymphoma, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent WHO Grade 2 Glioma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Histiocytic and Dendritic Cell Neoplasm, Refractory Langerhans Cell Histiocytosis, Refractory Lymphoma, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory WHO Grade 2 Glioma, Wilms Tumor

NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) - Phase 2 Subprotocol of LOXO-292 in Patients With Tumors Harboring RET Gene Alterations

PRIMARY OBJECTIVE: I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with selpercatinib (LOXO-292) with advanced solid tumors (including central nervous system \[CNS\] tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in the RET pathway. SECONDARY OBJECTIVES: I. To estimate the progression free survival in pediatric patients treated with selpercatinib (LOXO-292) with advanced solid tumors (including CNS tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in the RET pathway. II. To obtain information about the tolerability of selpercatinib (LOXO-292) in children and adolescents with relapsed or refractory cancer. EXPLORATORY OBJECTIVE: I. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA). OUTLINE: Patients receive selpercatinib orally (PO) twice daily (BID) on days 1-28 on study. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients may also undergo positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), PET/CT, PET/MRI, and/or CT/MRI, scintigraphy, and x-ray imaging throughout the trial. After completion of study treatment, patients are followed for 30 days, then periodically thereafter.

Advanced Malignant Solid Neoplasm, Malignant Solid Neoplasm, Recurrent Ependymoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdoid Tumor, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Ependymoma, Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Wilms Tumor

NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Ensartinib in Patients With Tumors Harboring ALK or ROS1 Genomic Alterations

PRIMARY OBJECTIVE: I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with ensartinib with advanced solid tumors (including central nervous system \[CNS\] tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor ALK or ROS1 fusions or that harbor ALK missense mutations. SECONDARY OBJECTIVES: I. To estimate the progression free survival in pediatric patients treated with ensartinib with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor ALK or ROS1 fusions or that harbor ALK missense mutations. II. To obtain information about the tolerability of ensartinib in children with relapsed or refractory cancer. III. To provide preliminary estimates of the pharmacokinetics of ensartinib in children with relapsed or refractory cancer. EXPLORATORY OBJECTIVES: I. To evaluate other biomarkers as predictors of response to ensartinib and specifically, whether tumors that harbor different missense mutations or fusions (including the crizotinib resistant F1174L ALK variant) will demonstrate differential response to ensartinib treatment. II. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA). OUTLINE: Patients receive ensartinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days for 2 years (up to 26 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET) scan, radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study. After completion of study treatment, patients are followed up for 30 days.

Malignant Solid Neoplasm, Recurrent Adrenal Gland Pheochromocytoma, Recurrent Ectomesenchymoma, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Hepatoblastoma, Recurrent Kidney Wilms Tumor, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Glioma, Recurrent Medulloblastoma, Recurrent Melanoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Rhabdoid Tumor, Recurrent Rhabdoid Tumor of the Kidney, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Recurrent Thyroid Gland Carcinoma, Recurrent WHO Grade 2 Glioma, Refractory Adrenal Gland Pheochromocytoma, Refractory Ependymoma, Refractory Ewing Sarcoma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Glioma, Refractory Medulloblastoma, Refractory Melanoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Rhabdoid Tumor, Refractory Rhabdoid Tumor of the Kidney, Refractory Rhabdomyosarcoma, Refractory Soft Tissue Sarcoma, Refractory Thyroid Gland Carcinoma, Refractory WHO Grade 2 Glioma

NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Tipifarnib in Patients With Tumors Harboring HRAS Genomic Alterations

PRIMARY OBJECTIVE: I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with tipifarnib with advanced solid tumors (including central nervous system \[CNS\] tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in HRAS. SECONDARY OBJECTIVES: I. To estimate the progression free survival in pediatric patients treated with tipifarnib with advanced solid tumors (including CNS tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in HRAS. II. To obtain information about the tolerability of tipifarnib in children and adolescents with relapsed or refractory cancer. EXPLORATORY OBJECTIVES: I. To evaluate other biomarkers as predictors of response to tipifarnib and specifically, whether tumors that harbor different missense mutations or variant allele frequency will demonstrate differential response to tipifarnib treatment. II. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA). OUTLINE: Patients receive tipifarnib orally (PO) or via nasogastric or gastric tube twice daily (BID) on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with positron emission tomography (PET) scan, computed tomography (CT) scan, magnetic resonance imaging (MRI), or meta-iodobenzylguanidine (MIBG) scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial. After completion of study treatment, patients are followed up at 30 days, then periodically thereafter.

Advanced Malignant Solid Neoplasm, Ann Arbor Stage III Non-Hodgkin Lymphoma, Ann Arbor Stage IV Non-Hodgkin Lymphoma, Histiocytic Sarcoma, Juvenile Xanthogranuloma, Langerhans Cell Histiocytosis, Malignant Glioma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdoid Tumor, Recurrent Soft Tissue Sarcoma, Refractory Ewing Sarcoma, Refractory Glioma, Refractory Hepatoblastoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Solid Neoplasm, Refractory Medulloblastoma, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Osteosarcoma, Refractory Peripheral Primitive Neuroectodermal Tumor, Refractory Primary Central Nervous System Neoplasm, Refractory Rhabdoid Tumor, Refractory Rhabdomyosarcoma, Rhabdoid Tumor, Stage III Osteosarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Osteosarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7, Wilms Tumor

NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) Screening Protocol

PRIMARY OBJECTIVES: I. To utilize clinical and biological data to screen for eligibility to phase 2 pathway-targeting specific subprotocols of pathway-targeting agents in pediatric patients with advanced solid tumors, non-Hodgkin lymphomas, and histiocytic disorders. II. To determine the proportion of pediatric patients whose advanced tumors have pathway alterations that can be targeted by select anti-cancer drugs. (Completed) III. To determine the objective response rates (ORR; complete response + partial response) in pediatric patients with advanced solid tumors, non-Hodgkin lymphomas, and histiocytic disorders harboring a priori specified genomic alterations treated with pathway-targeting agents. SECONDARY OBJECTIVES: I. To estimate the progression free survival in pediatric patients receiving targeted therapies for advanced solid tumors, non-Hodgkin lymphomas, and histiocytic disorders. II. To obtain preliminary or additional information about the tolerability of targeted therapies in children with advanced cancers. III. To provide preliminary estimates of the pharmacokinetics of targeted therapies in children with advanced cancers. IV. To obtain preliminary information on the response rate to targeted therapy in patients whose tumors lack actionable alterations as defined for the molecular analysis for therapy choice (MATCH) study, for selected agents for which efficacy is observed in the primary matched cohort. EXPLORATORY OBJECTIVES: I. To increase knowledge of the genomic landscape of advanced pediatric solid tumors, non-Hodgkin lymphomas, and histiocytic disorders. II. To describe the genomic changes that occur in advanced pediatric cancers between the time of initial diagnosis and relapse, in cases for which paired tumor specimens are available. III. To explore approaches to diagnosing and profiling genomics of advanced pediatric cancers through evaluation of circulating tumor deoxyribonucleic acid (DNA). IV. To determine the frequency and spectrum of germline cancer susceptibility mutations in children with relapsed solid tumors and non-Hodgkin lymphomas and assess the feasibility of return of those results in the National Clinical Trial Network (NCTN) group setting. OUTLINE: STEP 1 (SCREENING): Patients undergo biopsy along with tumor mutational screening of the biopsy material for specific, pre-defined mutations, amplifications, or translocations of interest via tumor sequencing and immunohistochemistry. Patients also undergo collection of blood samples for research purposes. STEP 2 (TREATMENT): Patients with a mutation targeted by one or more of the investigational drugs used in this study or those without mutations are assigned to 1 of 10 treatment subprotocols. APEC1621A: Patients with a NTRK1, NTRK2, or NTRK3 gene fusion receive larotrectinib sulfate orally (PO) or via nasogastric- or gastric-tube twice daily (BID) on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. APEC1621B: Patients with a FGFR1, FGFR2, FGFR3, or FGFR4 gene mutation receive erdafitinib PO once daily (QD) on days 1-28 of each cycle. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, computed tomography (CT scan), magnetic resonance imaging (MRI), radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study. APEC1621C: Patients with an EZH2, SMARCB1, or SMARCA4 gene mutation receive tazemetostat PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. APEC1621D: Patients with a TSC1, TSC2, or PI3K/mTOR gene mutations receive PI3K/mTOR inhibitor LY3023414 PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. APEC1621E: Patients with an activating MAPK pathway gene mutation receive selumetinib sulfate PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. APEC1621F: Patients with an ALK or ROS1 gene alteration receive ensartinib (ALK Inhibitor X-396) PO BID on days 1-28. Cycles repeat every 28 days for 2 years (up to 26 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo an x-ray, CT scan, MRI, PET scan, radionuclide imaging, and/or bone scan, as well as a bone marrow aspiration and/or biopsy during screening and on study. Patients also undergo blood sample collection on study. APEC1621G: Patients with a BRAF V600 gene mutation receive vemurafenib PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. APEC1621H: Patients with deleterious ATM, BRCA1, BRCA2, RAD51C, or RAD51D gene mutations receive olaparib PO BID on days 1-28. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. APEC1621I: Patients with Rb positive advanced solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with activating alterations in cell cycle genes receive palbociclib PO QD on days 1-21. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. APEC1621J: Patients with MAPK Pathway Mutations receive ulixertinib PO BID. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. APEC1621M: Patients with HRAS gene alterations receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. APEC1621N: Patients with activating RET gene alterations receive selpercatinib PO BID on days 1-28. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients may also undergo PET, CT, MRI, PET/CT, PET/MRI, and/or CT/MRI, scintigraphy, and x-ray imaging throughout the trial. After completion of study treatment, patients are followed up periodically.

Ganglioneuroblastoma, Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Regional Neuroblastoma, Stage 4 Neuroblastoma, Stage 4S Neuroblastoma

Neuroblastoma Biology Studies

PRIMARY OBJECTIVES: I. To prospectively analyze the factors that are currently used for risk-group assignment (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog \[MYCN\] copy number by fluorescent in situ hybridization \[FISH\], deoxyribonucleic acid \[DNA\] content by flow cytometry, and tumor histology using the International Neuroblastoma Pathologic Classification System) in neuroblastoma tumors at the time of diagnosis. II. To maintain a reference bank containing clinically and genetically characterized frozen tumor tissue, tumor DNA and ribonucleic acid (RNA), histology slides and paraffin blocks, neuroblastoma-derived cell lines, patient serum and paired normal DNA obtained at the time of diagnosis, at the time of second-look surgery and at the time of relapse for future research studies. III. To prospectively analyze 1p, 11q, 14q and 17q allelic status, MYCN copy number by quantitative polymerase chain reaction (PCR); and the expression pattern of neurotrophin-related genes in diagnostic neuroblastoma tumors, and assay for the presence of rare tumor cells in biological specimens by reverse transcription (RT)-PCR; these biological variables will be analyzed for independent clinical significance compared to MYCN amplification, International Neuroblastoma Staging System (INSS) stage, age, ploidy, and histologic variables in predicting either response to treatment or outcome. IV. To build a database of the known biologic prognostic factors for patients on therapeutic studies. V. To serve as a Registry for neuroblastoma patients whose tumors demonstrate clinical and genetic features defined as ?Low Risk? for treatment failure in the absence of adjuvant therapy. SECONDARY OBJECTIVES: I. To prospectively analyze the concordance between detection of MYCN amplification in tumor samples and quantitative detection of MYCN DNA in serum, and to analyze the prognostic significance of MYCN amplification as detected in serum samples. II. To build a database that includes information regarding the presentation and natural history of neuroblastoma-associated health problems including but not limited to opsoclonus myoclonus ataxia (OMA) and/or spinal cord compression. OUTLINE: Patients undergo collection of blood, tissue, and bone marrow samples for analysis via RT-PCR, quantitative PCR, flow cytometry, and FISH. After completion of study, patients are followed up periodically.

Childhood Malignant Neoplasm

Neuropsychological, Social, Emotional, and Behavioral Outcomes in Children With Cancer

PRIMARY OBJECTIVES: I. To institute procedures to ensure a consistent, streamlined, and efficient administration of the neuropsychological/behavioral tests in a cooperative group setting in order to maximize compliance with a standardized assessment battery conducted at 3 standardized time points. OUTLINE: Parent and child participants complete the COG Standard Neuropsychological and Behavioral Battery at approximately 9, 30, and 60 months post-diagnosis in a 1-2 hour testing session conducted by a neuropsychologist or psychologist. The Battery consists of measures of intelligence, processing speed, attention, memory, language preference, behavioral/social/emotional function, executive function, adaptive function, and quality of life.

Neuroblastoma

NMTT- Neuroblastoma Maintenance Therapy Trial Using Difluoromethylornithine (DFMO)

• 7175310003
• BCCEnroll@pennstatehealth.psu.edu

Rheumatic Joint Disease

Observational Study of Pediatric Rheumatic Diseases: The CARRA Registry

The original Childhood Arthritis \& Rheumatology Research Alliance (CARRA) Registry (Protocol Number: CRNT_REGST01) was first established in 2010 to advance alliance infrastructure, facilitate expanded clinical and translational pediatric research, and transform the culture of pediatric rheumatology toward universal participation in research. This original CARRA Registry will be referred to throughout the protocol as the CARRA Legacy Registry. Through the creation of a sophisticated informatics infrastructure, provision of comprehensive site support and the engagement of families, patients, and communities, the CARRA Registry will provide the opportunity for affected children at every CARRA Registry site to participate in high-quality clinical and translational research. Continuation of the CARRA Registry as described in this protocol will support data collection on patients with pediatric-onset rheumatic diseases. The CARRA Registry will form the basis for future CARRA studies. In particular, this observational registry will be used to answer pressing questions about therapeutics used to treat pediatric rheumatic diseases, including examining safety questions. The Duke Clinical Research Institute (DCRI) is serving as the CARRA Clinical and Data Coordinating Center (CDCC) for the protocol. Traditional exposure-based post-marketing registries of individual therapeutic agents for juvenile idiopathic arthritis (JIA), systemic lupus erythematosus, and other rheumatic diseases are inadequate for answering important safety questions for many reasons: * Sample sizes are too small to detect uncommon but important events * No unexposed comparators exist to evaluate risk attributable to underlying disease * Duration of follow-up of individual patients is too short to evaluate many potential delayed adverse events (AEs) * Sample sizes are inadequate to assess myriad complex and dynamic concurrent medication regimens common to treatment of rheumatic diseases * Selective patient enrollment limits evaluation of co-morbid conditions and other patient factors These limitations prevent patients, families, and providers from understanding the true risks and benefits of therapy in order to make appropriate and informed decisions. They also prevent drug manufacturers and regulatory agencies from conducting an informed review of marketed products for these diseases. A registry based on disease diagnosis rather than specific therapeutic agents overcomes many of the limitations of exposure-based single-agent registries in the assessment of delayed or uncommon safety events. Indeed, data from a consolidated disease-based registry "...could provide the information necessary for individual companies to satisfy post-marketing requirements and commitments and obviate the need for an individual product registry" (letters from the United States (US) Food and Drug Administration (FDA) to CARRA, 21 December 2010 and 9 December 2011). This protocol details the foundation of a registry to meet these objectives. The CARRA Registry aims to detect and understand the epidemiology of important AEs, including those that are delayed or uncommon. Subjects followed at active CARRA Registry sites are eligible for enrollment, regardless of past or current treatment. Each subject will be followed prospectively for a goal of 10 years duration; the study will continue indefinitely as resources allow and continued need exists. Data will be systematically collected, including important patient factors, therapies, serious adverse events (SAEs), and protocol-defined events of special interest. Selected safety events (e.g., malignancies) will be adjudicated by a panel of experts via a review of medical records. The CARRA Registry, a disease-based prospective observational registry, enables both detection of potential safety signals and hypothesis-driven, rigorous, and adequately-controlled pharmacoepidemiologic studies of important AEs and their associations with therapeutic agents. In addition to answering questions about the safety of therapeutics, the data collected in the CARRA Registry are anticipated to serve many other valuable uses. Within the confines of observational study design, the effectiveness of therapeutic agents may be examined for short- and long-term clinical and patient-centered outcomes. The Registry is the data collection platform for Consensus Treatment Plan (CTP) comparative effectiveness research in pediatric rheumatic disease. Patients enrolled in the Registry may also be eligible to be followed as part of a CTP subset. Examples of CTP projects include: FiRst line Options for Systemic JIA Treatment (FROST). The purpose of FROST was to compare the effectiveness of CARRA systemic JIA (sJIA) treatment strategies (biologic vs. non-biologic) in achieving clinically inactive disease in patients with new-onset sJIA. Additionally, FROST aimed to compare patient/caregiver reported outcomes between treatment strategies. FROST enrolled new-onset, previously untreated sJIA patients who are starting treatment with one of the 4 sJIA CTPs (glucocorticoid (GC) only; Methotrexate + GC; IL-1 inhibitor + GC; IL-6 + GC). Enrollment will occur over 3 years at all CARRA Registry sites. In addition to routine Registry data collection, patients followed as part of the FROST CTP completed additional questionnaires about their disease status and quality of life. Medication use for pediatric rheumatic diseases is dynamic and not well characterized. The CARRA Registry represents a powerful data source to follow drug use patterns and provides the opportunity to study predictors of medication use. Important outcomes are likely to be influenced by other factors in addition to therapy (e.g., disease severity) and the CARRA Registry is positioned to help answer these types of questions. Patient-reported outcomes (PROs) generated by patients outside the context of clinical encounters may be collected in the Registry to provide a rich, additional dimension of data to better understand rheumatic diseases. Practitioners may review clinical data from their sites as part of a quality improvement approach to better outcomes. Analyses of CARRA Registry data aim to provide results to guide the therapeutic decisions made by affected children, families, and providers while improving regulatory efficiency and reducing cost. Ultimately, this approach might serve as a model for successful collaboration between research community networks, industry, and public agencies to promote the effective and efficient evaluation of drugs and devices across the regulatory continuum.

• (919) 419-5032
• mara.becker@duke.edu

H3 K27M, Glioma

ONC201 for the Treatment of Newly Diagnosed H3 K27M-mutant Diffuse Glioma Following Completion of Radiotherapy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

• 1-919-806-1074
• clinicaltrials@chimerix.com

Hematopoietic and Lymphatic System Neoplasm, Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Recurrent Malignant Solid Neoplasm

Patient-Derived Models Tissue Procurement Protocol for the National Cancer Institute (NCI)

PRIMARY OBJECTIVE: I. To procure biologic tissues and materials to generate preclinical models of cancer. OUTLINE: This is an observational study. Tumor tissue and blood samples are procured during procedures that are required for the patients' clinical management and will be stored via xenograft (transplant to another species) models or in vitro cell culture for future analysis.

Hematopoietic and Lymphatic System Neoplasm, Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Recurrent Malignant Solid Neoplasm

Patient-Derived Models Tissue Procurement Protocol for the National Cancer Institute (NCI)

PRIMARY OBJECTIVE: I. To procure biologic tissues and materials to generate preclinical models of cancer. OUTLINE: This is an observational study. Tumor tissue and blood samples are procured during procedures that are required for the patients' clinical management and will be stored via xenograft (transplant to another species) models or in vitro cell culture for future analysis.

Alveolar Soft Part Sarcoma, Angiomatoid Fibrous Histiocytoma, Atypical Fibroxanthoma, Clear Cell Sarcoma of Soft Tissue, Epithelioid Malignant Peripheral Nerve Sheath Tumor, Epithelioid Sarcoma, Extraskeletal Myxoid Chondrosarcoma, Extraskeletal Osteosarcoma, Fibrohistiocytic Neoplasm, Fibrosarcoma, Inflammatory Myofibroblastic Tumor, Intimal Sarcoma, Leiomyosarcoma, Liposarcoma, Liver Embryonal Sarcoma, Low Grade Fibromyxoid Sarcoma, Low Grade Myofibroblastic Sarcoma, Malignant Peripheral Nerve Sheath Tumor, Malignant Skin Granular Cell Tumor, Malignant Triton Tumor, Mesenchymal Chondrosarcoma, Myxofibrosarcoma, Myxoid Chondrosarcoma, Myxoinflammatory Fibroblastic Sarcoma, Nerve Sheath Neoplasm, PEComa, Pericytic Neoplasm, Plexiform Fibrohistiocytic Tumor, Sclerosing Epithelioid Fibrosarcoma, Skin Glomus Tumor, Stage IB Soft Tissue Sarcoma AJCC v7, Stage IIB Soft Tissue Sarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Synovial Sarcoma, Undifferentiated High Grade Pleomorphic Sarcoma of Bone

Pazopanib Neoadjuvant Trial in Non-Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NSC# 737754)

PRIMARY OBJECTIVES: I. To identify the dose of pazopanib that is feasible when given in combination with radiation or chemoradiation in pediatric and adult patients newly diagnosed with unresected intermediate- and high-risk non rhabdomyosarcoma soft tissue sarcomas (NRSTS). II. To compare the rates of near complete pathologic response (\> 90% necrosis) with the addition of pazopanib to preoperative chemoradiation versus preoperative chemoradiation alone for potentially resectable \> 5 cm, grade 2 or 3 intermediate to high risk chemotherapy-sensitive NRSTS in the phase II portion of the study for this cohort. III. To compare the rates of near complete pathologic response (\> 90% necrosis) with the addition of pazopanib to preoperative radiotherapy versus preoperative radiotherapy alone for potentially resectable intermediate to high risk adult and pediatric NRSTS in the phase II portion of the study for this cohort (using a phase II decision rule to go onto the phase III portion of the study). IV. To compare the rates of event-free survival (EFS) with the addition of pazopanib to preoperative radiotherapy versus preoperative radiotherapy alone for localized intermediate to high risk adult and pediatric NRSTS in the phase III portion of the study for this cohort if the phase II decision rule is passed. SECONDARY OBJECTIVES: I. To estimate the rates of local failure, regional failure, distant metastasis free survival, disease-free survival, and overall survival with the addition of pazopanib to preoperative chemoradiation or preoperative radiation in intermediate to high risk adult and pediatric NRSTS. II. To compare the pattern of recurrence (local, regional and distant) between preoperative chemoradiation or radiation with the addition of pazopanib for adult and pediatric NRSTS. III. To define the toxicities of ifosfamide and doxorubicin chemotherapy and radiation when used in combination with pazopanib in intermediate to high risk adult and pediatric NRSTS. IV. To define the toxicities of preoperative radiotherapy when used in combination with pazopanib in intermediate to high risk adult and pediatric NRSTS. EXPLORATORY OBJECTIVES: I. To gain insight into the disease biology of childhood and adult NRSTS through analysis of actionable mutations and whole genome sequencing. II. To determine if microvessel density and circulating tumor deoxyribonucleic acid (DNA) predict response to pazopanib and outcome. III. To determine the effect of pazopanib on doxorubicin exposure in children and adults with NRSTS. IV. To evaluate change in fludeoxyglucose F 18 (FDG) positron emission tomography (PET) maximum standard uptake value (SUVmax) from baseline to week 10 or 13 in patients with unresected tumors and to correlate this change with pathologic response and EFS. V. To compare the rate of response by standard imaging and pathologic assessment to determine which correlates better with local tumor control, distant tumor control, EFS, and overall survival. OUTLINE: This study starts as a dose-escalation study of pazopanib. CHEMOTHERAPY COHORT: Patients eligible for chemotherapy cohort are randomized to 1 of 2 treatment regimens. REGIMEN A: INDUCTION PHASE: Patients receive pazopanib orally (PO) once daily (QD) on weeks 1-12, ifosfamide intravenously (IV) over 2-4 hours on days 1-3 on weeks 1, 4, 7, 10, and doxorubicin IV over 1-15 minutes on days 1-2 on weeks 1 and 4. At least 24 hours after the completion of week 4 doxorubicin, patients undergo radiation therapy on weeks 4-10. SURGERY: Patients undergo surgery on week 13. CONTINUATION PHASE: Patients receive pazopanib PO QD on weeks 16-25, ifosfamide IV over 2-4 hours on days 1-3 on weeks 16 and 19, and doxorubicin IV over 1-15 minutes on days 1-2 on weeks 16, 19, and 22. If applicable, patients undergo additional radiation therapy at week 16 REGIMEN B: INDUCTION PHASE: Patients receive ifosfamide IV over 2-4 hours on days 1-3 on weeks 1, 4, 7, 10 and doxorubicin hydrochloride IV over 1-15 minutes on days 1-2 on weeks 1 and 4. At least 24 hours after the completion of week 4 doxorubicin, patients undergo radiation therapy on weeks 4-10. SURGERY: Patients undergo surgery on week 13. CONTINUATION PHASE: Patients receive ifosfamide IV over 2-4 hours on days 1-3 on weeks 16 and 19 and doxorubicin IV over 1-15 minutes on days 1-2 on weeks 16, 19, and 22. If applicable, patients undergo additional radiation therapy at week 16. NON-CHEMOTHERAPY COHORT: Patients eligible for non-chemotherapy cohort are randomized to 1 of 2 treatment regimens. REGIMEN C: INDUCTION PHASE: Patients receive pazopanib PO QD on weeks 1-9. Patients undergo radiation therapy on weeks 1-7. SURGERY: Patients undergo surgery on week 10. CONTINUATION PHASE: Patients receive pazopanib PO QD on weeks 13-25. If applicable, patients undergo additional radiation therapy at week 13. REGIMEN D: INDUCTION PHASE: Patients undergo radiation therapy on weeks 1-7. SURGERY: Patients undergo surgery on week 10. CONTINUATION PHASE: If applicable, patients undergo additional radiation therapy at week 13. After completion of study treatment, patients are followed up at 6, 12, 18, 24, 30, 36, 48, and 60 months.

Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Acute Myeloid Leukemia Post Cytotoxic Therapy, Juvenile Myelomonocytic Leukemia, Mixed Phenotype Acute Leukemia, Myelodysplastic Syndrome, Myelodysplastic Syndrome Post Cytotoxic Therapy, Myeloid Leukemia Associated With Down Syndrome

Pediatric Acute Leukemia (PedAL) Screening Trial - Developing New Therapies for Relapsed Leukemias

PRIMARY OBJECTIVES: I. To utilize clinical and biological characteristics of acute leukemias to screen for patient eligibility for available phase I/II Pediatric Acute Leukemia (PedAL) sub-trials. II. To maintain a longitudinal and comprehensive registry, as well as a specimen bank, from relapse in children and young adults with acute leukemias. OUTLINE: Patients undergo collection of blood and/or bone marrow samples at baseline, end of treatment cycle(s), and at relapse/refractory disease status (if applicable). After completion of study, patients are followed up every 3 months for 2 years, and then every 6 months for 3 years.

Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Acute Myeloid Leukemia Post Cytotoxic Therapy, Juvenile Myelomonocytic Leukemia, Mixed Phenotype Acute Leukemia, Myelodysplastic Syndrome, Myelodysplastic Syndrome Post Cytotoxic Therapy, Myeloid Leukemia Associated With Down Syndrome

Pediatric Acute Leukemia (PedAL) Screening Trial - Developing New Therapies for Relapsed Leukemias

PRIMARY OBJECTIVES: I. To utilize clinical and biological characteristics of acute leukemias to screen for patient eligibility for available phase I/II Pediatric Acute Leukemia (PedAL) sub-trials. II. To maintain a longitudinal and comprehensive registry, as well as a specimen bank, from relapse in children and young adults with acute leukemias. OUTLINE: Patients undergo collection of blood and/or bone marrow samples at baseline, end of treatment cycle(s), and at relapse/refractory disease status (if applicable). After completion of study, patients are followed up every 3 months for 2 years, and then every 6 months for 3 years.

Childhood Hepatocellular Carcinoma, Childhood Malignant Liver Neoplasm, Fibrolamellar Carcinoma, Hepatoblastoma, Hepatocellular Malignant Neoplasm, Not Otherwise Specified

Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)

PRIMARY OBJECTIVES: I. To reduce therapy associated toxicity for patients with non-metastatic hepatoblastoma (HB) and hepatocellular carcinoma (HCC) without adversely affecting long term outcomes. II. To determine the event-free survival (EFS) in patients with HB whose tumor is completely resected at diagnosis and either receive no adjuvant chemotherapy (completely resected well differentiated fetal \[WDF\] histology HB) or 2 cycles of standard dose cisplatin monotherapy (completely resected non-well differentiated fetal histology HB - 100 mg/m\^2/cycle given 3 weeks apart). (Group A) III. To demonstrate that 4 to 6 cycles of interval compressed lower dose cisplatin monotherapy (80 mg/m\^2/cycle; 320-480 mg/m\^2 total) is adequate for low risk HB. (Group B) IIIa. In patients who are resected after 2 cycles of cisplatin monotherapy, to compare EFS following a randomized comparison of 2 versus 4 post-operative cycles of cisplatin monotherapy. (Group B) IIIb. In patients whose tumors are deemed unresectable after 2 cycles of cisplatin monotherapy, to determine the proportion of tumors rendered completely resectable by an additional 2 or 4 cycles of chemotherapy. (Group B) IV. To compare in a randomized fashion, EFS in patients with intermediate risk HB treated with 6 cycles of cisplatin/5-fluorouracil/vincristine/doxorubicin (C5VD) chemotherapy versus 6 cycles of interval compressed cisplatin monotherapy (100 mg/m\^2/dose). (Group C) V. To determine the EFS in patients with HCC whose tumor is completely resected at diagnosis who receive no adjuvant chemotherapy (completely resected HCC arising in the context of underlying liver disease) or 4 cycles of cisplatin/doxorubicin (PLADO) (completely resected de novo HCC). (Group E) VI. To improve the EFS of patients with high risk HB by treating them with interval compressed cisplatin and doxorubicin based induction regimen followed by response-adapted consolidation therapy. (Group D) VIa. In patients whose metastatic disease resolves with the administration of Societe Internationale d'Oncologie Pediatrique (SIOPEL) 4 Induction therapy, to determine if the promising pilot results observed in SIOPEL 4 can be validated in a large international study. (Group D1) VIb. In patients whose metastatic disease does not resolve with the administration of SIOPEL 4 Induction therapy, to determine in a randomized comparison which post induction treatment (irinotecan and vincristine sulfate \[vincristine\] alternating with carboplatin and doxorubicin or carboplatin and etoposide alternating with carboplatin and doxorubicin) results in superior outcomes. (Group D Arm CE \& Arm VI) VII. In patients with unresectable/metastatic HCC at diagnosis, to determine whether the addition of gemcitabine and oxaliplatin (GEMOX + sorafenib) to a cisplatin, doxorubicin and sorafenib backbone improves chemotherapy response, resectability and survival. (Group F) EXPLORATORY OBJECTIVES: I. To determine if the Childhood Hepatic tumor International Consortium (CHIC) hepatoblastoma risk stratification analysis of very low risk (Group A), low risk (Group B), intermediate risk (Group C) and high risk (Group D) groups stratifies patients allowing appropriate utilization of varying intensity chemotherapy regimens and surgical resection strategies. II. To define the prognostic relevance of a positive microscopic margin in Group A-D resected HB specimens. III. To define the frequency of histologically detectable multifocal lesions in liver explants and resected specimens in which multifocal disease was detected at diagnosis and disappeared on cross sectional imaging following treatment with chemotherapy. IV. To define the prognostic relevance in HB of a 'small cell undifferentiated' tumor component and percentage of tumor necrosis in post chemotherapy specimens. V. To determine the prognostic impact on EFS and overall survival (OS) of biopsy technique in liver tumors unresectable at diagnosis. VI. To determine the 3-year EFS and OS of HB patients who undergo liver transplantation vs extreme resection in Group C and D patients. VII. To determine the 3-year EFS and OS of Group D patients who undergo pulmonary metastasectomy. VIII. To determine the 3-year EFS and OS of patients who undergo liver transplantation for HCC. IX. To determine the frequency of relapse in non-metastatic HCC in children treated by liver transplantation versus conventional resection. X. To determine the concordance of Pretreatment Extent of Disease (PRETEXT) and Post-treatment Extent of disease (POSTTEXT) based surgical guidelines and the surgical intervention performed. XI. To collect for future analysis, HB and HCC tumor specimens that can be molecularly characterized to validate newly identified molecular and immunohistochemical biomarkers correlating with known clinical prognostic factors and outcome. XII. To evaluate the hepatoblastoma molecular risk-predictive model (HB-MRP) to risk stratify hepatoblastoma patients in the context of the current AHEP1531 trial. XIII. To collect for future analysis samples to assess the pharmacogenomics (PG) related to cisplatin therapy in pediatric and adolescent liver tumor patients and correlate PG with Boston Grading Scale for ototoxicity. XIV. To collect for future analysis samples such that novel biomarkers of renal toxicity (urine neutrophil gelatinase-associated lipocalin \[NGAL\], cystatin C and Kim1) from cisplatin therapy can be correlated with pharmacogenomics, other associated toxicities, and outcomes. XV. To determine which system (Children's Oncology Group \[COG\] PRETEXT, SIOPEL PRETEXT, or a new hybrid definition of PRETEXT) of the annotation factors for V, P, E, F and R provides the best prognostic information for determining response to chemotherapy, guiding risk based therapy, predicting surgical resectability, and EFS. XVI. To determine the concordance between institutional and expert panel review assessment of PRETEXT and POSTTEXT stage in an international cooperative group setting. OUTLINE: GROUP A (VERY LOW RISK HB): Patients are assigned to 1 of 2 groups. GROUP A1 (WDF): Patients undergo observation. GROUP A2 (NON-WDF): Patients receive cisplatin (CDDP) intravenously (IV) over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. GROUP B (LOW RISK HB): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 2 groups. GROUP B1 (RESECTABLE): Patients receive 2 cycles of cisplatin, undergo surgery, then are randomized to 1 of 2 arms (2 vs 4 additional cycles of cisplatin). GROUP B1 ARM 4-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 4 total cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity. GROUP B1 ARM 6-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity. GROUP B2 (UNRESECTABLE): Patients receive 2 cycles of cisplatin, then are assigned to 1 of 2 arms (resectable vs unresectable). GROUP B2 ARM I (RESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (4 pre-surgery, 2 post-surgery). After cycle 4, patients undergo surgery, then continue with 2 additional cycles of cisplatin. GROUP B2 ARM II (UNRESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles. GROUP C (INTERMEDIATE RISK HB): Patients are randomized to 1 of 2 arms. GROUP C ARM CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4. GROUP C ARM C5VD: Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over 1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4. GROUP D (HIGH RISK HB): SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9 (for cycles 1 and 2) and days 1 and 2 (for cycle 3). Cycles 1 and 2 are 28 days; cycle 3 is 21 days. Patients are then assigned to 1 of 2 arms. GROUP D1: CONSOLIDATION THERAPY: Patients with lung complete remission (either with chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. GROUP D2: Patients with residual metastatic disease are randomized to 1 of 2 arms. GROUP D2 ARM CE: Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin IV over 1 hour and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. GROUP D2 ARM VI: Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 60-90 minutes once daily (QD) on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. GROUP E (RESECTED HCC): Patients are assigned to 1 of 2 groups. GROUP E1: Patients with HCC secondary to underlying hepatic disease undergo observation only. GROUP E2 (PLADO): Patients with de novo HCC receive cisplatin IV over 6 hours on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. GROUP F (UNRESECTED AND/OR METASTATIC HCC): Patients are randomized to 1 of 2 arms. GROUP F ARM 1 (PLADO): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib orally (PO) twice daily (BID) on days 3-21. Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 cycles of the treatment. GROUP F ARM 2 (P/GEMOX): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3. Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 cycles of the treatment. Patients may undergo blood sample collection on study. After completion of study treatment, patients are followed up for a minimum of 2 years.

Childhood Hepatocellular Carcinoma, Childhood Malignant Liver Neoplasm, Fibrolamellar Carcinoma, Hepatoblastoma, Hepatocellular Malignant Neoplasm, Not Otherwise Specified

Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)

PRIMARY OBJECTIVES: I. To reduce therapy associated toxicity for patients with non-metastatic hepatoblastoma (HB) and hepatocellular carcinoma (HCC) without adversely affecting long term outcomes. II. To determine the event-free survival (EFS) in patients with HB whose tumor is completely resected at diagnosis and either receive no adjuvant chemotherapy (completely resected well differentiated fetal \[WDF\] histology HB) or 2 cycles of standard dose cisplatin monotherapy (completely resected non-well differentiated fetal histology HB - 100 mg/m\^2/cycle given 3 weeks apart). (Group A) III. To demonstrate that 4 to 6 cycles of interval compressed lower dose cisplatin monotherapy (80 mg/m\^2/cycle; 320-480 mg/m\^2 total) is adequate for low risk HB. (Group B) IIIa. In patients who are resected after 2 cycles of cisplatin monotherapy, to compare EFS following a randomized comparison of 2 versus 4 post-operative cycles of cisplatin monotherapy. (Group B) IIIb. In patients whose tumors are deemed unresectable after 2 cycles of cisplatin monotherapy, to determine the proportion of tumors rendered completely resectable by an additional 2 or 4 cycles of chemotherapy. (Group B) IV. To compare in a randomized fashion, EFS in patients with intermediate risk HB treated with 6 cycles of cisplatin/5-fluorouracil/vincristine/doxorubicin (C5VD) chemotherapy versus 6 cycles of interval compressed cisplatin monotherapy (100 mg/m\^2/dose). (Group C) V. To determine the EFS in patients with HCC whose tumor is completely resected at diagnosis who receive no adjuvant chemotherapy (completely resected HCC arising in the context of underlying liver disease) or 4 cycles of cisplatin/doxorubicin (PLADO) (completely resected de novo HCC). (Group E) VI. To improve the EFS of patients with high risk HB by treating them with interval compressed cisplatin and doxorubicin based induction regimen followed by response-adapted consolidation therapy. (Group D) VIa. In patients whose metastatic disease resolves with the administration of Societe Internationale d'Oncologie Pediatrique (SIOPEL) 4 Induction therapy, to determine if the promising pilot results observed in SIOPEL 4 can be validated in a large international study. (Group D1) VIb. In patients whose metastatic disease does not resolve with the administration of SIOPEL 4 Induction therapy, to determine in a randomized comparison which post induction treatment (irinotecan and vincristine sulfate \[vincristine\] alternating with carboplatin and doxorubicin or carboplatin and etoposide alternating with carboplatin and doxorubicin) results in superior outcomes. (Group D Arm CE \& Arm VI) VII. In patients with unresectable/metastatic HCC at diagnosis, to determine whether the addition of gemcitabine and oxaliplatin (GEMOX + sorafenib) to a cisplatin, doxorubicin and sorafenib backbone improves chemotherapy response, resectability and survival. (Group F) EXPLORATORY OBJECTIVES: I. To determine if the Childhood Hepatic tumor International Consortium (CHIC) hepatoblastoma risk stratification analysis of very low risk (Group A), low risk (Group B), intermediate risk (Group C) and high risk (Group D) groups stratifies patients allowing appropriate utilization of varying intensity chemotherapy regimens and surgical resection strategies. II. To define the prognostic relevance of a positive microscopic margin in Group A-D resected HB specimens. III. To define the frequency of histologically detectable multifocal lesions in liver explants and resected specimens in which multifocal disease was detected at diagnosis and disappeared on cross sectional imaging following treatment with chemotherapy. IV. To define the prognostic relevance in HB of a 'small cell undifferentiated' tumor component and percentage of tumor necrosis in post chemotherapy specimens. V. To determine the prognostic impact on EFS and overall survival (OS) of biopsy technique in liver tumors unresectable at diagnosis. VI. To determine the 3-year EFS and OS of HB patients who undergo liver transplantation vs extreme resection in Group C and D patients. VII. To determine the 3-year EFS and OS of Group D patients who undergo pulmonary metastasectomy. VIII. To determine the 3-year EFS and OS of patients who undergo liver transplantation for HCC. IX. To determine the frequency of relapse in non-metastatic HCC in children treated by liver transplantation versus conventional resection. X. To determine the concordance of Pretreatment Extent of Disease (PRETEXT) and Post-treatment Extent of disease (POSTTEXT) based surgical guidelines and the surgical intervention performed. XI. To collect for future analysis, HB and HCC tumor specimens that can be molecularly characterized to validate newly identified molecular and immunohistochemical biomarkers correlating with known clinical prognostic factors and outcome. XII. To evaluate the hepatoblastoma molecular risk-predictive model (HB-MRP) to risk stratify hepatoblastoma patients in the context of the current AHEP1531 trial. XIII. To collect for future analysis samples to assess the pharmacogenomics (PG) related to cisplatin therapy in pediatric and adolescent liver tumor patients and correlate PG with Boston Grading Scale for ototoxicity. XIV. To collect for future analysis samples such that novel biomarkers of renal toxicity (urine neutrophil gelatinase-associated lipocalin \[NGAL\], cystatin C and Kim1) from cisplatin therapy can be correlated with pharmacogenomics, other associated toxicities, and outcomes. XV. To determine which system (Children's Oncology Group \[COG\] PRETEXT, SIOPEL PRETEXT, or a new hybrid definition of PRETEXT) of the annotation factors for V, P, E, F and R provides the best prognostic information for determining response to chemotherapy, guiding risk based therapy, predicting surgical resectability, and EFS. XVI. To determine the concordance between institutional and expert panel review assessment of PRETEXT and POSTTEXT stage in an international cooperative group setting. OUTLINE: GROUP A (VERY LOW RISK HB): Patients are assigned to 1 of 2 groups. GROUP A1 (WDF): Patients undergo observation. GROUP A2 (NON-WDF): Patients receive cisplatin (CDDP) intravenously (IV) over 6 hours on day 1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. GROUP B (LOW RISK HB): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients are then assigned to 1 of 2 groups. GROUP B1 (RESECTABLE): Patients receive 2 cycles of cisplatin, undergo surgery, then are randomized to 1 of 2 arms (2 vs 4 additional cycles of cisplatin). GROUP B1 ARM 4-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 4 total cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity. GROUP B1 ARM 6-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity. GROUP B2 (UNRESECTABLE): Patients receive 2 cycles of cisplatin, then are assigned to 1 of 2 arms (resectable vs unresectable). GROUP B2 ARM I (RESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles (4 pre-surgery, 2 post-surgery). After cycle 4, patients undergo surgery, then continue with 2 additional cycles of cisplatin. GROUP B2 ARM II (UNRESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles. GROUP C (INTERMEDIATE RISK HB): Patients are randomized to 1 of 2 arms. GROUP C ARM CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4. GROUP C ARM C5VD: Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over 1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle 2 or 4. GROUP D (HIGH RISK HB): SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over 1-15 minutes on days 8 and 9 (for cycles 1 and 2) and days 1 and 2 (for cycle 3). Cycles 1 and 2 are 28 days; cycle 3 is 21 days. Patients are then assigned to 1 of 2 arms. GROUP D1: CONSOLIDATION THERAPY: Patients with lung complete remission (either with chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. GROUP D2: Patients with residual metastatic disease are randomized to 1 of 2 arms. GROUP D2 ARM CE: Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin IV over 1 hour and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. GROUP D2 ARM VI: Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 60-90 minutes once daily (QD) on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. GROUP E (RESECTED HCC): Patients are assigned to 1 of 2 groups. GROUP E1: Patients with HCC secondary to underlying hepatic disease undergo observation only. GROUP E2 (PLADO): Patients with de novo HCC receive cisplatin IV over 6 hours on day 1 and doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. GROUP F (UNRESECTED AND/OR METASTATIC HCC): Patients are randomized to 1 of 2 arms. GROUP F ARM 1 (PLADO): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib orally (PO) twice daily (BID) on days 3-21. Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 cycles of the treatment. GROUP F ARM 2 (P/GEMOX): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3. Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 cycles of the treatment. Patients may undergo blood sample collection on study. After completion of study treatment, patients are followed up for a minimum of 2 years.

Ewing Sarcoma, Solid Tumors, Rhabdoid Tumor, Rhabdomyosarcoma, Neuroblastoma, Medulloblastoma, Diffuse Intrinsic Pontine Glioma

PHASE 1/2 STUDY TO EVALUATE PALBOCICLIB (IBRANCE®) IN COMBINATION WITH IRINOTECAN AND TEMOZOLOMIDE OR IN COMBINATION WITH TOPOTECAN AND CYCLOPHOSPHAMIDE IN PEDIATRIC PATIENTS WITH RECURRENT OR REFRACTORY SOLID TUMORS

Sickle Cell Disease, Pain

Phase 1-2 Trial of Gamunex (intravenous Gammaglobulin) for Sickle Cell Acute Pain

Patients will be randomized to a single dose of IVIG versus normal saline placebo during an uncomplicated pain crisis. Length of VOC and other secondary endpoints will be monitored.

• 718-741-2342
• dmanwani@montefiore.org

Neuroblastoma, Sarcoma

Phase 2 Study of Cabozantinib As a Maintenance Agent to Prevent Progression or Recurrence in High-Risk Pediatric Solid Tumors

The study hypothesizes that use of cabozantinib in patients with ultra-high-risk pediatric solid tumors who have achieved and maintained (for at least 4 weeks) a "best response" to their most recent line of therapy, as defined in the inclusion criteria below, can prevent and/or slow recurrent tumor formation in pediatric solid tumors, improve one-year progression-free survival by 20% as compared to historical controls, and also improve longer-term progression-free and overall survival without significant impact on quality of life. We also hypothesize, in an exploratory aim, that there will be improvement in two-year progression free survival in patients with metastatic Ewing sarcoma and osteosarcoma specifically. The study proposes to evaluate the efficacy of up to one year of treatment with cabozantinib in pediatric solid tumors after completion of last therapy with a "best response." There are multiple reasons for this approach, as opposed to continual therapy until toxicity or disease progression alone. First, for most of these ultra-high-risk diseases, the greatest risk of recurrence has historically been within 12 months after last therapy, and often times considerably sooner. As such, we should be able to evaluate a meaningful difference within 12 months. Second, the goal of this study is to evaluate if, during a critical period of disease control, use of cabozantinib can induce a durable remission. There are active Phase 2 and 3 studies of cabozantinib, including with the Children's Oncology Group, evaluating the efficacy of cabozantinib in controlling pediatric cancers with measurable burden of disease. However, we know that, in patients with "ultra-high-risk" disease who have achieved a best response including stable disease, partial response or even complete response, there is still active disease with high risk of growth, as demonstrated in the studies cited above. Our study seeks to augment ongoing work in pediatric cancers by testing the hypothesis that cabozantinib can durably silence cancer cell viability after a best response to prior treatment. Third, this work would mark a fundamental change in the indication for use of cabozantinib in pediatric cancers, broadening its utility from a "rescue" agent to a maintenance therapy that may be critical for disease control, during either primary or secondary remission. This study will expand the types of pediatric cancers being evaluated for response to cabozantinib. The current COG study is restricted to Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, and a handful of uncommon tumors. The proposed study will extend this evaluation to tumors that have been shown to either express known targets of cabozantinib or with preclinical evidence of efficacy, including specifically neuroblastomas. These tumors have high morbidity and mortality, particularly in the relapse setting, and few or no proven therapeutic options. As such, evaluation of cabozantinib in these studies is warranted.

• 6147223686
• megan.blue@nationwidechildrens.org

Recurrent Langerhans Cell Histiocytosis, Refractory Langerhans Cell Histiocytosis

Phase 2 Study of Tovorafenib (DAY101) in Relapsed and Refractory Langerhans Cell Histiocytosis

PRIMARY OBJECTIVE: I. To determine overall response rate (ORR) for children and young adults with relapsed or refractory BRAFV600E positive (cohort 1) and BRAFV600E negative (cohort 2) Langerhans cell histiocytosis (LCH) treated with tovorafenib (DAY101) after 2 cycles and must be maintained 4 weeks later. SECONDARY OBJECTIVES: I. To determine nature and severity of adverse events in patients treated with tovorafenib (DAY101) for relapsed or refractory LCH. II. To describe event-free survival (EFS) at 1 year in children and young adults with relapsed and refractory LCH treated with tovorafenib (DAY 101) for up to 1 year. III. To determine durability of response in children and young adults with relapsed or refractory LCH treated with tovorafenib (DAY101) following cessation of therapy in patients with complete response (CR) at 1 year. IV. To describe progression-free (and relapse-free) survival (PFS) and overall survival (OS) in children and young adults with relapsed or refractory LCH treated with tovorafenib (DAY101) for up to 1 year. EXPLORATORY OBJECTIVES: I. To determine potential role of pathogenic tumor mutation in response to tovorafenib (DAY101), and to evaluate changes in bone marrow and peripheral blood cell populations carrying pathogenic mutations in response to tovorafenib (DAY101) therapy. Ia. To define somatic mutations in LCH lesion biopsies; Ib. To determine impact of tovorafenib (DAY101) on bone marrow and blood BRAFV600E+ mononuclear cells; Ic. To determine impact of tovorafenib (DAY101) on cerebral spinal fluid and disease response; Id. To determine the performance of standardized immunohistochemical analysis of LCH lesion biopsies. II. To compare performance of LCH-specific response criteria to Response Evaluation Criteria in Solid Tumors (RECIST). III. To describe the pharmacokinetics of tovorafenib (DAY101) when administered to pediatric and young adult patients with relapse or refractory LCH. OUTLINE: This is a dose escalation study of tovorafenib followed by a phase II trial. Patients receive tovorafenib orally (PO) once weekly (QW) on days 1, 8, 15, and 22 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo multi-gated acquisition (MUGA) or echocardiography (ECHO) scans, and fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) or computed tomography (CT) throughout the trial, and collection of blood samples on study. Patients with suspicion of bone marrow and/or central nervous system involvement will also undergo bone marrow biopsy and aspiration and lumbar puncture on study and during follow up. After completion of study treatment, patients are followed up at 28 days, months 3, 6, 9, and 12, and then at 2 years post cycle 12.

Acute Lymphoblastic Leukemia, Leukemia, Acute Myeloid (AML), Child, Lymphoma, Non-Hodgkin, Myelodysplastic Syndromes, Primary Immune Deficiency Disorder, Osteopetrosis, Cytopenia, Hemoglobinopathy in Children, Anemia, Aplastic

Phase I/II Study of CaspaCIDe® T Cells From an HLA-Partially Matched Family Donor After Negative Selection of TCR αβ+T Cells in Pediatric Patients Affected by Hematological Disorders

This is a Phase 1/2 study evaluating the safety and feasibility of BPX-501 T cells infused after partially mismatched, related, TCR alpha beta T cell depleted hematopoietic stem cell transplant (HSCT) in pediatric patients. The purpose of this clinical trial is to determine whether BPX-501 infusion can enhance immune reconstitution in those patients with hematologic disorders, with the potential for reducing the severity and duration severe acute graft versus host disease (GvHD). The trial will also evaluate the treatment of GvHD by the infusion of dimerizer drug (AP1903/rimiducid) in those subjects who present with GVHD that does not adequately respond to standard of care therapy.

Osteosarcoma, Ewing Sarcoma, Rhabdomyosarcoma, Soft Tissue Sarcoma

Phase II Study of Nab-Paclitaxel in Combination With Gemcitabine for Treatment of Recurrent/Refractory Sarcoma in Teenagers and Young Adults

Pediatric Heart Transplantation, Immunosuppression, Chronic Kidney Diseases, Cardiac Allograft Vasculopathy, Heart Transplant Failure and Rejection, Post-transplant Lymphoproliferative Disorder, Heart Transplant Infection

Phase III Multicenter Open-label Randomized Clinical Trial Comparing Everolimus and Low Dose Tacrolimus to Tacrolimus and Mycophenolate Mofetil at 6 mo Post-Transplant to Prevent Long-term Complications After Pediatric Heart Transplantation

Median survival after pediatric heart transplantation (HT) is 15 years in the current era. This means that a substantial fraction of patients transplanted during childhood fail to survive to adulthood, or require heart re-transplantation, because of complications related to heart transplant. These complications include heart transplant rejection, infection, coronary artery disease, post-transplant lymphoproliferative disorder (PTLD; a form of lymphoma seen in transplant recipients), and kidney failure. Most complications stem not from the heart transplant itself, but from the drugs commonly used to suppress the immune system in order to prevent rejection. In the US, tacrolimus (TAC) and mycophenolate mofetil (MMF), have emerged over the past decade as the standard of care for pediatric heart transplant immunosuppression. While pediatric survival has improved significantly in the era of TAC and MMF, post-HT complications remain a major problem that limits median survival to 15 years. Recently, everolimus (EVL) has emerged as a potential alternative immunosuppressant that may prevent rejection, coronary artery disease and kidney failure more effectively than TAC/MMF when administered in combination with low-dose tacrolimus (LDTAC). Preliminary studies suggest that EVL, and its first-generation analog sirolimus, are well tolerated in children after HT, regardless of whether it is started in response to coronary artery disease, in response to chronic kidney disease, or empirically 4-6 months after transplant in an effort to prevent the development of these complications1. However, studies are generally limited to single-center experiences using historical controls and have inadequate statistical power to demonstrate treatment differences. This will be the first multicenter randomized clinical trial of maintenance immunosuppression in pediatric heart transplantation to systematically evaluate the safety and efficacy of EVL with LDTAC vs. TAC/MMF to prevent long-term complications which lead to death/graft loss. The major adverse transplant event (MATE) score will serve as the primary endpoint to power the trial. Because no Food \& Drug Administration (FDA)-approved immunosuppressants currently exist for children after heart transplant (all prescriptions are off-label) and market incentives to support a trial are limited, the investigators have funded the trial through a Fiscal Year 2016 Peer Reviewed Medical Research Program Clinical Trial Award sponsored by the Department of Defense office of the Congressionally Directed Medical Research Programs. It is worth noting that in contrast to adults, children have a substantially longer potential life expectancy if post-transplant complications can be minimized, making the prevention of late complications an urgent priority for the pediatric heart transplant community.

Anaplastic Ependymoma, Brain Ependymoma, Cellular Ependymoma, Clear Cell Ependymoma, Ependymoma, Papillary Ependymoma

Phase III Randomized Trial of Post-Radiation Chemotherapy in Patients With Newly Diagnosed Ependymoma Ages 1 to 21 Years

PRIMARY OBJECTIVE: I. To determine the event free survival (EFS) and overall survival (OS) of children with completely resected ependymoma treated with post-operative conformal radiation therapy (cRT) and then randomized to receive or not receive four cycles of post radiation maintenance chemotherapy (vincristine, cisplatin, etoposide and cyclophosphamide \[VCEC\]). EXPLORATORY OBJECTIVES: I. To estimate the EFS and OS of children with incompletely resected ependymoma who are unable to achieve a complete response (CR) by post-operative induction chemotherapy or by second surgery who will then be non-randomly assigned to cRT followed by four cycles of maintenance chemotherapy (VCEC). II. To further evaluate the EFS and OS of children with supratentorial classic ependymoma who achieve a complete resection at first or second resection OR children who achieve a CR to short course induction chemotherapy following first surgery. III. To evaluate whether the addition of maintenance chemotherapy post-radiation therapy contributes to neurobehavioral morbidity and reduced functional outcomes over time, compared to patients treated with radiation therapy followed by observation alone. IV. To examine differences in neurobehavioral outcomes and quality of life of children treated with proton beam radiation therapy compared to children treated with conventional radiation delivery techniques. V. To evaluate biologic prognostic factors in childhood ependymoma by studying molecular groups as defined by deoxyribonucleic acid (DNA) methylation profiling and immunohistochemistry, copy number variants to identify 1q gain in posterior fossa ependymomas, CDKN2A loss (homozygous deletion) in supratentorial ependymomas and specific genetic alterations such as RELA fusions, YAP1 fusions and the H3 K27M mutation on initial tumor samples and correlating these data with clinical outcome. Va. To explore prognostic molecular signatures and genomic alterations in ependymomas by building upon the data derived from ACNS0121 to correlate biomarkers listed above with World Health Organization (WHO) grade, location, extent of resection, treatment, EFS and OS. OUTLINE: This is a multicenter study partially randomized phase III study. Patients are randomized or non-randomly treated according to tumor location and extent of surgical resection or post-surgery induction chemotherapy response. Arm I: Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization. ARM III: Patients with supratentorial ependymoma (Grade II without GTR1 or ST Grade III) or any infratentorial ependymoma (Grade II or III) who have undergone gross or near total resection or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks and then undergo observation. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization. ARM IV: Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are non-randomly assigned to Arm II treatment. After completion of study therapy, patients are followed up every 4 months for 5 years, and then annually thereafter.

Chronic Kidney Diseases

Phosphate Binder Therapy and Chronic Kidney Disease in Children

We will conduct a double-blind, randomized, placebo-controlled trial to assess the effects of therapy with ferric citrate (FC) on changes in intact FGF23 levels (iFGF23, primary endpoint) aged 6-18 years of either sex with chronic kidney disease (CKD) stages 3-4 and age-appropriate normal serum phosphate levels. Participants will be randomized to one of the two groups: 1) FC or 2) FC placebo. Participants will be recruited from 20 core clinical sites. Schedule of Intervention: During the 12-month trial, participants will be given a daily fixed weight-based dose of FC. Schedule for data collection/analyses to be performed: Blood for primary outcome assessments will be collected at screening, baseline and at months 3, 6, 9, 12. Blood for safety assessments will be collected at the the months 1, 2, 3, 6, 9, 12. The primary analyses for this 2-arm trial will compare log-transformed iFGF23 values over 12 months between the treatment and the placebo arms. The analysis will use a linear mixed-effects model, including stratification factors CKD stage and urine protein to creatinine ratio, with random participant effects accounting for repeated measurements, and a fixed treatment effect, which interacts with a time indicator (Months 3-12 vs. Baseline/Screening). Primary objectives: * To assess the effects of therapy with FC on iFGF23 levels * To determine safety and tolerability of FC. Secondary objectives: • To assess the effects of FC on anemia and indices of mineral and bone metabolism. Primary Endpoint: • iFGF23 level Safety and Tolerability Endpoints: • Ability to safely tolerate FC Secondary Endpoints: * Anemia * Indices of mineral and bone metabolism This is a Phase 2 study with participation from 20 sites that will take 36 months to complete enrollment and a total of 48 months to complete data collection with each participant being part of the study for 12 months. Study website: fit4kid.dgsom.ucla.edu

• 310-7943144
• jbrook@mednet.ucla.edu

COVID-19 Infection, Hematopoietic and Lymphatic System Neoplasm, Malignant Solid Neoplasm

Prospective Cohort Study to Evaluate Immunologic Response Following COVID-19 Vaccination in Children, Adolescents and Young Adults With Cancer

PRIMARY OBJECTIVE: I. Characterize the immunologic response following severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 vaccination in children, adolescents, and young adults with cancer who are currently receiving or who recently completed treatment with immunosuppressive therapy. EXPLORATORY OBJECTIVES: I. Describe the rate of post-vaccination symptomatic SARS-CoV-2 infections. II. Assess the durability of immune response to SARS-CoV-2 vaccine over 2 years. III. Describe the longer-term impacts of vaccine immune response including subsequent COVID-19-related serious illness. IV. To help guide future vaccine dosing and timing, at each SARS-CoV-2 vaccine dose administration determine the degree of: IVa. Lymphopenia (absolute lymphocyte count cells/mm\^3); IVb. Helper T-cell suppression (CD4 count); IVc. B-cell suppression (CD19 count). V. Provide a mechanism for data collection and banking of biospecimens for use in research regarding immune response to SARS-CoV-2 vaccination. OUTLINE: Patients receive COVID-19 vaccine per standard of care. Patients also complete a survey at 1 month and undergo collection of blood samples at 1, 3, 6, 12, 18, and 24 months. Patients may complete an additional survey at 1 month after each vaccine boost and undergo collection of blood samples before each vaccine boost, 1 month after each vaccine boost, and at the time of COVID-19 infection.

Autologous Stem Cell Transplantation, Allogeneic Stem Cell Transplantation, Solid Tumors, Blood Cancers, CAR-T, Gene Therapy, Non-malignant Disease

Protocol for a Research Database for Hematopoietic Stem Cell Transplantation, Other Cellular Therapies and Marrow Toxic Injuries

• 763 406 3280
• databaseIRB@nmdp.org

Cmv Congenital, CMV, Congenital Cmv, SNHL, Sensorineural Hearing Loss

Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants: ValEAR Trial

Cytomegalovirus (CMV) can be transmitted from the mother to the fetus and is a leading cause of sensorineural hearing loss (SNHL), which is a condition where the inner ear is unable to convert sound into nerve impulses to the brain. This hearing loss and its detrimental effect on language development contribute nearly $4 billion annually to the health care costs in the U.S. Unlike other types of SNHL, CMV induced hearing loss can be treated. Several clinical trials have demonstrated that antiviral therapy may prevent progressive hearing loss if administered early in life for severely affected (symptomatic CMV) infants. These promising findings have given rise to a debate regarding the best method for identifying and treating the more numerous asymptomatic CMV-infected infants. One approach is to conduct universal newborn hearing screens, and then do CMV diagnostic testing only on the infants who fail the hearing screen. This targeted approach should identify those infants at greatest risk of developing progressive hearing loss and consequent communicative difficulties. Utah is the first state to mandate this approach whereby infants under three weeks of age who fail their newborn hearing screening undergo CMV testing. In this trial, the hearing screen targeted approach will be used to identify patients eligible for participation in a double blind placebo controlled randomized clinical trial of antiviral valganciclovir therapy. The results of this trial will inform public policy, potentially shift our current clinical practice regarding pediatric hearing loss evaluation, and potentially offer a therapeutic option to asymptomatic CMV-infected infants with SNHL.

Metastatic Ewing Sarcoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Bone Marrow, Metastatic Malignant Neoplasm in the Lung, Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone, Peripheral Primitive Neuroectodermal Tumor of Soft Tissues

Randomized Phase 3 Trial Evaluating the Addition of the IGF-1R Monoclonal Antibody Ganitumab (AMG 479, NSC# 750008) to Multiagent Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma

PRIMARY OBJECTIVES: I. To determine if event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy is improved with the addition of ganitumab (AMG 479). SECONDARY OBJECTIVES: I. To describe the toxicity of the addition of ganitumab to multimodality therapy for patients with newly diagnosed metastatic Ewing sarcoma. II. To compare overall survival in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy with and without the addition of ganitumab. EXPLORATORY OBJECTIVES: I. To compare bone marrow response rates in patients with newly diagnosed metastatic Ewing sarcoma treated with multiagent chemotherapy with and without the addition of ganitumab. II. To describe the toxicity of 6 months of ganitumab monotherapy as maintenance therapy following multimodality therapy in patients with newly diagnosed metastatic Ewing sarcoma. III. To describe trough levels of ganitumab in a cohort of patients with Ewing sarcoma \< 21 years of age treated with 18 mg/kg. IV. To describe the feasibility of and local failure rates following hypofractionated stereotactic body radiotherapy (SBRT) directed at bone metastases in patients with newly diagnosed metastatic Ewing sarcoma. V. To determine if EFS, overall survival, bone marrow response rates, and toxicity differ based on serum markers of the insulin-like growth factor 1 (IGF-1) pathway in patients with newly diagnosed metastatic Ewing sarcoma treated with interval compressed chemotherapy with and without the addition of ganitumab. VI. To determine if EFS, overall survival, and bone marrow response rates differ based on protein, deoxyribose nucleic acid (DNA), and ribonucleic acid (RNA) marker in patients with newly diagnosed metastatic Ewing sarcoma treated with interval compressed chemotherapy with and without the addition of ganitumab. VII. To evaluate bone marrow micrometastatic disease and tumor cell surface IGF-1R expression at diagnosis and after 3 and 6 cycles of study therapy in patients with newly diagnosed metastatic Ewing sarcoma. VIII. To determine if the presence of germline polymorphisms in EGFR correlate with response to multiagent therapy with and without ganitumab. IX. To investigate the ability of fludeoxyglucose F 18-positron emission tomography (FDG-PET) to augment conventional response assessment of primary Ewing sarcoma tumors by magnetic resonance imaging (MRI). X. To explore FDG-PET response at the primary tumor as a prognostic marker and as a predictive biomarker of clinical activity of IGF-1R inhibition in patients with newly diagnosed metastatic Ewing sarcoma. XI. To collect data on institutional testing for Ewing sarcoma breakpoint region 1 (EWSR1) translocation status in patients enrolling on study. XII. To explore the capacity of plasma cell-free DNA analysis to detect tumor-specific genetic changes at initial diagnosis and after initiation of protocol therapy. XIII. To collect a population of bone marrow metastatic tumor cells by flow cytometry for genomic profiling. OUTLINE: Patients are randomized to 1 of 2 treatment regimens. (As of 3/20/2019, the study is closed to accrual and patients in Regimen B no longer receive ganitumab.) REGIMEN A (vincristine sulfate, doxorubicin hydrochloride and cyclophosphamide \[VDC\] and ifosfamide and etoposide phosphate \[IE\]): INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) over 1 minute on day 1, doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2, and cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 5, and 9, and ifosfamide IV over 1 hour on days 1 to 5 and etoposide phosphate IV over 1-2 hours on days 1 to 5 of weeks 3, 7, and 11. LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks 1, 7, 9, and 13; doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2 of weeks 1 and 7, cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 7, 9, and 13, ifosfamide IV over 1 hour on days 1 to 5 of weeks 3, 5, 11, and 15, and etoposide phosphate IV over 1-2 hours on days 1 to 5 of weeks 3, 5, 11, and 15. METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or external beam radiation therapy (EBRT). REGIMEN B (VDC/IE + ganitumab): INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11. LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy. CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15. METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT. MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles. After completion of study treatment, patients are followed for 10 years.

Acute Lymphoblastic Leukemia, Lymphoblastic Lymphoma

Randomized Study of Intravenous Calaspargase Pegol (SC-PEG Asparaginase) and Intravenous Oncaspar in Children and Adolescents With Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

To determine whether or not children and adolescents with ALL or lymphoblastic lymphoma are eligible to participate in this study, screening tests will be performed, which may include the following: medical history, bone marrow tests, assessment of your tumor, blood tests and/or an EKG. Participants who enroll in this study will receive with anti-leukemia drugs called chemotherapy. During study treatment, the study doctors will continue to perform tests on blood, bone marrow and spinal fluid to assess how the disease is responding to the study treatment and to look for possible side effects. Scans (for example, x-ray, CT scan or MRI scan) may also be done after beginning study treatment to look for possible side effects. If the disease was initially diagnosed by a scan, it will also be repeated during the study treatment to assess how it is responding. There are three different treatment groups in which leukemia and lymphoblastic lymphoma can be divided and they differ slightly in the types and amounts of chemotherapy drugs used during the 2-years of therapy. Participants are assigned to the different categories based on the features of their leukemia or lymphoma, such as their age, white blood cell count, and results of other tests. The three different treatment groups are called "Standard Risk", "High Risk" and "Very High Risk". Participants will be given several different chemotherapy drugs during many periods of treatment (called "phases"). These drugs are known to kill lymphoblastic cancer cells. Some of the drugs are given by mouth, some into the veins (intravenously), and others as an injection (a shot) into the muscle. Some chemotherapy drugs will be given directly into your spinal fluid (called intrathecal chemotherapy) during a lumbar puncture (spinal tap). This treatment helps prevent the cancer cells from coming back in the spinal fluid and brain. The first phase of treatment is steroid prophase. This phase of treatment is typically given in the hospital. This phase of treatment will begin immediately. after enrolling on the study. The second phase of treatment is remission induction. This phase will begin immediately after the steroid prophase and will last four weeks. Participants typically remain in the hospital for most (sometimes all) of this phase. At the end of the remission induction phase, participants will undergo tests to determine if they are in remission. This testing will involve getting samples of blood, bone marrow and spinal fluid to look for cancer cells under the microscope. This testing will also involve getting repeat scans if these were not normal at the time of diagnosis. Remission means that cancer cells cannot be detected under the microscope in the blood, marrow and spinal fluid, and that any cancer previously seen on a scan has significantly improved or is no longer seen. Participants must be in remission to go onto the next phases of treatment; alternative treatments will be discussed with participants who are not in remission at the end of the induction phase. The Consolidation I phase begins once it is determined that a participant is in remission. This phase lasts about three weeks. This phase of treatment is given in the hospital, but participants may be able to leave the hospital after the first week of the phase. The purpose of this phase is to further reduce the number of cancer cells in the body. The next phase is the Central Nervous System (CNS) phase, and is usually given in the outpatient setting. Participants may need to be admitted to the hospital during this phase of treatment if a complication develops, such as infection. This phase of therapy begins immediately after the Consolidation I phase and lasts about 3 weeks. Treatment involves a series of lumbar punctures with anti-leukemia drugs given intrathecally over a two week period. Anti-leukemia drugs will also be given by mouth and by vein during this phase as well. Some participants may receive radiation therapy during this phase, although most do not. The decision to treat with radiation or not is based on characteristics of the cancer at diagnosis and whether or not cancer cells were seen in spinal fluid at that time. Radiation therapy is a painless procedure, the purpose of which is to prevent leukemia from coming back in the brain. For participants who receive radiation therapy, it will be given in either 8 or 10 daily treatments, depending on how many leukemia cells were seen in the spinal fluid under the microscope at diagnosis. The next phase of the study is Consolidation II. This phase begins about 3 weeks after starting the CNS phase and lasts for about 27 weeks. During this phase, chemotherapy is given in three-week cycles, with some drugs given in clinic and some drugs given by mouth at home. Participants are typically treated as outpatients during this phase. The last phase is called Continuation. This is also usually given as an outpatient. The goal of this phase is to rid the body of all remaining cancer cells. The cycles of chemotherapy during this phase are repeated every 3 weeks, with some drugs given in clinic and some drugs given by mouth at home. This phase will ends two years after remission was documented. The randomization in this study involves the two forms of asparaginase, Oncaspar and SC-PEG asparaginase. Because no one knows which of the study options is best, participants will be "randomized" into one of the study groups: to receive Oncaspar or to receive SC-PEG. Randomization means that participants are put into a group by chance. Participants who are placed in the Oncaspar group will receive a single dose of Oncaspar on Day 7 of the Remission Induction phase, and then every 2 weeks for 30 weeks starting in the CNS phase (16 total doses of Oncaspar). Participants placed in the SC-PEG group will receive SC-PEG asparaginase on Day 7 of the remission induction phase and then every 3 weeks beginning in the CNS phase (11 total doses of SC-PEG). Minimal Residual Disease (MRD) testing is a way to look for very low levels of leukemia in the body that cannot be seen under the microscope. These test will be done in a laboratory at Dana-Farber Cancer Institute. If the MRD results are in the low range on Day 32, thre will be no change to the treatment program described above. If the MRD results are in the high range, then it will be recommended that treatment be changed. Participants will receive a fluoroquinolone antibiotic beginning during the first phase of treatment and continuing until the neutrophils and monocytes (two types of white blood cells in the blood that help fight infection) have increased. The goal of giving the antibiotics is to prevent infection during the first few weeks of treatment. Participants who agree to have extra blood drawn to test for vitamin D levels in the blood will have 1 teaspoon of blood drawn at the following times: start of treatment, at the end of the first month of treatment, at the start of the continuation phase, and at the end of treatment. Participants will receive the results of these tests. If the vitamin D level is low, the study doctor will recommend that the participant take a vitamin D supplement. Participants may choose not to have blood drawn to check vitamin D levels, or may choose not to take the vitamin D supplement. Participants will be asked at the time of study entry if they agree to provide additional blood and bone marrow samples for research. These additional samples will be used to learn more about the biology of ALL and lymphoblastic lymphoma. Stored specimens may also be used for future research regarding leukemia. After completing all treatment, participants will be asked to come in for physical exams and blood work every month for the first six months after the final treatment, then every two months for the next 6 months, then every four months for the next year, and then every six months for the next year. After that we will ask you to come in once a year. The investigators would like to keep track of the medical condition of all participants for the rest of their lives. This will be done by reviewing medical records of participants. The investigators may telephone participants who have finished treatment to see how they are doing if they have not been seen by their doctor for at least a year.

Advanced Melanoma

Randomized, Ph3 Clinical Study Comparing Vusolimogene Oderparepvec in Combination With Nivolumab Vs Treatment of Physician's Choice in Patients With Advanced Melanoma That Progressed on Anti-PD-1 and Anti-CTLA-4 Containing Treatment

• 1-781-222-9570
• clinicaltrials@replimune.com

Acute Ischemic Stroke, Vessel Occlusion, Stroke, Ischemic

REal-World Analyses of Stroke - Thrombus Occlusion REtrieval

This is a prospective, multi-center, single arm, observational, Real World Evidence (RWE) post-market study with two cohorts. The primary objective of Cohort I of the RESTORE study is to determine the proportion of subjects achieving successful revascularization (mTICI ≥ 2b) with the SOFIA® Flow Plus 6F Aspiration Catheter when used in conjunction with the direct aspiration as first line treatment technique for patients with acute ischemic stroke in the anterior circulation based on collection of real-world evidence data. Secondary objectives include the evaluation of good functional outcome (defined as mRS ≤ 2 at day 90), revascularization time, and procedure related major neurological complications, all based on real-world evidence data collected. The objective of Cohort II of the study is to evaluate standard outcomes such as successful revascularization (mTICI ≥ 2b), good functional outcome (defined as mRS ≤ 2 at day 90), revascularization time, and procedure related major neurological complications based on real-world evidence data. Additional outcomes may be defined and research questions generated based on review of the collected data.

Asthma

Registry of Asthma Patients Initiating DUPIXENT® (RAPID)

3-year registry of real-world use of DUPIXENT® for asthma in patients age 12 and over

Adult Cystic Nephroma, Anaplastic Kidney Wilms Tumor, Angiolipoma, Cellular Congenital Mesoblastic Nephroma, Classic Congenital Mesoblastic Nephroma, Clear Cell Sarcoma of the Kidney, Congenital Mesoblastic Nephroma, Cystic Partially Differentiated Kidney Nephroblastoma, Diffuse Hyperplastic Perilobar Nephroblastomatosis, Extrarenal Rhabdoid Tumor, Kidney Medullary Carcinoma, Kidney Neoplasm, Kidney Oncocytoma, Kidney Wilms Tumor, Metanephric Adenofibroma, Metanephric Adenoma, Metanephric Stromal Tumor, Metanephric Tumor, Mixed Congenital Mesoblastic Nephroma, Ossifying Renal Tumor of Infancy, Papillary Renal Cell Carcinoma, Renal Cell Carcinoma, Renal Cell Carcinoma Associated With Xp11.2 Translocations/TFE3 Gene Fusions, Rhabdoid Tumor of the Kidney, Wilms Tumor

Renal Tumors Classification, Biology, and Banking Study

PRIMARY OBJECTIVES: I. Classify patients with renal tumors by histological categorization, surgico-pathological stage, presence of metastases, age at diagnosis, tumor weight, and loss of heterozygosity for chromosomes 1p and 16q, to define eligibility for a series of therapeutic studies. (As of Amendment 8, this aim is limited to patients with institutionally classified Stage I to IV focal or diffuse anaplasia identified at initial biopsy or primary nephrectomy OR at delayed nephrectomy/second biopsy.) II. To maintain a biological samples bank to make specimens available to scientists to evaluate additional potential biological prognostic variables and for the conduct of other research by scientists. SECONDARY OBJECTIVES: I. To monitor outcome for those patients who are not eligible for a subsequent therapeutic study. II. To describe whether the pulmonary tumor burden correlates with outcome in Stage IV patients.(Completed as of Amendment 7) III. To describe the sensitivity and specificity of abdominal computed tomography (CT) by comparison with surgical and pathologic findings for identification of local tumor spread beyond the renal capsule to adjacent muscle and organs, lymph node involvement at the renal hilum and in the retroperitoneum, preoperative tumor rupture and metastases to the liver. (Completed as of Amendment 7) IV. To compare the sensitivity and specificity of preoperative abdominal CT and MRI for the identification and differentiation of nephrogenic rests and Wilms tumor in children with multiple renal lesions. (Completed as of Amendment 7) V. To correlate the method of conception (natural versus assisted reproductive technology) with the development of Wilms tumor. (Completed as of Amendment 7) VI. To evaluate the frequency of integrase interactor 1 (INI1) mutations in renal and extrarenal malignant rhabdoid tumor of the kidney and to determine the incidence of germline and inherited versus somatic mutations to facilitate clinical correlations on the companion study AREN0321. (Completed as of Amendment 7) OUTLINE: Tumor tissue, blood, and urine samples are collected for research studies, including immunohistochemistry. CT scans and MRIs are also performed. Loss of heterozygosity analyses (chromosome 1p and 16q) are performed by extraction of DNA. DNA polymorphisms are assayed by polymerase chain reaction using standard methodology. Leftover specimens are archived for future studies. (LOH and INI1 testing discontinued as of April 2014) Patients are followed up periodically for 5 years.

Acute Myeloid Leukemia, Down Syndrome, Myelodysplastic Syndrome, Myeloid Leukemia Associated With Down Syndrome, Myeloproliferative Neoplasm

Risk-Stratified Therapy for Acute Myeloid Leukemia in Down Syndrome

PRIMARY OBJECTIVES: I. To determine the 2-year event-free-survival (EFS) for children with standard risk Down syndrome (DS) acute myeloid leukemia (AML) (minimal residual disease \[MRD\]-negative after one cycle of induction therapy) after elimination of high dose (HD) Ara-C (cytarabine) from the treatment regimen. II. To determine the 2-year EFS for children with high risk DS AML (MRD-positive after one cycle of induction therapy) after intensification of treatment equivalent to that used for high risk AML in children without DS. EXPLORATORY OBJECTIVES: I. To compare the feasibility and analytical characteristics of flow cytometry, polymerase chain reaction (PCR) and targeted error-corrected sequencing of GATA binding protein 1 (globin transcription factor 1) (GATA1) mutations as methods to detect MRD in DS AML. II. To establish a DS AML cell bank of viably frozen bone marrow samples collected at the end of induction and corresponding non-tumor deoxyribonucleic acid (DNA) samples collected at end of Induction 1. OUTLINE: INDUCTION I: Patients receive cytarabine intrathecally (IT) on day 1 and intravenously (IV) continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine orally (PO) twice daily (BID) on days 1-4. Induction I continues for a minimum of 28 days. Patients are assigned to 1 of 2 treatment arms based on their MRD status after completion of Induction I. ARM A (STANDARD RISK) (Closed to accrual and treatment with amendment #4A 01/07/2019): INDUCTION II: Patients receive cytarabine IV continuously over 96 hours, daunorubicin hydrochloride IV over 1-15 minutes, and thioguanine PO BID on days 1-4. Induction II continues for a minimum of 28 days. INDUCTION III: Patients receive cytarabine, daunorubicin hydrochloride, and thioguanine as in Induction II. Induction III continues for a minimum of 28 days. INTENSIFICATION I: Patients receive cytarabine IV continuously over 168 hours on days 1-7 and etoposide IV over 60-120 minutes on days 1-3. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive cytarabine and etoposide as in Intensification I. Intensification II continues for a minimum of 28 days. ARM B (HIGH RISK): INDUCTION II: Patients receive high dose cytarabine IV over 1-3 hours every 12 (Q12) hours on days 1-4 and mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6. Induction II continues for a minimum of 28 days. INTENSIFICATION I: Patients receive high dose cytarabine IV over 1-3 hours Q12 hours and etoposide IV over 90-120 minutes on days 1-5. Intensification I continues for a minimum of 28 days. INTENSIFICATION II: Patients receive high dose cytarabine IV over 3 hours Q12 hours on days 1, 2, 8, and 9. Patients also receive asparaginase or asparaginase Erwinia chrysanthemi (E. carotovora) intramuscularly (IM) or IV over 30 minutes on days 2 and 9. Intensification II continues for a minimum of 28 days. After completion of study treatment, patients are followed up at 1 month, monthly for 12 months, every 3 months for 12 months, every 6 months for 3 years, annually for 10 years, and in case of relapse.

Aortic Stenosis, Severe

Safety and Effectiveness of Balloon-Expandable Bioprosthetic SAPIEN X4 Transcatheter Heart Valve

This is a prospective, single arm, multicenter study. Subjects with bicuspid aortic valve morphology will be enrolled in a separate registry.

Sickle Cell Disease

Sickle Cell Disease (SCD) Biochip': Towards a Simple and Reliable Way to Monitor Sickle Cell Disease

Novel biofluidic chip technology can investigate surface characteristics that are typically measured with conventional techniques, such as fluorescent activated cell sorting (FACS), immunohistochemistry, or microscopic imaging methods. In FACS, cells of interest are isolated, extensively processed, incubated with a fluorescent-labeled antibody and sorted by optical recognition. In the proposed SCD biofluidic chip (SCD biochip), the interrogating antibody coats the microchannel surface and captures the cell population(s) of interest, without processing, incubation, or in vitro manipulation. The SCD biochip can also quantitate cellular adherence to experimental biological surfaces that are comprised of subcellular components. The SCD biochip is technically simple and experimentally flexible, whereby the population of interest is retained on the chip and quantitated in situ. The microchip system allows retrieval of viable isolated cells for potential downstream processing, analysis, and in vitro culture.

• (216) 368-6447
• umut@case.edu

Bone Cyst

Simple Bone Cysts in Kids (SBoCK)

In general, few randomized clinical trials have been undertaken in paediatric orthopaedics, and only one to date has addressed the problem of simple bone cysts (SBCs). Also known as unicameral bone cysts, they are the commonest bone lesion in children. Despite general opinion, these cysts do not resolve at skeletal maturity. Many forms of treatment have been recommended but none, including the popular methods of corticosteroid or bone marrow injections, have reliably eradicated SBC. Although the lesions are considered benign (non-cancerous), they cause pain, frequently interfere with function, dramatically restrict play activity, may re-fracture leading to growth arrest and/or deformity, and cause enormous anxiety for children and their families. With a well-developed network of surgeons and researchers, we will provide evidence comparing the effectiveness of two treatment interventions for SBC. More specifically, our goals for this study are: 1. to compare the rate of radiographic healing between two standard treatments including curettage with puncture alone, and curettage with puncture followed by injection with Vitoss morsels; 2. to identify prognostic radiographic factors associated with simple bone cyst healing and fracture; 3. to determine the impact of simple bone cyst on children/family functioning.

• sbock.study@sickkids.ca

Chronic Phase Chronic Myeloid Leukemia, BCR-ABL1 Positive

Stopping Tyrosine Kinase Inhibitors (TKI) to Assess Treatment-Free Remission (TFR) in Pediatric Chronic Myeloid Leukemia - Chronic Phase (CML-CP)

PRIMARY OBJECTIVES: I. To determine the 2-year treatment free remission (TFR) rate of children, adolescents, and young adults with chronic myeloid leukemia - chronic phase (CML-CP) following discontinuation tyrosine kinase inhibitor (TKI). II. To estimate the re-induction rate and maintenance of molecular remission (BCR-ABL1 =\< 0.1%) at 1 year after restarting TKI for children, adolescents, and young adults. SECONDARY OBJECTIVE: I. To describe clinical factors and laboratory correlates affecting the persistence of major molecular remission (MMR) and re-initiation of treatment after stopping TKI (e.g. patient demographics, duration and level of prior molecular remission, duration and type of TKI, clinical presentation at diagnosis and immune studies). EXPLORATORY OBJECTIVES: I. To describe change in height standard deviation score over time in patients who are able to discontinue their TKI. II. To describe the long-term health outcomes including but not limited to gonadal function, endocrine function, and bone metabolism in patients who are able to discontinue TKI as well as those that need to restart TKIs. III. To describe differences in patient-reported health status after stopping TKIs, including those who need to resume TKI after stopping. IV. To describe the incidence and characteristics of TKI withdrawal syndrome in children. V. To evaluate changes in neurocognitive outcomes of patients enrolled on this study using a patient-completed, performance-based, computerized measure of neuropsychological functioning and a parent-report/self-report questionnaire. OUTLINE: Patients stop taking TKI medication within 10 days after enrollment. Patients undergo peripheral blood collection to monitor loss of MMR every 4 weeks in year 1, every 6 weeks in year 2, and every 12 weeks in year 3. Patients who lose their molecular remission may restart TKI medication and are monitored every 4 weeks in year 1, every 6 weeks in year 2, and every 12 weeks in year 3. After completion of study treatment, patients are followed up annually.

Heart Transplant Rejection

Surveillance HeartCare® Outcomes Registry

HeartCare is a service which includes AlloMap® and AlloSure-Heart® to provide information to help clinicians to more comprehensively monitor heart transplant recipients for allograft rejection. An approach to surveillance using HeartCare provides information from two complementary measures; AlloMap is a gene-expression profile based measure of host immune activity and risk of acute rejection. AlloSure-Heart monitors graft injury. AlloMap is the first FDA cleared test and is the only non-invasive, blood test method recommended in the International Society for Heart and Lung Transplantation (ISHLT) guidelines for surveillance of heart transplant recipients for rejection. AlloSure-Heart measures donor-derived cell-free DNA (dd-cfDNA) to help discriminate acute cellular rejection and antibody-mediated rejection from no rejection. Patients who receive HeartCare, as part of their post-transplant management, will give informed consent for information on their outcomes and other relevant clinical information, found in their medical records, to be entered into a SHORE database for purposes of the study.

Autism Spectrum Disorder

Testing the Feasibility of a Teletherapy Plus Parent Coaching Intervention for Children With Autism

Autism Spectrum Disorder (ASD) is one of the most frequently occurring childhood-onset neurodevelopmental disorders affecting 1 in every 54 children1. As a lifelong condition, individuals with ASD experience a range of intellectual, behavioral, sensory, motor, and functional challenges that impact successful participation in daily life activities and tasks. As a result, occupational therapy (OT) intervention is a frequently requested and utilized service in ASD, and clinically validated OT approaches are needed. In a series of studies funded by the NIH and autism foundations, our team manualized and studied an OT intervention that targets the sensory and motor factors impacting participation in daily life activities and tasks and showed significant improvements in those that received the intervention in comparison to controls 2-4. In this project, the investigators plan to adapt our existing protocol to a telehealth model of service delivery, and evaluate its feasibility and preliminary effectiveness. The COVID-19 global pandemic created a call to action for healthcare providers to design unique and innovative methods for therapeutic service delivery. This shift creates an urgent need for remote solutions so that therapeutic services can be delivered in safely and effectively. Since the onset of the COVID-19 pandemic, families have reported regression in adaptive functioning in addition to a negative impact on social skills and increased anxiety, and an impact to daily routines of children with ASD5. In a recent survey of families with children with ASD, 95% of the parents reported that disruptions in services/therapies negatively impacted their child's behaviors and only 35% of families were receiving telehealth services/therapies6. To address these increased needs for children with ASD and to meet the need of manualized telehealth intervention, the investigators propose to adapt the existing intervention to a telehealth delivery model. This intervention, termed occupational therapy for children with Autism Spectrum Disorder (OT4ASD) targets the sensory motor factors that impact behavior and participation in life activities and tasks. This project is significant in that it will address the need for evidence-based OT services for children with ASD using an innovative telehealth model. Given that many children with ASD require treatment for the sensory and motor symptoms that impact their optimal participation in a range of daily life activities and tasks, and that the current COVID 19 pandemic has compromised access to this therapy, this project is urgently needed. Innovation: Telehealth offers an emerging and innovative approach for OT intervention. Research shows that children with ASD require intensive intervention to assure best outcomes and telehealth offers an innovative solution for providing therapy during a pandemic. To the investigator's knowledge, this will be the first telehealth manualized protocol to address the sensory motor symptoms of ASD and measure outcomes at the activity and participation levels of the ICF framework. Importantly, the investigators will adapt an evidence-based, manualized intervention with solid data on outcomes to a telehealth model. The protocol will operationalize the data-driven decision making (DDDM) approach into an on-line format. DDDM is innovative in that it explicitly guides the therapist to contextualize intervention within the child and family's real life participation challenges and use data from assessment to individualize the intervention. DDDM measures outcomes at the proximal (sensory and motor factors) and distal (functional/participation-based goals) levels facilitating an intervention that is context-specific and participation-oriented. Methods: The project will first adapt the existing protocol into a telehealth delivery model using a formative approach that includes a modified Delphi process to obtain input and consensus from experts in telehealth and autism interventions and key stakeholders (parents and clinical interventionists). Next, the investigators will conduct a feasibility trial to assess the acceptability, satisfaction and implementation fidelity as well as gather data on clinically meaningful outcomes. Outcomes will be measured at the proximal and distal levels using validated outcome measures to assure information gained is relevant and scientifically rigorous. Data from the feasibility trial will be used to support an R01 application to conduct a randomized trial of OT4ASD. To implement the project, the investigators utilize a highly skilled team of clinicians and scientists with experience in conducting randomized trials in autism who will work collaboratively to translate knowledge gained into useful information that will impact the lives of families and children with ASD. Our approach is consistent with contemporary models of evidence-based practice and rehabilitation science promoting promote high integrity, evidence-based information from research that targets relevant and meaningful areas for each child and family. The timeline is ambitious and the investigators feel well-equipped to meet it given past experiences and expertise. In summary, this project addresses an urgent need to provide rehabilitation services to children with ASD using remote technology. It will operationalize best practices in telehealth to adapt an existing evidence-based OT intervention and utilize a skilled and experienced team of investigators. As such, this project is consistent with the AACPDM mission to promote excellence in research and services for persons with childhood-onset disabilities.

• 6102912179
• roseann.schaaf@jefferson.edu

Autism Spectrum Disorder

Testing the Feasibility of a Teletherapy Plus Parent Coaching Intervention for Children With Autism

Autism Spectrum Disorder (ASD) is one of the most frequently occurring childhood-onset neurodevelopmental disorders affecting 1 in every 54 children1. As a lifelong condition, individuals with ASD experience a range of intellectual, behavioral, sensory, motor, and functional challenges that impact successful participation in daily life activities and tasks. As a result, occupational therapy (OT) intervention is a frequently requested and utilized service in ASD, and clinically validated OT approaches are needed. In a series of studies funded by the NIH and autism foundations, our team manualized and studied an OT intervention that targets the sensory and motor factors impacting participation in daily life activities and tasks and showed significant improvements in those that received the intervention in comparison to controls 2-4. In this project, the investigators plan to adapt our existing protocol to a telehealth model of service delivery, and evaluate its feasibility and preliminary effectiveness. The COVID-19 global pandemic created a call to action for healthcare providers to design unique and innovative methods for therapeutic service delivery. This shift creates an urgent need for remote solutions so that therapeutic services can be delivered in safely and effectively. Since the onset of the COVID-19 pandemic, families have reported regression in adaptive functioning in addition to a negative impact on social skills and increased anxiety, and an impact to daily routines of children with ASD5. In a recent survey of families with children with ASD, 95% of the parents reported that disruptions in services/therapies negatively impacted their child's behaviors and only 35% of families were receiving telehealth services/therapies6. To address these increased needs for children with ASD and to meet the need of manualized telehealth intervention, the investigators propose to adapt the existing intervention to a telehealth delivery model. This intervention, termed occupational therapy for children with Autism Spectrum Disorder (OT4ASD) targets the sensory motor factors that impact behavior and participation in life activities and tasks. This project is significant in that it will address the need for evidence-based OT services for children with ASD using an innovative telehealth model. Given that many children with ASD require treatment for the sensory and motor symptoms that impact their optimal participation in a range of daily life activities and tasks, and that the current COVID 19 pandemic has compromised access to this therapy, this project is urgently needed. Innovation: Telehealth offers an emerging and innovative approach for OT intervention. Research shows that children with ASD require intensive intervention to assure best outcomes and telehealth offers an innovative solution for providing therapy during a pandemic. To the investigator's knowledge, this will be the first telehealth manualized protocol to address the sensory motor symptoms of ASD and measure outcomes at the activity and participation levels of the ICF framework. Importantly, the investigators will adapt an evidence-based, manualized intervention with solid data on outcomes to a telehealth model. The protocol will operationalize the data-driven decision making (DDDM) approach into an on-line format. DDDM is innovative in that it explicitly guides the therapist to contextualize intervention within the child and family's real life participation challenges and use data from assessment to individualize the intervention. DDDM measures outcomes at the proximal (sensory and motor factors) and distal (functional/participation-based goals) levels facilitating an intervention that is context-specific and participation-oriented. Methods: The project will first adapt the existing protocol into a telehealth delivery model using a formative approach that includes a modified Delphi process to obtain input and consensus from experts in telehealth and autism interventions and key stakeholders (parents and clinical interventionists). Next, the investigators will conduct a feasibility trial to assess the acceptability, satisfaction and implementation fidelity as well as gather data on clinically meaningful outcomes. Outcomes will be measured at the proximal and distal levels using validated outcome measures to assure information gained is relevant and scientifically rigorous. Data from the feasibility trial will be used to support an R01 application to conduct a randomized trial of OT4ASD. To implement the project, the investigators utilize a highly skilled team of clinicians and scientists with experience in conducting randomized trials in autism who will work collaboratively to translate knowledge gained into useful information that will impact the lives of families and children with ASD. Our approach is consistent with contemporary models of evidence-based practice and rehabilitation science promoting promote high integrity, evidence-based information from research that targets relevant and meaningful areas for each child and family. The timeline is ambitious and the investigators feel well-equipped to meet it given past experiences and expertise. In summary, this project addresses an urgent need to provide rehabilitation services to children with ASD using remote technology. It will operationalize best practices in telehealth to adapt an existing evidence-based OT intervention and utilize a skilled and experienced team of investigators. As such, this project is consistent with the AACPDM mission to promote excellence in research and services for persons with childhood-onset disabilities.

• 6102912179
• roseann.schaaf@jefferson.edu

Adrenal Gland Pheochromocytoma, Carcinoma In Situ, Central Nervous System Neoplasm, Childhood Immature Teratoma, Childhood Langerhans Cell Histiocytosis, Childhood Mature Teratoma, Congenital Mesoblastic Nephroma, Desmoid Fibromatosis, Ganglioneuroma, Lymphoproliferative Disorder, Malignant Neoplasm, Malignant Solid Neoplasm, Melanocytic Neoplasm, Myeloproliferative Neoplasm, Neoplasm of Uncertain Malignant Potential, Neuroendocrine Neoplasm, Stromal Neoplasm

The Project: EveryChild Protocol: A Registry, Eligibility Screening, Biology and Outcome Study

PRIMARY OBJECTIVES: I. To maintain a Childhood Cancer Registry for infants, children, adolescents, and young adults with cancer. II. To utilize clinical and biological data to help determine eligibility or stratification, based on childhood cancer disease classification schemas, for potential enrollment of research subjects onto Children's Oncology Group (COG) therapeutic clinical trials. III. To develop a well annotated childhood cancer biorespository for current and future research through the collection of biospecimens (at diagnosis, time of progression, time of recurrence and/or post-mortem), including tumor, host and when feasible parental germline deoxyribonucleic acid (DNA); and key clinical data, including presentation, diagnostic, staging, summary treatment, and outcome information, from every child diagnosed with cancer at COG institutions. IV. To allow use of registry data for permission to be contacted in the future to consider participating in non-therapeutic and prevention research studies involving the child or their parents. OUTLINE: Patients undergo medical data review to create a Childhood Cancer Registry. Patients also undergo collection of biospecimen samples (e.g., tissue, blood, bone marrow, plasma, serum, buccal swab, saliva, cerebrospinal fluid, or urine).

Arteriovenous Malformations, Cerebral, Unruptured Brain Arteriovenous Malformation, Ruptured Brain Arteriovenous Malformation

Transvenous Approach for the Treatment of Cerebral Arteriovenous Malformations (TATAM): A Randomized Controlled Trial and Registry

Adult Kidney Wilms Tumor, Beckwith-Wiedemann Syndrome, Childhood Kidney Wilms Tumor, Diffuse Hyperplastic Perilobar Nephroblastomatosis, Rhabdoid Tumor of the Kidney, Stage I Kidney Wilms Tumor, Stage II Kidney Wilms Tumor, Stage III Kidney Wilms Tumor, Stage IV Kidney Wilms Tumor, Stage V Kidney Wilms Tumor

Treatment for Patients With Bilateral, Multicentric, or Bilaterally-Predisposed Unilateral Wilms Tumor

OBJECTIVES: I. To improve 4-year event-free survival (EFS) to 73% for young patients with bilateral Wilms tumor (BWT). II. To prevent complete removal of at least one kidney in 50% of patients with BWT by using prenephrectomy 3-drug chemotherapy induction with vincristine (vincristine sulfate), dactinomycin, and doxorubicin (doxorubicin hydrochloride). III. To evaluate the efficacy of chemotherapy in preserving renal units in children with diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) and preventing Wilms tumor development. IV. To facilitate partial nephrectomy in lieu of nephrectomy in 25% of children with unilateral tumors and aniridia, Beckwith-Wiedemann syndrome (BWS), hemihypertrophy or other overgrowth syndromes, by using prenephrectomy 2-drug chemotherapy induction with vincristine and dactinomycin. V. To have 75% of patients with BWT undergo definitive surgical treatment by 12 weeks after initiation of chemotherapy. OUTLINE: Patients are assigned to 1 of 3 arms. ARM 1 (Bilateral Wilms Tumors): Patients start with three drug chemotherapy (Regimen VAD; vincristine, dactinomycin and doxorubicin) and are evaluated and six and 12 weeks for feasibility of undergoing a partial nephrectomy/renal sparing surgery. At week 12 definitive surgery takes place followed by chemotherapy and radiation therapy based on histology and stage. Treatment continues for 25 or 31 weeks depending on histology. Patients are followed for up to 10 years following end of therapy. ARM 2 (Unilateral High Risk tumors bilaterally predisposed): Patients start with either 2 drug or three drug chemotherapy (Regimen VA, VAD) and are evaluated a 6 and 12 weeks for feasibility of undergoing a partial nephrectomy. At week 12 definitive surgery takes place followed by chemotherapy. ARM 3 (DHPLN): Patients with this rare disease are diagnosed based on cross-sectional imaging characteristics and undergo 2 drug chemotherapy (Regimen;VA). Patients are reassessed at 6 weeks and 12 weeks. If disease has responded or stayed stable chemotherapy is completed for 19 weeks (Regimen EE4A). If disease has progress a biopsy is performed to assess histology and adjust therapy based on the biopsy. This therapy may include, nephrectomy, chemotherapy or radiation therapy. VAD REGIMEN: Patients receive vincristine sulfate intravenously (IV) over 1 minute on days 1, 8, 15, 22, 29, and 36 (weeks 1-6) and dactinomycin IV and doxorubicin hydrochloride IV over 15-120 minutes on days 1 and 22 (weeks 1 and 4). EE4A REGIMEN: Patients receive vincristine sulfate IV over 1 minute on days 1, 8, 15, 22, 29, and 36 (weeks 1-6) and dactinomycin IV over 1-5 minutes on days 1 and 22 (weeks 1 and 4). After completion of study treatment, patients are followed up periodically for 10 years.

PRETEXT I Hepatoblastoma, PRETEXT II Hepatoblastoma, PRETEXT III Hepatoblastoma, PRETEXT IV Hepatoblastoma

Treatment of Children With All Stages of Hepatoblastoma With Temsirolimus (NSC#683864) Added to High Risk Stratum Treatment

PRIMARY OBJECTIVES: I. To estimate the event-free survival (EFS) in children with stage I (non-pure fetal histology \[PFH\], non-small cell undifferentiated \[SCU\]) and stage II (non-SCU) hepatoblastoma treated with surgical resection followed by 2 cycles of cisplatin, fluorouracil, and vincristine sulfate (C5V). II. To determine the feasibility and toxicity of adding doxorubicin (doxorubicin hydrochloride) to the chemotherapy regimen of C5V for children with intermediate-risk hepatoblastoma. III. To estimate the response rate to vincristine (vincristine sulfate), irinotecan (irinotecan hydrochloride), and temsirolimus in previously untreated children with high-risk, metastatic hepatoblastoma. IV. To determine whether timely (between diagnosis and end of second cycle of chemotherapy) consultation with a treatment center with surgical expertise in major pediatric liver resection and transplant can be achieved in 70% of patients with potentially unresectable hepatoblastoma. V. To foster the collection of tumor tissue and biologic samples to facilitate translational research and to provide data that may aid in risk-adapted approaches for subsequent clinical trials. SECONDARY OBJECTIVES: I. To estimate the EFS of patients with stage I PFH treated with surgery alone. II. To determine whether orthotopic liver transplantation (OLT) can be accomplished after successful referral and completion of 4 cycles of initial chemotherapy. III. To estimate the 2-year EFS for patients once identified as candidates for possible OLT, the 2-year EFS for patients referred to a transplant center that are resected without OLT, and the 2-year EFS for patients referred to a transplant center who receive OLT. IV. To register children with hepatoblastoma who receive OLT with PLUTO (Pediatric Liver Unresectable Tumor Observatory), an international cooperative registry for children transplanted for liver tumors. V. To determine if pretreatment extent of disease (PRETEXT) grouping can predict tumor resectability. VI. To monitor the concordance between institutional assessment of PRETEXT grouping and PRETEXT grouping as performed by expert panel review. VII. To estimate the proportion of stage IV patients who have surgical resection of metastatic pulmonary lesions. VIII. To determine the proportion and estimate the EFS of patients with potentially poor prognostic factors including alpha fetoprotein (AFP) \< 100 ng/mL at diagnosis, microscopic positive surgical margins, surgical complications, multifocal tumors, microscopic vascular invasion, macrotrabecular histologic subtype, and SCU histologic subtype. OUTLINE: Patients are assigned to 1 of 4 treatment groups according to risk group. VERY LOW-RISK GROUP: Patients undergo surgery and receive no further treatment. LOW-RISK GROUP: (regimen T) Patients undergo surgery and then receive adjuvant cisplatin intravenously (IV) over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, and vincristine sulfate IV over 1 minute on days 2, 9, and 16. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. INTERMEDIATE-RISK GROUP: (regimen F) (closed to accrual as of 3/12/2012) Patients receive C5VD chemotherapy comprising cisplatin IV over 6 hours on day 1, fluorouracil IV over 2-4 minutes on day 2, vincristine sulfate IV over 1 minute on days 2, 9, and 16, and doxorubicin hydrochloride IV over 15 minutes on days 1-2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also undergo surgical resection after course 2 OR surgical resection or liver transplantation after course 4 of C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. HIGH-RISK GROUP: (regimen W) (regimen W replaced by regimen H as of Amendment 3B) Patients receive up front VI chemotherapy comprising vincristine sulfate IV on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5. Treatment with VI repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 1 courses of VI in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. HIGH-RISK GROUP: (regimen H) Patients receive up front VIT chemotherapy comprising vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan hydrochloride IV over 90 minutes on days 1-5, and temsirolimus IV over 30 minutes on days 1 and 8. Treatment with VIT repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with disease response then receive 6 courses of C5VD with 4 courses of VIT in between each 2-course block. Patients with no disease response receive 6 courses of C5VD in the absence of disease progression or unacceptable toxicity. Patients undergo tumor resection or liver transplant after course 4 of C5VD followed by 2 courses of adjuvant C5VD. Patients may also receive dexrazoxane IV over 5-15 minutes on days 1-2 of courses 5 and 6. After completion of study therapy, patients who receive chemotherapy are followed up periodically for at least 4 years.

Acute Lymphoblastic Leukemia, Pediatric

Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia in Children and Adolescents

There are a standard set of risk factors which are used to decide how strong treatment should be for a child with ALL. These risk factors include the child's age when the leukemia is diagnosed, how high the white blood cell count (WBC) is in the blood, whether or not leukemia cells are seen in the spinal fluid (referred to as Central Nervous System or CNS status), and whether or not the leukemia has certain abnormalities in their chromosomes (genetic material in the cell). Another risk factor is the amount of leukemia in the marrow that can be measured by a special laboratory test called "MRD" (Minimal Residual Disease) after the first month of treatment. Over the last several years, new factors have been identified which help predict how well a child's leukemia may respond to treatment. These new risk factors include additional abnormalities in the genes of the leukemia cell, as well the amount of leukemia (MRD level) at second time point (about 2-3 months after starting treatment). In this trial, the investigators will use the new risk factors along with old risk factors to decide how strong the treatment will be. The goal is to better identify those participants who might benefit from stronger treatment in order to improve their chance for cure. The investigators also hope to better identify participants who have a high chance of being cured with standard treatment in order to reduce their chance of side effects while maintaining the chance of cure. This trial also aims to study the dosing of a drug called pegaspargase. Pegaspargase is a chemotherapy drug that is an important part of ALL treatment but it is also can cause many side effects. With the standard dose of pegaspargase, levels of the drug in the blood are higher than may be necessary to effectively treat leukemia. On this research study, the investigators will be comparing the standard dose of pegaspargase with a new way of dosing the drug based on levels of the drug that we can measure in the blood. With the new way of doing, treatment will begin with a lower dose. If the levels are high, the dose will be decreased one more time; however, if at any time the levels are too low, dosing will be switched back up to the standard dose. The goal of this research study is to learn whether this new way of dosing (starting at a lower dose and changing the dose based on drug levels in the blood) will decrease side effects but still be as effective as the standard dosing of the drug.

Anaplastic Kidney Wilms Tumor, Recurrent Kidney Wilms Tumor, Stage II Kidney Wilms Tumor, Stage III Kidney Wilms Tumor, Stage IV Kidney Wilms Tumor

Treatment of Newly Diagnosed Diffuse Anaplastic Wilms Tumors (DAWT) and Relapsed Favorable Histology Wilms Tumors (FHWT)

PRIMARY OBJECTIVES: I. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/ carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the event-free survival (EFS) of patients with newly diagnosed stage 4 diffuse anaplastic Wilms tumor (DAWT) as compared to historical controls. II. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the EFS of patients with standard-risk relapsed favorable histology Wilms tumor (SRrFHWT) as compared to historical controls. SECONDARY OBJECTIVES: I. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the overall survival (OS) of patients with newly diagnosed stage 4 DAWT as compared to historical controls. II. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the OS of patients with SRrFHWT as compared to historical controls. III. To evaluate whether the addition of vincristine/irinotecan to cyclophosphamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide improves the EFS and OS of patients with newly diagnosed stage 2 and 3 DAWT as compared to historical controls. IV. To establish EFS and OS for high-risk (HRrFHWT) and very high risk (VHRrFHWT) relapsed favorable histology Wilms tumor treated with ifosfamide/carboplatin/etoposide alternating with cyclophosphamide/ topotecan. EXPLORATORY OBJECTIVES: I. To describe renal toxicity of ifosfamide/carboplatin/etoposide in HRrFHWT and VHRrFHWT patients using conventional and novel biomarkers of renal toxicity (urine NGAL, cystatin C and Kim1) in the context of the chemotherapy regimens used on this study. II. To collect and bank serial blood and urine samples in patients with newly diagnosed DAWT or relapsed FHWT and tumor tissue in patients with relapsed FHWT, for future analysis. III. To assess the impact of p53 gene and protein expression on outcome for patients with newly diagnosed DAWT. IV. To determine EFS/OS in the subsets of patients with newly diagnosed DAWT or relapsed FWHT who undergo gross total resection at all disease sites at diagnosis or after neoadjuvant chemotherapy. V. To describe the rate of regional lymph node sampling at the time of nephrectomy with the use of a pre-operative surgical checklist for patients with newly diagnosed DAWT. VI. To determine the feasibility of intensity modulated radiation therapy (IMRT) with central quality assurance (QA) monitoring to reduce radiation induced toxicity to the heart, thyroid, breast and solitary kidney for children with lung and liver metastases (part of an overarching aim in this study and across frontline favorable histology Wilms tumor studies). VII. To validate that circulating tumor-derived deoxyribonucleic acid (ctDNA) can identify high-risk genomic features, define prognostic risk groups, and identify patterns of tumor evolution associated with the development of treatment resistance. OUTLINE: Patients are assigned to 1 of 2 arms. ARM I (REGIMEN UH-3): CYCLES 1, 5, 7, 10, AND 13: Patients receive vincristine intravenously (IV) via minibag per institutional policy on days 1, 8, and 15. Patients also receive doxorubicin IV over 1-15 minutes and cyclophosphamide IV over 30-60 minutes on day 1. Treatment repeats every 21 days during cycles 1, 5, 7, 10, and 13 in the absence of disease progression or unacceptable toxicity. CYCLES 2, 6, 9, 12, AND 14: Patients receive carboplatin IV over 15-60 minutes on day 1. Patients also receive cyclophosphamide IV over 15-30 minutes and etoposide IV over 1-2 hours on days 1-4. Treatment repeats every 21 days during cycles 2, 6, 9, 12, and 14 in the absence of disease progression or unacceptable toxicity. CYCLES 3, 4, 8, AND 11: Patients receive vincristine IV via minibag per institutional policy on days 1 and 8 and irinotecan IV over 90 minutes on days 1-5. Treatment repeats every 21 days during cycles 3, 4, 8, and 11 in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy (RT) at week 7 of cycle 3 as clinically indicated. Patients undergo a computed tomography (CT) scan, a positron emission tomography (PET) scan, a chest x-ray, magnetic resonance imaging (MRI), an abdominal ultrasound, and/or a bone scan throughout the trial. Patients may also undergo blood specimen collection and biopsy throughout the trial. ARM II (REGIMEN IFOSFAMIDE, CARBOPLATIN, ETOPOSIDE \[ICE\]/CYCLOPHOSPHAMIDE \[CYCLO\]/TOPOTECAN \[TOPO\]): CYCLES 1, 2, 4, 5, 7, AND 9: Patients receive carboplatin IV over 15-60 minutes on day 1. Patients also receive etoposide IV over 1-2 hours and ifosfamide IV over 2-4 hours on days 1-3. Treatment repeats every 21 days during cycles 1, 2, 4, 5, 7, and 9 in the absence of disease progression or unacceptable toxicity. CYCLES 3, 6, 8, AND 10: Patients receive cyclophosphamide IV over 15-30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days during cycles 3, 6, 8, and 10 in the absence of disease progression or unacceptable toxicity. Patients undergo surgery and/or RT during cycles 4, 7, and 10 as clinically indicated. Patients undergo a CT scan, a PET scan, a chest x-ray, MRI, an abdominal ultrasound, and/or a bone scan throughout the trial. Patients may also undergo blood specimen collection and biopsy throughout the trial. After completion of study treatment, patients are followed up every 3 months for years 1-2, every 6 months for years 3-4, and once at year 5.

Acute Lymphoblastic Leukemia, Adult B Lymphoblastic Lymphoma, Ann Arbor Stage I B Lymphoblastic Lymphoma, Ann Arbor Stage II B Lymphoblastic Lymphoma, Childhood B Acute Lymphoblastic Leukemia, Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, Childhood B Lymphoblastic Lymphoma, Down Syndrome, Hypodiploid B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Positive

Treatment of Patients With Newly Diagnosed Standard Risk B-Lymphoblastic Leukemia (B-ALL) or Localized B-Lineage Lymphoblastic Lymphoma (B-LLy)

PRIMARY OBJECTIVES: l. To determine if a maintenance regimen containing weekly oral methotrexate at 40 mg/m\^2/week will result in an improved disease free survival (DFS) compared to that containing weekly oral methotrexate at 20 mg/m\^2/week in the average-risk (AR) subset of patients with standard-risk B-precursor acute lymphoblastic leukemia (ALL). (Complete effective January 13, 2017) II. To determine whether a reduced-pulses maintenance regimen with vincristine (vincristine sulfate)/dexamethasone pulses delivered every 12 weeks can be used without adversely impacting DFS as compared to pulses given every 4 weeks in the AR subset of patients with standard risk B-precursor ALL. III. To confirm that patients in the low-risk (LR) subset of standard risk B-precursor ALL, based on clinical and cytogenetic features and minimal residual disease (MRD) criteria, can attain a 5 year DFS of at least 95% with either a P9904 based regimen that includes 6 courses of intermediate dose (1 g/m\^2 over 24 hours) methotrexate without alkylating agents or anthracyclines (Arm LR-M), or an outpatient based regimen identical to that of AR patients with reduced vincristine/dexamethasone pulses at 12 week intervals during maintenance (Arm LR-C). IV. To provide standardized treatment and enhanced supportive care to children with standard-risk (SR) Down syndrome B-ALL in order to improve outcomes and facilitate further study of this biologically and clinically unique patient subgroup. V. To improve understanding of the biology of localized B-lineage lymphoblastic lymphoma (B-LLy) and Down syndrome (DS) B-LLy by obtaining biologic data, including fluorescence in situ hybridization (FISH) for recurrent cytogenetic lesions on paraffin specimen, and banking tissue for future research. VI. To describe the 5-year event free survival (EFS) and overall survival (OS) of patients with Murphy stage I and II B-LLy receiving modified AR B-ALL therapy. SECONDARY OBJECTIVES: I. To assess the burden of AR B-ALL therapy as measured by surveys of the child's quality of life, missed days of school/daycare/work by children and parents, family functioning, parental perception of the child's health vulnerability, physical functioning, and emotional distress, 1) overall at different time points during and at the end of therapy, and by 2) comparing children randomized to every 4 week vs. every 12 week dexamethasone/vincristine pulses during maintenance. (Closed to accrual as of April 19, 2013) II. To characterize the onset, severity, and natural history of vincristine associated neuropathy by physical therapists (or occupational therapists) in children undergoing therapy for AR B-ALL, 1) overall at different time points during and at the end of therapy, and by 2) comparing children randomized to every 4 week vs. every 12 week dexamethasone/vincristine pulses during maintenance. (Closed to accrual as of March 15, 2013) TERTIARY OBJECTIVES: I. To explore the correlation of minimal marrow disease (MMD) at diagnosis and outcome for patients with B-LLy. (Closed effective Amendment #5) OUTLINE: All patients receive induction therapy comprising intrathecal (IT) cytarabine on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily (BID) on days 1-28; pegaspargase IV over 1-2 hours on day 4; and IT methotrexate* on days 8 and 29. Patients with Philadelphia chromosome-positive disease are eligible to transfer to COG-AALL0622 by day 15 of induction therapy and patients with high-risk (HR) or very high-risk (VHR) disease are eligible to transfer to a COG HR or VHR trial at the end of induction therapy. Patients with standard-risk disease with Down syndrome (DS) who have bone marrow minimal residual disease 0.01% are eligible to transfer to the DS stratum of the HR trial. Patients with induction failure (defined as M3 \[\> 25% lymphoblasts\] on day 29) may be eligible for the COG VHR-acute lymphoblastic leukemia study. NOTE: *Patients with DS also receive oral leucovorin calcium every 12 hours on days 10-11 and 31-32. STANDARD-RISK WITH DOWN SYNDROME: Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1; mercaptopurine PO on days 1-28; IT methotrexate on days 1, 8, and 15; and leucovorin calcium PO every 12 hours on days 3-4, 10-11, and 17-18. Interim maintenance I therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41; IT methotrexate on day 31; and leucovorin calcium PO every 12 hours on days 36-34. Delayed-intensification therapy (8 weeks): Patients receive dexamethasone PO or IV BID on days 1-7 and 15-21; vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 29-32 and 33-39; IT methotrexate on days 1 and 29; and leucovorin calcium PO every 12 hours on days 3-4 and 31-32. Interim maintenance II therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41; IT methotrexate on days 1 and 31; and leucovorin calcium PO every 12 hours on days 3-4 and 33-34. Maintenance therapy: Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. Courses repeat every 12 weeks for 2 years (timed from the start of interim maintenance I therapy). B-LLy: Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1; mercaptopurine PO on days 1-28; IT methotrexate on days 1, 8, and 15; and leucovorin calcium PO every 12 hours on days 3-4, 10-11, and 17-18. Interim maintenance I therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41; IT methotrexate on day 31; and leucovorin calcium PO every 12 hours on days 36-34. Delayed-intensification therapy (8 weeks): Patients receive dexamethasone PO or IV BID on days 1-7 and 15-21; vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 29-32 and 33-39; IT methotrexate on days 1 and 29; and leucovorin calcium PO every 12 hours on days 3-4 and 31-32. Interim maintenance II therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41; IT methotrexate on days 1 and 31; and leucovorin calcium PO every 12 hours on days 3-4 and 33-34. Maintenance therapy: Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. Courses repeat every 4 weeks for 2 years (timed from the start of interim maintenance I therapy). AVERAGE-RISK: Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1; mercaptopurine PO on days 1-28; and IT methotrexate on days 1, 8, and 15.Interim maintenance I therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on day 31. Delayed intensification therapy (8 weeks): Patients receive dexamethasone PO or IV BID on days 1-7 and 15-21; vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and IT methotrexate on days 1 and 29. Interim maintenance II therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on days 1 and 31. Maintenance therapy: Patients are randomized to 1 of 4 maintenance therapy treatment arms. Arm A: Patients receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone PO BID on days 1-5, 29-33, and 57-61; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. Arm B: Patients receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone PO BID on days 1-5, 29-33, and 57-61; higher-dose methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. Arm C: Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. Arm D: Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; higher-dose methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. In all arms, maintenance therapy courses repeat every 12 weeks for 2 years for girls and for 3 years for boys (timed from the start of interim maintenance I therapy). LOW-RISK: Patients are randomized to 1 of 2 treatment arms. Arm I (LR-M): Consolidation therapy (19 weeks): Beginning one week after completion of induction therapy, patients receive vincristine sulfate IV on days 15, 22, 78, and 85; methotrexate IV over 24 hours and IT methotrexate on days 8, 29, 50, 71, 92, and 113; leucovorin calcium PO or IV on days 9-10, 30-31, 51-52, 72-73, 93-94, and 114-115; dexamethasone PO BID or IV on days 15-21 and 78-84; and PO mercaptopurine on days 1-133.Maintenance therapy: Patients receive vincristine sulfate IV on days 1 and 8; dexamethasone PO BID on days 1-7; methotrexate* PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, and 106; and mercaptopurine PO on days 1-112. Courses repeat every 16 weeks. Patients also receive IT methotrexate on days 1 and 85 (courses 1 and 4), day 57 (courses 2 and 5), or day 29 (courses 3 and 6). Patients then receive course 7 comprising vincristine sulfate IV on days 1 and 8; dexamethasone PO BID on days 1-7; methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64; and mercaptopurine PO on days 1-70. Treatment continues for 2 and ½ years (timed from the date of diagnosis).NOTE: *Patients do not receive methotrexate PO on the days that they receive IT methotrexate. Arm II (LR-C): Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1; oral mercaptopurine on days 1-28; and IT methotrexate on days 1, 8, and 15. Interim maintenance I therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on day 31. Delayed-intensification therapy (8 weeks): Patients receive dexamethasone PO or IV BID on days 1-7 and 15-21; vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39; and IT methotrexate on days 1 and 29.Interim maintenance II therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on days 1 and 31. Maintenance therapy: Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. Courses repeat every 12 weeks for 2 years for girls and for 3 years for boys (timed from the start of interim maintenance I therapy). After completion of study treatment, patients are followed up periodically for 10 years from study entry.

Heart Transplant Rejection

Trifecta-Heart cfDNA-MMDX Study: Comparing the DD-cfDNA Test to MMDx Microarray Test and Central HLA Antibody Test

The current standard for assessment of rejection in heart transplants is an endomyocardial biopsy (EMB) interpreted by histology according to ISHLT guidelines. This has considerable error rates, many due to the high disagreement among pathologists in assessing lesions and diagnoses. To address the unmet need for precision and accuracy, the Alberta Transplant Applied Genomics Centre (ATAGC, University of Alberta) has developed a new diagnostic system - the Molecular Microscope® Diagnostic System (MMDx), which uses microarrays to define the global gene expression features of rejection and injury. Now a new screening test is being introduced: the monitoring of donor-derived cell-free DNA (DD-cfDNA) released in the blood by the heart during rejection. The Natera Inc DD-cfDNA Prospera® test is based on the massively multiplex polymerase chain reaction that targets 13,392 single nucleotide polymorphisms and targeted sequences are quantified by Next Generation Sequencing. The Prospera® test has been done on kidney transplant recipients and detected "active rejection" and differentiated it from borderline rejection and no rejection. However, Prospera® test was not examined (the DD-cfDNA results) in heart transplant recipients. DD-cf-DNA test for heart transplants must now be calibrated against MMDx that is based on global gene expression, the new standard for biopsy interpretation. The present study will calibrate centrally measured (Natera Inc) DD-cfDNA levels obtained at the time of an indication or protocol biopsy against the MMDx measurements of T cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR) and early and late tissue injury. The present study will compare DD-cfDNA and MMDx in 300 prospectively collected biopsies for clinical indications and protocol, and accompanying 600 blood samples, to calibrate the DD-cfDNA (Natera Inc.) levels against the MMDx biopsy diagnoses of TCMR, ABMR (and its stages), and acute (early) and chronic (late) injury, , as well as central assessment of HLA antibody (One Lambda) in 300 blood samples, interpreted centrally as donor specific antibody (DSA) based on the tissue typing results. Trifecta-Heart collected 575 biopsies and 573 cfDNA samples, and 573 One Lambda samples so far. Due to a considerable interest from participation centers, this study aims to collect 300 more biopsies and corresponding blood samples. This study is an extension of the INTERHEART ClinicalTrials.gov Identifier: NCT02670408

• 1 780 782 9463
• konrad@ualberta.ca

Hematopoietic Cell Transplantation Recipient, Leukemia, Solid Tumor

Umbrella Long-Term Follow-Up Protocol

PRIMARY OBJECTIVES: I. To develop a mechanism for tracking and retaining patients enrolled on Children's Oncology Group (COG) protocols. II. To maintain regular, lifetime contact with patients in order to obtain current identification and contact information, and self/parent-reported quality of life and health status. III. To locate patients who are lost-to-follow-up for COG (or Legacy Group) protocols targeted for follow-up by the Long-Term Follow-Up Center (LTFC). IV. To provide current patient contact information and self/parent-reported health status updates to the COG Statistics and Data Center (SDC) and to each patient's COG institution. V. To facilitate collection of protocol-specific outcome data through collaboration with the LTFC Oversight Committee, the SDC, and the member institutions. OUTLINE: This is an umbrella protocol for all long-term follow-up at COG institutions. Within 3 months of enrollment on ALTE05N1, patients receive a packet introducing the Long-Term Follow-Up Center (LTFC). Patients are asked to complete a patient response form, verify information provided in packet, and update contact and health status information. The Health Status Update Form is a brief document including questions about current health status, disease status, and cancer therapy received since the last mailing. Patients may respond by use of postage prepaid envelopes, secure online form, or 24-hour toll-free telephone number. After initial contact, the LTFC will contact the patient annually.

Ganglioneuroblastoma, Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Neuroblastoma

Utilizing Response- and Biology-Based Risk Factors to Guide Therapy in Patients With Non-High-Risk Neuroblastoma

PRIMARY OBJECTIVES: I. To eliminate therapy as the initial approach for infants \< 12 months of age with small International Neuroblastoma Risk Group (INRG) stage L1 neuroblastoma while maintaining an overall survival (OS) of 99%. II. To eliminate therapy as the initial approach for non-high-risk patients \< 18 months of age with localized neuroblastoma and favorable biology (histologic and genomic features) while maintaining an OS of 99%. III. To achieve a 3-year OS of \> 81% for infants \< 18 months of age with INRG stage Ms neuroblastoma using objective criteria for early initiation of a response-based treatment algorithm. EXPLORATORY OBJECTIVES: I. To describe the time to intervention or tumor progression, type of intervention and site of progression for patients with localized neuroblastoma who experience progression after an initial period of observation. II. To characterize the pharmacokinetic profile of the chemotherapeutic agents carboplatin and etoposide in patients with stage Ms disease. III. To define the genomic profile of tumors from patients with non-high-risk neuroblastoma both at initial biopsy and at the time of subsequent biopsy or surgical resection. IV. To describe the histology of tumor specimens obtained at the time of subsequent biopsy or surgical resection. V. To determine the salvage rate (OS) of patients with tumor relapse or disease progression. VI. To determine the procedural complication rate (initial biopsy, resection \[intraoperative and postoperative\], subsequent biopsy) and correlate with the degree of surgical resection. VII. To determine the rate of reduction in image defined risk factors (IDRF) in L2 tumors following observation or chemotherapy. OUTLINE: Patients are assigned to 1 of 3 treatment groups. GROUP A: Patients undergo clinical observation for 96 weeks in the absence disease progression. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or ultrasound throughout the trial. GROUP B: Patients undergo clinical observation for 3 years in the absence of disease progression. Upon disease progression, patients undergo surgery or receive first-line chemotherapy comprising carboplatin intravenously (IV) over 1 hour on day 1 (courses 1, 2, 4, 6, and 7), etoposide IV over 1 hour on days 1-3 (courses 1, 3, 4, 5, and 7), cyclophosphamide IV over 1 hour on day 1 (courses 2, 3, 5, 6, and 8), and doxorubicin hydrochloride IV over 15 minutes on day 1 (courses 2, 4, 6 and 8). Treatment with chemotherapy repeats every 21 days for 2-8 courses in the absence of disease progression or unacceptable toxicity. Once a partial response (PR) or better is achieved, patients undergo clinical observation for 3 years. Patients also undergo CT, MRI, and/or ultrasound throughout the trial and undergo bone marrow aspiration, bone marrow biopsy, and tumor biopsy at screening and time of progression. GROUP C: Patients at high risk for deterioration and a poor outcome immediately receive first-line chemotherapy as in Group B. All other patients undergo clinical observation for 3 years in the absence of disease progression. Upon disease progression, patients receive first-line chemotherapy as in Group B. Once a PR or better is achieved, patients undergo clinical observation for 3 years. Patients also undergo CT, MRI, and/or ultrasound throughout the trial and undergo bone marrow aspiration, bone marrow biopsy, and tumor biopsy at screening and time of progression. After completion of study treatment, patients are followed up annually for up to 10 years post-enrollment.