Hematology, Oncology, and Cellular Therapy

Trial DescriptionA Comprehensive Approach to Improve Medication Adherence in Pediatric ALL - PRIMARY OBJECTIVES: I. Determine the impact of interventions proposed in intervention program (IP) versus (vs.) education alone (EDU) on adherence to oral 6MP (mercaptopurine) in children with acute lymphoblastic leukemia (ALL). Adherence will be measured by: i) Medication Event Monitoring Systems (MEMS) (primary measure of adherence to oral 6MP, providing real-time data; ii) red cell thioguanine nucleotide (TGN) levels (providing data on chronic, systemic 6MP exposure). SECONDARY OBJECTIVES: I. Examine the modifying effect of sociodemographic and psychosocial variables, and the mediating effect of health beliefs/ knowledge on change in adherence with intervention. II. Determine impact of IP vs. EDU on risk of relapse of ALL. OUTLINE: Patients are randomized to 1 of 2 intervention arms. ARM I: Patients receive the Patients Supply Kit containing an electronic pill monitoring system, a MEMS® medication bottle with TrackCap™ with standard resistant cap, and written instructions for the patient and pharmacist. Parents and/or caregivers are also trained to supervise patients' intake of the medication. Beginning on day 1, patients start using the MEMS® medication bottle with TrackCap™. Clinical research assistants contact patients and parents by telephone the next day to confirm that TrackCap™ is being used, to identify any obstacles, and to determine solutions. Beginning on day 29, patients and caregivers view an interactive multimedia educational program on-line or via DVD. Patients also receive a customized electronic mercaptopurine schedule and automated customized text message reminders delivered via cellular phone or web-based interface. Patients and caregivers are instructed to return the MEMS® medication bottle with TrackCap™ to the clinic by day 141. ARM II: Patients receive the usual standard of care and the mercaptopurine from the MEMS® medication bottle with TrackCap™ as patients in arm I. Patients and caregivers also view an interactive multimedia educational program on day 29. After completion of study treatment, patients are followed up every 6 months for 5 years and then annually until 10 years from diagnosis.NCT01503632

Disease/ConditionAcute Lymphoblastic Leukemia

Principal InvestigatorLisa Gennarini

Trial DescriptionA Long-term Safety Study to Assess the Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution NCT05044819

Disease/ConditionLennox Gastaut Syndrome
Dravet Syndrome
Tuberous Sclerosis Complex

Principal InvestigatorPuja Patel

Trial DescriptionA 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 mcLNCT01351545

Disease/ConditionHematologic 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

Principal InvestigatorDavid Loeb

Trial DescriptionA 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.NCT05457556

Disease/ConditionAcute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Mixed Phenotype Acute Leukemia
Myelodysplastic Syndrome

Principal InvestigatorAlice Lee

Trial DescriptionA Phase 1, First-in-Human, Dose Escalation and Expansion Study to Evaluate the Safety and Tolerability of XmAb541 in Advanced Solid Tumors NCT06276491

Disease/ConditionOvarian Cancer
Endometrial Cancer
Germ Cell Tumor
Testicular Germ Cell Tumor
Ovarian Germ Cell Tumor

Principal InvestigatorEric Feldman

Trial DescriptionA Phase 1/2, Open-label, Dose-Escalation and Dose-Expansion Cohort Study of SNDX-5613 in Patients With Relapsed/Refractory Leukemias, Including Those Harboring an MLL/KMT2A Gene Rearrangement or Nucleophosmin 1 (NPM1) Mutation - Phase 1: Oral revumenib; sequential cohorts of escalating dose levels of revumenib to identify the MTD and RP2D. Participants will be enrolled in one of six dose-escalation arms: Arm A: Participants not receiving any strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducers or fluconazole. Arm B: Participants receiving itraconazole, ketoconazole, posaconazole, or voriconazole (strong CYP3A4 inhibitors) for antifungal prophylaxis. Arm C: Participants receiving revumenib and cobicistat. Arm D: Participants receiving fluconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis. Arm E: Participants not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers. Arm F: Participants receiving isavuconazole (moderate CYP3A4 inhibitor) for antifungal prophylaxis. In Phase 2, participants will be enrolled in 3 indication-specific expansion cohorts to determine the efficacy, short- and long-term safety, and tolerability of revumenib: * Cohort 2A: Participants with KMT2Ar acute lymphoblastic leukemia (ALL)/mixed phenotype acute leukemia (MPAL) * Cohort 2B: Participants with KMT2A AML * Cohort 2C: Participants with NPM1m AMLNCT04065399

Disease/ConditionAcute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Mixed Lineage Acute Leukemia
Mixed Phenotype Acute Leukemia
Acute Leukemia of Ambiguous Lineage

Principal InvestigatorIoannis Mantzaris

Trial DescriptionA 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.NCT03794349

Disease/ConditionHigh Risk Neuroblastoma
Recurrent Neuroblastoma
Refractory Neuroblastoma

Principal InvestigatorAlice Lee

Trial DescriptionA 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.NCT03919071

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

Principal InvestigatorAlice Lee

Trial DescriptionA 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 NCT02723994

Disease/ConditionLeukemia

Principal InvestigatorLisa Gennarini

Trial DescriptionA 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.NCT03581292

Disease/ConditionAnaplastic Astrocytoma
Glioblastoma
Malignant Glioma

Principal InvestigatorLisa Gennarini

Trial DescriptionA 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.NCT04684368

Disease/ConditionCentral 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

Principal InvestigatorLisa Gennarini

Trial DescriptionA 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.NCT05235165

Disease/ConditionMetastatic Malignant Neoplasm in the Lung
Metastatic Osteosarcoma
Osteosarcoma

Principal InvestigatorAlice Lee

Trial DescriptionA 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.NCT04293562

Disease/ConditionAcute Myeloid Leukemia

Principal InvestigatorAlice Lee

Trial DescriptionA 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.NCT03959085

Disease/ConditionB Acute Lymphoblastic Leukemia
B Lymphoblastic Lymphoma
Central Nervous System Leukemia
Mixed Phenotype Acute Leukemia
Testicular Leukemia

Principal InvestigatorAlice Lee

Trial DescriptionA 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 NCT04293185

Disease/ConditionSickle Cell Disease

Principal InvestigatorDeepa Manwani

Trial DescriptionA 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.NCT03126916

Disease/ConditionGanglioneuroblastoma
Neuroblastoma

Principal InvestigatorAlice Lee

Trial DescriptionA Phase 3 Study of Active Surveillance for Low Risk and a Randomized Trial of Carboplatin vs. Cisplatin for Standard Risk Pediatric and Adult Patients With Germ Cell Tumors - PRIMARY OBJECTIVES: I. To evaluate whether a strategy of complete surgical resection followed by surveillance can maintain an overall survival rate of at least 95.7% at two years for pediatric, adolescent and adult patients with stage I (low risk) malignant germ cell tumors, and at least 95% for patients with ovarian pure immature teratoma. II. To compare the event-free survival of a carboplatin versus (vs.) cisplatin-based regimen in the treatment of pediatric, adolescent and young adult patients with standard risk non-seminomatous germ cell tumors. IIa. To compare the event free survival (EFS) of a carboplatin-based regimen (carboplatin \[C\] etoposide \[E\] bleomycin \[b\]) vs. a cisplatin-based regimen (cisplatin \[P\]Eb) in children (less than 11 years in age) with standard risk germ cell tumors (GCT). IIb. To compare the EFS of a carboplatin-based regimen (BEC) vs. a cisplatin-based regimen (BEP) in adolescents and young adults (ages 11 - \< 25 years) with standard risk GCT. SECONDARY OBJECTIVES: I. To compare the incidence of ototoxicity in children, adolescents and young adults with standard risk germ cell tumors treated with carboplatin-based chemotherapy as compared to cisplatin-based chemotherapy. II. To refine and validate a novel patient-reported measure of hearing outcomes for children, adolescents and young adults with standard risk germ cell tumors. EXPLORATORY OBJECTIVES: I. To prospectively determine the correlation of tumor marker decline (alpha-fetoprotein \[FP\] and beta-human chorionic gonadotropin \[HCG\]) with clinical outcome in low and standard risk germ cell tumor patients. II. To compare self-reported peripheral neuropathy and other patient-reported outcomes between children, adolescents and young adults with standard risk germ cell tumors treated with carboplatin-based chemotherapy as compared to cisplatin-based chemotherapy. III. Assess the relationship between hearing loss as measured by audiometry with the effects of tinnitus as assessed on the Adolescent and Young Adult Hearing Screening (AYA-HEARS) instrument. IV. To evaluate the prognostic significance of serum micro ribonucleic acid (miRNA)s in stage I testicular cancer (seminoma and non-seminoma) patients by collecting clinical data and serum specimens for future analysis. OUTLINE: Patients with low-risk stage I grade 2, 3 ovarian immature teratoma or stage I non-seminoma malignant germ cell tumors (MGCT)s undergo observation and can transfer to standard risk arm at time of recurrence if eligibility criteria are met. Patients with stage I seminoma testicular MGCT undergo observation, and those with residual/recurrent disease are treated at the discretion of their physician. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or chest x-ray as well as blood sample collection throughout the trial to monitor for response and recurrence. Patients may also undergo a tumor biopsy throughout the trial. Patients with standard risk 1 are randomized into 1 of 2 arms. ARM I (CEb): Patients receive bleomycin intravenously (IV) over 10 minutes and carboplatin IV over 1 hour on day 1. Patients also receive etoposide IV over 1-2 hours on days 1-5. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or chest x-ray as well as blood sample collection throughout the trial. Patients may also undergo a tumor biopsy throughout the trial. Patients undergo a pulmonary function test on study. ARM II (PEb): Patients receive bleomycin IV over 10 minutes on day 1. Patients also receive etoposide IV over 1-2 hours and cisplatin IV over 1-3 hours on days 1-5. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or chest x-ray as well as blood sample collection throughout the trial. Patients may also undergo a tumor biopsy throughout the trial. Patients undergo a pulmonary function test on study. Patients with standard risk 2 are randomized into 1 of 2 arms. ARM III (BEC): Patients receive bleomycin IV over 10 minutes on days 1, 8, and 15, etoposide IV over 1-2 hours on days 1-5, and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or chest x-ray as well as blood sample collection throughout the trial. Patients may also undergo a tumor biopsy throughout the trial. Patients undergo a pulmonary function test on study. ARM IV (BEP): Patients receive bleomycin IV over 10 minutes on days 1, 8, and 15, etoposide IV over 1-2 hours on days 1-5, and cisplatin IV over 1-3 hours on days 1-5. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI, and/or chest x-ray as well as blood sample collection throughout the trial. Patients may also undergo a tumor biopsy throughout the trial. Patients undergo a pulmonary function test on study. After completion of study treatment, patients are followed up every 2 months for 12 months, every 3-6 months to 24 months, every 6 months for years 3-5, and then annually for up to 10 years.NCT03067181

Disease/ConditionChildhood Extracranial Germ Cell Tumor
Extragonadal Embryonal Carcinoma
Germ Cell Tumor
Malignant Germ Cell Tumor
Malignant Ovarian Teratoma
Stage I Ovarian Choriocarcinoma
Stage I Ovarian Embryonal Carcinoma AJCC v6 and v7
Stage I Ovarian Teratoma AJCC v6 and v7
Stage I Ovarian Yolk Sac Tumor AJCC v6 and v7
Stage I Testicular Choriocarcinoma AJCC v6 and v7
Stage I Testicular Embryonal Carcinoma AJCC v6 and v7
Stage I Testicular Seminoma AJCC v6 and v7
Stage I Testicular Yolk Sac Tumor AJCC v6 and v7
Stage II Ovarian Choriocarcinoma
Stage II Ovarian Embryonal Carcinoma AJCC v6 and v7
Stage II Ovarian Yolk Sac Tumor AJCC v6 and v7
Stage II Testicular Choriocarcinoma AJCC v6 and v7
Stage II Testicular Embryonal Carcinoma AJCC v6 and v7
Stage II Testicular Yolk Sac Tumor AJCC v6 and v7
Stage III Ovarian Choriocarcinoma
Stage III Ovarian Embryonal Carcinoma AJCC v6 and v7
Stage III Ovarian Yolk Sac Tumor AJCC v6 and v7
Stage III Testicular Choriocarcinoma AJCC v6 and v7
Stage III Testicular Embryonal Carcinoma AJCC v6 and v7
Stage III Testicular Yolk Sac Tumor AJCC v6 and v7
Stage IV Ovarian Choriocarcinoma
Stage IV Ovarian Embryonal Carcinoma AJCC v6 and v7
Stage IV Ovarian Yolk Sac Tumor AJCC v6 and v7
Testicular Mixed Choriocarcinoma and Embryonal Carcinoma
Testicular Mixed Choriocarcinoma and Teratoma
Testicular Mixed Choriocarcinoma and Yolk Sac Tumor

Principal InvestigatorAlice Lee

Trial DescriptionA 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.NCT03914625

Disease/ConditionB Acute Lymphoblastic Leukemia
B Lymphoblastic Lymphoma
Down Syndrome

Principal InvestigatorAlice Lee

Trial DescriptionA 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) NCT04562766

Disease/ConditionImmune Thrombocytopenia

Principal InvestigatorIrina Murakhovskaya

Trial DescriptionA 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.NCT03628209

Disease/ConditionOsteosarcoma
Osteosarcoma in Children
Osteosarcoma Recurrent
Sarcoma

Principal InvestigatorDaniel Weiser

Trial DescriptionA 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.NCT01274338

Disease/ConditionMelanoma 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

Principal InvestigatorJoseph Sparano

Trial DescriptionA 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.NCT02883049

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

Principal InvestigatorLisa Gennarini

Trial DescriptionA 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.NCT01371981

Disease/ConditionAcute Myeloid Leukemia
Leukemia Cutis
Myeloid Neoplasm
Myeloid Sarcoma

Principal InvestigatorLisa Gennarini

Trial DescriptionA 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.NCT04385277

Disease/ConditionGanglioneuroblastoma, Nodular
Neuroblastoma

Principal InvestigatorLisa Gennarini

Trial DescriptionA 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.NCT05304585

Disease/ConditionEmbryonal Rhabdomyosarcoma
Fusion-Negative Alveolar Rhabdomyosarcoma
Spindle Cell/Sclerosing Rhabdomyosarcoma

Principal InvestigatorAlice Lee

Trial DescriptionA 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.NCT05675410

Disease/ConditionLugano Classification Limited Stage Hodgkin Lymphoma AJCC v8

Principal InvestigatorAlice Lee

Trial DescriptionA 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.NCT02567435

Disease/ConditionAlveolar Rhabdomyosarcoma
Botryoid-Type Embryonal Rhabdomyosarcoma
Embryonal Rhabdomyosarcoma
Rhabdomyosarcoma
Sclerosing Rhabdomyosarcoma
Spindle Cell Rhabdomyosarcoma

Principal InvestigatorAlice Lee

Trial DescriptionA 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.NCT04759586

Disease/ConditionPrimary Mediastinal Large B-Cell Lymphoma

Principal InvestigatorAlice Lee

Trial DescriptionA 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. 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.NCT04994132

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

Principal InvestigatorAlice Lee

Trial DescriptionA Randomized Phase III Trial Comparing Conventional-Dose Chemotherapy Using Paclitaxel, Ifosfamide, and Cisplatin (TIP) with High-Dose Chemotherapy Using Mobilizing Paclitaxel Plus Ifosfamide Followed by High-Dose Carboplatin and Etoposide (TI-CE) As First Salvage Treatment in Relapsed or Refractory Germ Cell Tumors - The study is an international collaboration with European sites. Collaborators on the study include the National Cancer Institute, the European Organization for Research and Treatment of Cancer and the Movember Foundation. Randomization will be stratified by region (North America and Europe) and by modified IPFSG (International Prognostic Factor Study Group) risk classification (low, intermediate and high). The primary and secondary objectives are described below. Primary Objective: 1. To compare the overall survival in patients treated with conventional-dose chemotherapy using the TIP regimen with high-dose chemotherapy (HDCT) plus autologous stem cell transplant (ASCT) using the TI-CE regimen as initial salvage treatment of patients with relapsed or refractory germ cell tumors (GCT) Secondary Objectives: 1. To compare the progression-free survival (PFS) of patients treated with initial salvage HDCT with TI-CE versus initial salvage CDCT with TIP 2. To compare the favorable response rate (FRR) of patients treated with initial salvage HDCT with TI-CE versus initial salvage CDCT with TIP 3. To compare the toxicity, including treatment-related mortality, associated with high-dose chemotherapy and ASCT using TI-CE compared with conventional-dose chemotherapy using TIP as initial salvage treatment for patients with relapsed or refractory GCT 4. To prospectively evaluate the IPFSG scoring system as a predictor of outcome to initial salvage therapy in patients with relapsed or refractory GCT. In this trial, randomization will be stratified by a modification of their IPFSG category and we will prospectively evaluate whether or not actual outcomes vary by risk group in the appropriate manner (low risk patients have higher OS than high-risk group). 5. To evaluate the association between tumor marker decline rates of Alpha-Fetoprotein (AFP) and Human Chorionic Gonadotropin (HCG) with OS and PFS. Treatment is to continue until disease progression, unacceptable toxicity or completion of all protocol treatment.NCT02375204

Disease/ConditionGerm Cell Tumor
Teratoma
Choriocarcinoma
Germinoma
Mixed Germ Cell Tumor
Yolk Sac Tumor
Childhood Teratoma
Malignant Germ Cell Neoplasm
Extragonadal Seminoma
Non-seminomatous Germ Cell Tumor
Seminoma

Principal InvestigatorBenjamin Gartrell

Trial DescriptionA 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).NCT05602194

Disease/ConditionB 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

Principal InvestigatorAlice Lee

Trial DescriptionA 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.NCT05219617

Disease/ConditionSeizures
Lennox Gastaut Syndrome

Principal InvestigatorAlexis Boro

Trial DescriptionAn 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.NCT04624659

Disease/ConditionSickle Cell Disease

Principal InvestigatorDeepa Manwani

Trial DescriptionCancer 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 and blood samples prior to initiation of treatment, during treatment, post treatment and at 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. Patient medical records are reviewed, and data is collected for at least 5 years.NCT04314401

Disease/ConditionAcute Myeloid Leukemia
Anatomic Stage III Breast Cancer AJCC v8
Anatomic Stage IV Breast Cancer AJCC v8
Clinical Stage III Cutaneous Melanoma AJCC v8
Clinical Stage IV Cutaneous Melanoma AJCC v8
Clinical Stage IV Esophageal Adenocarcinoma AJCC v8
Clinical Stage IV Esophageal Squamous Cell Carcinoma AJCC v8
Clinical Stage IV Gastric Cancer AJCC v8
Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
Lung Non-Small Cell Carcinoma
Lung Small Cell Carcinoma
Malignant Solid Neoplasm
Metastatic Prostate Carcinoma
Multiple Myeloma
Stage III Lung Cancer AJCC v8
Stage III Ovarian Cancer AJCC v8
Stage IV Colorectal 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

Principal InvestigatorBalazs Halmos

Trial DescriptionChronic Health Conditions in Down Syndrome-Associated Acute Leukemia: The Down Syndrome Phenotyping Acute Leukemia Study in Survivors (DS-PALS Survivors) - PRIMARY OBJECTIVE: I. To determine the prevalence, type, and severity of chronic health conditions (CHC) in survivors of Down syndrome-associated acute leukemia (DS-AL), and to compare CHC with frequency-matched DS individuals that have no cancer history. SECONDARY OBJECTIVES: I. To characterize post-treatment clinical outcomes of DS-AL by prospective, in-person assessment. II. To determine the prevalence and severity of parent-reported neuropsychological (NP) in survivors of DS-AL, compared with frequency-matched DS individuals with no cancer history. III. To determine health-related quality of life (HRQOL) in survivors of DS-AL, compared with frequency-matched DS individuals with no cancer history. IV. To identify clinical risk determinants of CHC, NP, and clinical outcomes in survivors of DS-AL. V. To establish a well-annotated cohort of survivors of DS-AL and associated biobank as a resource for future investigations. EXPLORATORY OBJECTIVES: I. For DS-acute lymphoblastic leukemia (DS-ALL), test if structural birth defects and genetic associations with etiology extend to CHC. II. For DS-ALL, test if telomere length determined by polygenic risk score and telomere flow-fluorescence in situ hybridization (FISH) are associated with outcomes from in-person NP assessment. OUTLINE: Patients undergo an optional saliva/buccal swab in part 1 and clinical assessment in part 2 of the study. Patients may then undergo blood sample collection in part 3 of the study.NCT05702645

Disease/ConditionB Acute Lymphoblastic Leukemia Associated With Down Syndrome
Down Syndrome
Myeloid Leukemia Associated With Down Syndrome

Principal InvestigatorAlice Lee

Trial DescriptionEROS: 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.NCT01806129

Disease/ConditionMalignant Neoplasm

Principal InvestigatorDella Makower

Trial DescriptionEstablishing Continuous Cell Lines and Xenografts From Pediatric Cancers for Biological and Pre-Clinical Therapeutic Studies - PRIMARY OBJECTIVES: I. Establish and bank cell lines and/or xenografts from pediatric patients with cancer. II. Establish continuous cell lines, under carefully controlled conditions, from pediatric patients with cancer. III. Establish transplantable xenografts in immunocompromised mice from tumor cells that are difficult to establish as continuous cell lines in vitro. IV. Create a bank of cell lines and generate sufficient vials of cryopreserved cells for distribution to investigators with approved COG biology protocols. V. Characterize cell lines from childhood cancers with respect to DNA short tandem repeat molecular profile as a "fingerprint" of original cell line identity. VI. Characterize cell lines for the ability for sustained growth in tissue culture and/or as mouse xenografts. VII. Characterize cell lines for mycoplasma contamination. VIII. Characterize cell lines for expression of molecular makers that confirm the tumor-type of the cell line and the immortal nature of the cells (telomerase) and the expression of molecular markers that may correlate with drug resistance. OUTLINE: This is a multicenter study. Specimens are stratified according to disease (acute lymphoblastic leukemia vs acute myeloid leukemia vs lymphoma vs osteogenic sarcoma vs Ewing family of tumors vs rhabdomyosarcoma vs primitive neuroectodermal tumor vs glioma vs astrocytoma vs rhabdoid tumors vs hepatoblastoma vs retinoblastoma vs Wilms tumor vs germ cell tumors vs other diagnoses). Leftover tissue from diagnostic procedures and/or surgery is cryopreserved and banked. Blood and/or bone marrow are also collected and banked. Cell lines are established and characterized via reverse-transcriptase polymerase chain reaction and/or flow cytometry for biomarkers and by DNA fingerprinting. Markers to be identified may include the following: NEUROBLASTOMA: tyrosine hydroxylase, protein gene product (PGP) 9.5, GD2, HLA class I, and HSAN 1.2 antigens EWING FAMILY OF TUMORS: EWS-FLI1, EWS-ERG, and PGP 9.5 RETINOBLASTOMA: interphotoreceptor retinoid-binding protein ACUTE LYMPHOBLASTIC LEUKEMIA: immunophenotype ALVEOLOR RHADOMYOSARCOMA: PAX3-FKHR, PAX7-FKHR, and MyoD1 ALL CELL TYPES: telomerase expression including hTR and hTERTMutations of TP53 gene are detected by flow cytometry and/or immunocytochemistry. No results of these tests are provided to the patient, the patient's physician, or the patient's medical records.NCT00898755

Disease/ConditionAcute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Central Nervous System Neoplasm
Ewing Sarcoma
Germ Cell Tumor
Leukemia
Lymphoma
Malignant Neoplasm
Neuroblastoma
Osteosarcoma
Retinoblastoma
Rhabdoid Tumor
Rhabdomyosarcoma
Soft Tissue Sarcoma

Principal InvestigatorPeter Cole

Trial DescriptionEvaluation 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.NCT04576442

Disease/ConditionAsthma in Children

Principal InvestigatorMarina Reznik

Trial DescriptionEvolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma NCT04388839

Disease/ConditionRhabdomyosarcoma

Principal InvestigatorAlice Lee

Trial DescriptionInternational 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.NCT03007147

Disease/ConditionAcute Lymphoblastic Leukemia
B Acute Lymphoblastic Leukemia
Mixed Phenotype Acute Leukemia
T Acute Lymphoblastic Leukemia

Principal InvestigatorAlice Lee

Trial DescriptionLarotrectinib (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 2 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.NCT03834961

Disease/ConditionCentral Nervous System Neoplasm
Infantile Fibrosarcoma
Recurrent Acute Leukemia
Refractory Acute Leukemia
Solid Neoplasm

Principal InvestigatorLisa Gennarini

Trial DescriptionMetformin 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.NCT04758000

Disease/ConditionOsteosarcoma
Ewing Sarcoma

Trial DescriptionMinimizing 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.NCT03587272

Disease/ConditionSickle Cell Disease

Principal InvestigatorMichelle Lee

Trial DescriptionMolecular 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.NCT05564377

Disease/ConditionAdvanced 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

Principal InvestigatorBalazs Halmos

Trial DescriptionNCI 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.NCT04387656

Disease/ConditionCOVID-19 Infection
Hematopoietic and Lymphatic System Neoplasm
Malignant Solid Neoplasm
Metastatic Malignant Solid Neoplasm

Principal InvestigatorLisa Gennarini

Trial DescriptionNCI-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.NCT04195555

Disease/ConditionRecurrent 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

Principal InvestigatorLisa Gennarini

Trial DescriptionNCI-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.NCT03210714

Disease/ConditionAdvanced 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

Principal InvestigatorLisa Gennarini

Trial DescriptionNCI-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.NCT03213704

Disease/ConditionAdvanced 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

Principal InvestigatorLisa Gennarini

Trial DescriptionNCI-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.NCT04320888

Disease/ConditionHematopoietic 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

Principal InvestigatorLisa Gennarini

Trial DescriptionNCI-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.NCT03213652

Disease/ConditionAdvanced 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

Principal InvestigatorLisa Gennarini

Trial DescriptionNCI-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.NCT04284774

Disease/ConditionMalignant 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

Principal InvestigatorLisa Gennarini

Trial DescriptionNCI-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.NCT03155620

Disease/ConditionAdvanced 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

Principal InvestigatorAlice Lee

Trial DescriptionNeuroblastoma 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.NCT00904241

Disease/ConditionGanglioneuroblastoma
Localized Resectable Neuroblastoma
Localized Unresectable Neuroblastoma
Regional Neuroblastoma
Stage 4 Neuroblastoma
Stage 4S Neuroblastoma

Principal InvestigatorLisa Gennarini

Trial DescriptionNMTT- Neuroblastoma Maintenance Therapy Trial Using Difluoromethylornithine (DFMO) NCT02679144

Disease/ConditionNeuroblastoma

Principal InvestigatorDaniel Weiser

Trial DescriptionOptimizing the Patient Experience: Virtual Reality Goggle Utilization for Venipuncture Distraction - Can we Decrease Anxiety and Pain During This Common Procedure? - Study personnel will identify patients on CHAM 6 and CHAM 8 scheduled for lab draw prior to child life rounds and subsequently ask the health care providers if there are any patients that are not developmentally or physically appropriate to use the VR equipment. They will then screen and consent the patients approximately 1 hour prior to the Child Life rounds (see appendix A \& B). Patients aged 12-17 years old who are able to read the form will be asked to fill out an assent form (see appendix C) and patients aged 5-12 years old and those unable to read the form will be read the assent form to ensure verbal assent. Those patients who consent to the study will be randomized to a VR arm and non VR arm using computer generated randomization. Lidocaine 2.5%/Prilocaine 2.5% cream will be placed on all patients that have consented to the study by the patient's nurse if they don't already have it applied. After consent and assurance of topical anesthetic application, a brief demographic questionnaire (see appendix D) will also be completed. For efficiency and feasibility, two study personnel will screen and consent families, assist with VR set up and removal, and conduct post procedure assessment.NCT04479735

Disease/ConditionPain, Procedural

Principal InvestigatorCourtney Mcnamara

Trial DescriptionPazopanib 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.NCT02180867

Disease/ConditionAlveolar 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

Principal InvestigatorLisa Gennarini

Trial DescriptionPediatric 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.NCT04726241

Disease/ConditionAcute 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

Principal InvestigatorAlice Lee

Trial DescriptionPHASE 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 NCT03709680

Disease/ConditionEwing Sarcoma
Solid Tumors
Rhabdoid Tumor
Rhabdomyosarcoma
Neuroblastoma
Medulloblastoma
Diffuse Intrinsic Pontine Glioma

Principal InvestigatorAlice Lee

Trial DescriptionPhase 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.NCT01757418

Disease/ConditionSickle Cell Disease
Pain

Principal InvestigatorDeepa Manwani

Trial DescriptionPhase 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.NCT05828069

Disease/ConditionRecurrent Langerhans Cell Histiocytosis
Refractory Langerhans Cell Histiocytosis

Principal InvestigatorAlice Lee

Trial DescriptionPhase 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.NCT03301168

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

Principal InvestigatorMichelle Lee

Trial DescriptionPhase II Study of Nab-Paclitaxel in Combination With Gemcitabine for Treatment of Recurrent/Refractory Sarcoma in Teenagers and Young Adults NCT02945800

Disease/ConditionOsteosarcoma
Ewing Sarcoma
Rhabdomyosarcoma
Soft Tissue Sarcoma

Principal InvestigatorDaniel Weiser

Trial DescriptionPhase III Randomized Study of Chimeric Antibody 14.18 (Ch14.18) in High Risk Neuroblastoma Following Myeloablative Therapy and Autologous Stem Cell Rescue - PRIMARY OBJECTIVES: I. Determine if monoclonal antibody Ch14.18 (dinutuximab) + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves event free survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-autologous stem cell transplant (ASCT) response of complete response (CR), very good partial response (VGPR), or partial response (PR). SECONDARY OBJECTIVES: I. Determine if monoclonal antibody Ch14.18 + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves overall survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR. II. Determine if immunotherapy + RA improves event free survival and overall survival as compared to RA alone, in the subgroup of high risk International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR. III. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with cytokines. IV. To compare the outcome data of the patients with persistent disease documented by biopsy (Stratum 07) to the historical data for the analogous patients from Children's Cancer Group (CCG)-3981. V. To further describe and refine the event free survival (EFS) and overall survival (OS) estimates and baseline characteristics for subjects receiving Ch14.18 + cytokines + RA, following cessation of the randomized portion of the study. VI. To further describe the safety and toxicity of Ch14.18 + cytokines + RA under the new administration guidelines implemented following cessation of the randomized portion of the study with focus on: a) number of courses delivered per subject; b) number of dose reductions or stoppage (ch14.18 and/or interleukin \[IL\]-2); and c) number of toxic deaths. TERTIARY OBJECTIVES: I. In the subgroup of neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR, determine if there is a difference between the two randomized regimens in reducing the minimal residual disease (MRD) burden as detected by the following parameters: meta-iodobenylguanidine (MIBG) scan, immunocytology (IC) of blood and bone marrow samples, reverse transcriptase-polymerase chain reaction (RT-PCR) for tyrosine hydroxylase, phosphoglycolate phosphatase (PGP) 9.5, and melanoma antigen family A, 1 (MAGE-1) in blood and bone marrow. II. Determine if change from baseline of MRD is associated with event free and overall survival. III. Determine whether tumor biology at diagnosis correlates with event-free and overall survival, for either of the randomized regimens. IV. To explore the relationship between antibody-dependent cellular cytoxicity (ADCC) and EFS. V. To determine a descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy. VI. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters and determine if these levels and/or genetic variations correlate with EFS or systemic toxicity. VII. To determine the potential effect of ch14.18 on cardiac repolarization and to evaluate ch14.18 plasma levels. VIII. To determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions and blood levels of ch14.18. IX. To determine if the genotype of Fc receptor (FcR) and killer cell immunoglobulin-like receptor (Kir)/Kir-ligand correlate with EFS. X. To determine if natural killer cell p30-related protein (NKp30) isoform expression and single nucleotide polymorphism (SNP), and circulating ligand B7-H6 are prognostic of EFS or OS. OUTLINE: Patients stratified with biopsy-confirmed post-ASCT persistent disease who are also enrolled on Children's Oncology Group (COG)-A3973 or COG-ANBL0532 are assigned to treatment Arm II. Patients in the first set of strata are randomized to 1 of 2 treatment arms. ARM I: Beginning on day 56-85 post-ASCT, patients receive isotretinoin orally (PO) twice daily (BID) for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy. (closed to accrual as of 4/16/2009) ARM II: Beginning on day 56-85 post-ASCT, patients receive immunotherapy comprising sargramostim (GM-CSF) subcutaneously (SC) or intravenously (IV) over 2 hours on days 0-13 during courses 1, 3, and 5 and dinutuximab IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive aldesleukin IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive isotretinoin as in Arm I beginning on day 11 of immunotherapy. After completion of study treatment, patients are followed up periodically for 10 years.NCT00026312

Disease/ConditionLocalized Resectable Neuroblastoma
Localized Unresectable Neuroblastoma
Recurrent Neuroblastoma
Regional Neuroblastoma
Stage 4 Neuroblastoma
Stage 4S Neuroblastoma

Principal InvestigatorJonathan Gill

Trial DescriptionProspective 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.NCT05228275

Disease/ConditionCOVID-19 Infection
Hematopoietic and Lymphatic System Neoplasm
Malignant Solid Neoplasm

Principal InvestigatorAlice Lee

Trial DescriptionRandomized 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.NCT02306161

Disease/ConditionMetastatic 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

Principal InvestigatorAlice Lee

Trial DescriptionRandomized 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.NCT01574274

Disease/ConditionAcute Lymphoblastic Leukemia
Lymphoblastic Lymphoma

Principal InvestigatorLisa Gennarini

Trial DescriptionRenal 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.NCT00898365

Disease/ConditionAdult 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

Principal InvestigatorLisa Gennarini

Trial DescriptionRisk-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.NCT02521493

Disease/ConditionAcute Myeloid Leukemia
Down Syndrome
Myelodysplastic Syndrome
Myeloid Leukemia Associated With Down Syndrome
Myeloproliferative Neoplasm

Principal InvestigatorLisa Gennarini

Trial DescriptionSickle 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.NCT02824471

Disease/ConditionSickle Cell Disease

Principal InvestigatorDeepa Manwani

Trial DescriptionStopping 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.NCT03817398

Disease/ConditionChronic Phase Chronic Myeloid Leukemia, BCR-ABL1 Positive

Principal InvestigatorAlice Lee

Trial DescriptionThe 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).NCT02402244

Disease/ConditionAdrenal 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

Principal InvestigatorAlice Lee

Trial DescriptionTreatment 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.NCT00945009

Disease/ConditionAdult 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

Principal InvestigatorLisa Gennarini

Trial DescriptionTreatment 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). 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.NCT04322318

Disease/ConditionAnaplastic Kidney Wilms Tumor
Recurrent Kidney Wilms Tumor
Stage II Kidney Wilms Tumor
Stage III Kidney Wilms Tumor
Stage IV Kidney Wilms Tumor

Principal InvestigatorAlice Lee

Trial DescriptionTreatment 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.NCT01190930

Disease/ConditionAcute 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

Principal InvestigatorAlice Lee

Trial DescriptionUmbrella 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.NCT00736749

Disease/ConditionHematopoietic Cell Transplantation Recipient
Leukemia
Solid Tumor

Principal InvestigatorAlice Lee

Trial DescriptionUtilizing 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.NCT02176967

Disease/ConditionGanglioneuroblastoma
Localized Resectable Neuroblastoma
Localized Unresectable Neuroblastoma
Neuroblastoma

Principal InvestigatorAlice Lee