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Clinical Trials
NCT06317662

Testing the Addition of the Anti-cancer Drug Venetoclax and/or the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia

Last Updated: 2025-12-26

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

153 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-06-05

Study Completion Date

2028-12-31

Brief Summary

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This phase II trial tests the addition of venetoclax and/or blinatumomab to usual chemotherapy for treating infants with newly diagnosed acute lymphoblastic leukemia (ALL) with a KMT2A gene rearrangement (KMT2A-rearranged \[R\]) or without a KMT2A gene rearrangement (KMT2A-germline \[G\]). Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Blinatumomab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Adding venetoclax and/or blinatumomab to standard chemotherapy may be more effective at treating patients with ALL than standard chemotherapy alone, but it may also cause more side effects. This clinical trial evaluates the safety and effectiveness of adding venetoclax and/or blinatumomab to chemotherapy for the treatment of infants with KMT2A-R or KMT2A-G ALL.

Detailed Description

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PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of venetoclax in addition to a standard chemotherapy backbone and two cycles of blinatumomab in infants (aged 365 days or less at diagnosis) with newly diagnosed KMT2A-R ALL.

II. To determine in a randomized manner if the addition of venetoclax to induction chemotherapy improves end of induction minimal residual disease (MRD)-negative remission rates in infants with KMT2A-R ALL.

SECONDARY OBJECTIVES:

I. To estimate the MRD-negative remission rate for all eligible infants with KMT2A-R ALL treated with venetoclax at the recommended phase 2 dose (RP2D).

II. To compare event free survival (EFS) rates of infants with KMT2A-R ALL treated on arm B to those treated on arm A.

III. To compare 3-year EFS rates of infants with KMT2A-R ALL treated on arm A to historical controls.

IV. To determine the feasibility of treating infants with KMT2A-G ALL with a Children's Oncology Group (COG) high risk ALL chemotherapy backbone and two cycles of blinatumomab and estimate the 3-year EFS rate of infants with KMT2A-G ALL treated on arm C.

V. To characterize the pharmacokinetics (PK) of venetoclax in infants.

EXPLORATORY OBJECTIVES:

I. To describe 3-year EFS rate of infants with KMT2A-R ALL treated on arm B. II. To evaluate the use of high-throughput sequencing (HTS) for MRD detection in infant ALL compared to centralized flow cytometry.

III. To characterize the PK of calaspargase pegol-mknl in infants with ALL. IV. To report the incidence of CD19 negative relapse and myeloid switch relapse with protocol therapy.

V. To evaluate the impact of venetoclax in combination with chemotherapy on T-cell subsets and function.

VI. To describe the feasibility of T-cell collection and success of T-cell manufacturing for infants with KMT2A-R ALL who receive chimeric antigen receptor (CAR) T- cell therapy after coming off protocol therapy.

VII. To determine predictors of response and resistance to venetoclax and overall protocol therapy.

VIII. To evaluate the impact of subsequent anti-cancer therapy on overall survival after coming off protocol therapy.

OUTLINE:

STEROID PREPHASE: All patients receive prednisone or prednisolone orally (PO) or nasogastrically (NG) three times daily (TID) or methylprednisolone intravenously (IV) TID for 7 days prior to the start of induction therapy (on days 1-7).

Patients who are KMT2A gene rearrangement positive are assigned to the safety phase cohort during the safety phase of the study, or randomized between Arm A and Arm B during the expansion phase of the study. Patients who are KMT2A gene rearrangement negative are assigned to Arm C.

SAFETY PHASE COHORT:

INDUCTION: Patients receive venetoclax PO or NG once daily (QD) on days 1-7, 1-10, or 1-14, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy (methotrexate, hydrocortisone, cytarabine) intrathecally (IT) on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when absolute neutrophil counts (ANC) \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \>= 1% or who have residual non-central nervous system (CNS) extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine subcutaneously (SC) QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV or levoleucovorin IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

EXPANSION PHASE: After completion of Safety phase, patients who are KMT2A gene rearrangement positive are randomized to Arm A or Arm B.

ARM A:

INDUCTION: Patients receive daunorubicin IV over 1-15 minutes on days 1 and 2, cytarabine SC or IV over 15-30 minutes on days 1-14, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29, or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \>= 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV or levoleucovorin IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

ARM B: Patients are assigned to 1 of 4 cohorts.

COHORT 1:

INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \>= 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

MARMA + VENETOCLAX: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV or levoleucovorin IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, venetoclax PO or NG QD, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

COHORT 2:

INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \>= 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

CONSOLIDATION + VENETOCLAX: Patients receive venetoclax PO or NG QD, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV or levoleucovorin IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

COHORT 3:

INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \>= 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

CONSOLIDATION + VENETOCLAX: Patients receive venetoclax PO or NG QD, cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

MARMA + VENETOCLAX: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV or levoleucovorin IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, venetoclax PO or NG QD, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

COHORT 4:

INDUCTION + VENETOCLAX: Patients receive venetoclax PO or NG QD, daunorubicin IV over 1-15 minutes on days 1 and 2, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29 or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and intrathecal therapy IT on days 15 and 29. Patients who are MRD \>= 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, and intrathecal therapy IT on day 29. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to MARMA the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

MARMA: Patients receive mercaptopurine PO or NG QD on days 1-14, high dose methotrexate IV over 24 hours on days 1 and 8, leucovorin PO, NG, or IV or levoleucovorin IV on days 3-4 and 10-11, intrathecal therapy IT on days 1 and 8, high dose cytarabine IV over 3 hours on days 22-23 and 29-30, and recombinant crisantaspase IM or crisantaspase IM or IV over 1-2 hours on days 23 and 30. At the end of MARMA (day 49), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28 and intrathecal therapy IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive calaspargase pegol IV over 1-2 hours on day 1, dexamethasone PO, NG, or IV TID on days 1-21, thioguanine PO or NG on days 1-28 and 36-49, vincristine IV on days 1, 8, 15, and 22, daunorubicin IV over 1-15 minutes on days 1, 8, 15, and 22, cytarabine SC or IV over 15-30 minutes on days 2-5, 9-12, 16-19, 23-26, 37-40, and 44-47, cyclophosphamide IV over 15-30 minutes on days 36 and 50, and intrathecal therapy IT on days 1 and 15. At the end of delayed intensification (day 63), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

MAINTENANCE: Patients receive mercaptopurine PO or NG on days 1-84 of each cycle, methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle, and intrathecal therapy IT on day 1 of cycles 1-3. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of MARMA in the absence of disease progression or unacceptable toxicity.

ARM C:

INDUCTION: Patients receive daunorubicin IV over 1-15 minutes on days 1 and 2, cytarabine SC or IV over 15-30 minutes on days 1-14, vincristine IV on days 1, 8, 15, and 22, dexamethasone PO, NG, or IV TID on days 1-28, calaspargase pegol IV over 1-2 hours on day 4, and intrathecal therapy IT on days 1, 15, and 29, or days 1, 8, 15, 22, and 29. Patients with \< 5% blasts by morphology in the bone marrow at the end of induction (day 35) proceed directly to blinatumomab block 1 on the next day or when ANC \>= 500/uL and platelets \>= 50,000/uL. Patients with \>= 5% blasts by morphology in the bone marrow at the end of induction proceed to blinatumomab block 1 as soon as marrow results are known, irrespective of ANC or platelet values.

BLINATUMOMAB BLOCK 1: Patients receive dexamethasone PO, NG, or IV on day 1 or days 1 and 8, blinatumomab IV on days 1-28, 1-7, or 8-28, and methotrexate IT on days 15 and 29. Patients who are MRD \>= 1% or who have residual non-CNS extramedullary disease at the end of blinatumomab block 1 (day 35) discontinue protocol therapy. All other patients proceed directly to consolidation on the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29, cytarabine SC QD or IV over 15-30 minutes on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO or NG QD on days 1-14 and 29-42, methotrexate IT on days 8, 15, and 22, vincristine IV on days 15, 22, 43, and 50, and calaspargase pegol IV over 1-2 hours on days 15 and 43. Patients who are MRD \>= 0.01% at the end of consolidation therapy (day 56) discontinue protocol therapy. All other patients proceed directly to interim maintenance 1 the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

INTERIM MAINTENANCE 1: 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, mercaptopurine PO or NG on days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or NG or IV or levoleucovorin IV on days 3-4, 17-18, 31-32, and 45-46. At the end of interim maintenance 1 (day 63), all patients proceed directly to blinatumomab block 2 the next day or when peripheral counts recover to ANC \>= 500/uL and platelets \>= 50,000/uL.

BLINATUMOMAB BLOCK 2: Patients receive blinatumomab IV on days 1-28, and methotrexate IT on days 1 and 15. At the end of blinatumomab block 2 (day 35), all patients proceed directly to delayed intensification the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

DELAYED INTENSIFICATION: Patients receive methotrexate IT on days 1, 29, and 36, dexamethasone PO, NG, or IV TID on days 1-7 and 15-21, vincristine IV on days 1, 8, 15, 43, and 50, doxorubicin IV over 3-15 minutes on days 1, 8, and 15, calaspargase pegol IV over 1-2 hours on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO or NG on days 29-42, and cytarabine SC or IV over 15-30 minutes on days 29-32 and 36-39. At the end of delayed intensification (day 63), all patients proceed directly to interim maintenance 2 the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

INTERIM MAINTENANCE 2: Patients receive vincristine IV on days 1, 11, 21, 31, and 41, methotrexate IV push over 2-5 minutes of IV over 10-15 minutes on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and calaspargase pegol IV over 1-2 hours on days 2 and 23. At the end of interim maintenance 2 (day 56), all patients proceed directly to maintenance the next day or when peripheral counts recover to ANC \>= 750/uL and platelets \>= 75,000/uL.

MAINTENANCE: Patients receive methotrexate IT on day 1 of each cycle, vincristine IV on day 1 of each cycle, prednisone or prednisolone PO or NG BID or methylprednisolone IV BID on days 1-5 of each cycle, mercaptopurine PO or NG on days 1-84 of each cycle, and methotrexate PO, NG, or IV on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 of each cycle. Cycles repeat every 12 weeks (84 days) for up to 2 years from the start of interim maintenance 1 in the absence of disease progression or unacceptable toxicity.

All patients undergo bone marrow aspiration, collection of blood samples and echocardiography (ECHO) or multigated acquisition scan (MUGA) throughout the trial. Patients may undergo computed tomography (CT), magnetic resonance imaging (MRI), fludeoxyglucose-positron emission tomography (FDG-PET), and/or lumbar puncture if clinically indicated.

After completion of study treatment, patients are followed up for up to 3 years.

Conditions

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Acute Leukemia of Ambiguous Lineage B Acute Lymphoblastic Leukemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SEQUENTIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type DRUG

Given PO or NG

Prednisone

Intervention Type DRUG

Given PO or NG

Discover alternative or legacy names that may be used to describe the listed interventions across different sources.

Asparaginase Erwinia chrysanthemi (Recombinant)-rywn Asparaginase Erwinia chrysanthemi, Recombinant-rywn Asparaginase Erwinia chrysanthemi-rywn Crisantaspase Crisantaspase Biobetter JZP-458 Crisantaspasum Enrylaze Erwinase Erwinaze JZP 458 JZP-458 JZP458 PF743 RC-P JZP-458 Recombinant Asparaginase erwinia chrysanthemi JZP-458 Recombinant Crisantaspase JZP-458 Recombinant Erwinia asparaginase JZP-458 Rylaze Biological Sample Collection Biospecimen Collected Specimen Collection AMG 103 AMG-103 AMG103 Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103 Blincyto MEDI 538 MEDI-538 MEDI538 MT 103 MT-103 MT103 Asparaginase (Escherichia coli Isoenzyme II), Conjugate with alpha-(((2,5-Dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl) Asparlas Calaspargase Pegol-mknl EZN-2285 SC-PEG E. Coli L-Asparaginase Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase CAT CAT Scan Computed Axial Tomography Computerized Axial Tomography Computerized axial tomography (procedure) Computerized Tomography Computerized Tomography (CT) scan CT CT Scan Diagnostic CAT Scan Diagnostic CAT Scan Service Type tomography (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Asta B 518 B 518 B-518 B518 Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR 138719 WR- 138719 WR-138719 WR138719 .beta.-Cytosine arabinoside 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-.beta.-D-Arabinofuranosylcytosine 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-Beta-D-arabinofuranosylcytosine 1.beta.-D-Arabinofuranosylcytosine 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl- 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl- Alexan Ara-C ARA-cell Arabine Arabinofuranosylcytosine Arabinosylcytosine Aracytidine Aracytin Aracytine Beta-Cytosine Arabinoside CHX-3311 Cytarabinum Cytarbel Cytosar Cytosine Arabinoside Cytosine-.beta.-arabinoside Cytosine-beta-arabinoside Erpalfa Starasid Tarabine PFS U 19920 U-19920 Udicil WR-28453 Daunomycin Daunorrubicina DNR Leukaemomycin C Rubidomycin Rubomycin C Aacidexam Adexone Aknichthol Dexa Alba-Dex Alin Alin Depot Alin Oftalmico Amplidermis Anemul mono Auricularum Auxiloson Baycadron Baycuten Baycuten N Cortidexason Cortisumman Decacort Decadrol Decadron Decadron DP Decalix Decameth Decasone R.p. Dectancyl Dekacort Deltafluorene Deronil Desamethasone Desameton Dexa-Mamallet Dexa-Rhinosan Dexa-Scheroson Dexa-sine Dexacortal Dexacortin Dexafarma Dexafluorene Dexalocal Dexamecortin Dexameth Dexamethasone Intensol Dexamethasonum Dexamonozon Dexapos Dexinoral Dexone Dinormon Dxevo Fluorodelta Fortecortin Gammacorten Hemady Hexadecadrol Hexadrol LenaDex Lokalison-F Loverine Methylfluorprednisolone Millicorten Mymethasone Orgadrone Spersadex TaperDex Visumetazone ZoDex Adriablastin Hydroxydaunomycin Hydroxyl Daunorubicin Hydroxyldaunorubicin EC Echocardiography FDG FDG-PET FDG-PET Imaging Folinic acid CL-307,782 Elvorine, Isovorin, Levofolene, Levorin Isovorin L-Leucovorin Levofolinate Levofolinic acid LP Spinal Tap Magnetic Resonance Magnetic Resonance Imaging (MRI) Magnetic resonance imaging (procedure) Magnetic Resonance Imaging Scan Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance MR MR Imaging MRI MRI Scan MRIs NMR Imaging NMRI Nuclear Magnetic Resonance Imaging sMRI Structural MRI 3H-Purine-6-thiol 6 MP 6 Thiohypoxanthine 6 Thiopurine 6-Mercaptopurine 6-Mercaptopurine Monohydrate 6-MP 6-Purinethiol 6-Thiopurine 6-Thioxopurine 6H-Purine-6-thione, 1,7-dihydro- (9CI) 7-Mercapto-1,3,4,6-tetrazaindene Alti-Mercaptopurine Azathiopurine Bw 57-323H Flocofil Ismipur Leukerin Leupurin Mercaleukim Mercaleukin Mercaptina Mercaptopurinum Mercapurin Mern NCI-C04886 Puri-Nethol Purimethol Purine, 6-mercapto- Purine-6-thiol (8CI) Purine-6-thiol, monohydrate Purinethiol Purinethol U-4748 WR-2785 Abitrexate Alpha-Methopterin Amethopterin Brimexate CL 14377 CL-14377 Emtexate Emthexat Emthexate Farmitrexat Fauldexato Folex Folex PFS Jylamvo Lantarel Ledertrexate Lumexon Maxtrex Medsatrexate Metex Methoblastin Methotrexate LPF Methotrexate Methylaminopterin Methotrexatum Metotrexato Metrotex Mexate Mexate-AQ MTX Novatrex Rheumatrex Texate Tremetex Trexeron Trixilem WR-19039 Adlone Caberdelta M DepMedalone Depo Moderin Depo-Nisolone Duralone Emmetipi Esametone Firmacort Medlone 21 Medrate Medrol Medrol Veriderm Medrone Mega-Star Meprolone Methylprednisolonum Metilbetasone Solubile Metrocort Metypresol Metysolon Predni-M-Tablinen Prednilen Radilem Sieropresol Solpredone Summicort Urbason Veriderm Medrol Wyacort Blood Pool Scan Equilibrium Radionuclide Angiography Gated Blood Pool Imaging Gated Heart Pool Scan MUGA MUGA Scan Multi-Gated Acquisition Scan Radionuclide Ventriculogram Scan Radionuclide Ventriculography RNV Scan RNVG SYMA Scanning Synchronized Multigated Acquisition Scanning (11beta)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione .delta.1-Hydrocortisone Adnisolone Aprednislon Capsoid Cortalone Cortisolone Dacortin H Decaprednil Decortin H Delta(1)Hydrocortisone Delta- Cortef Delta-Cortef Delta-Diona Delta-F Delta-Phoricol Delta1-dehydro-hydrocortisone Deltacortril Deltahydrocortisone Deltasolone Deltidrosol Dhasolone Di-Adreson-F Dontisolon D Estilsona Fisopred Frisolona Gupisone Hostacortin H Hydeltra Hydeltrasol Klismacort Kuhlprednon Lenisolone Lepi-Cortinolo Linola-H N Linola-H-Fett N Longiprednil Metacortandralone Meti Derm Meticortelone Opredsone Panafcortelone Precortisyl Pred-Clysma Predeltilone Predni-Coelin Predni-Helvacort Prednicortelone Prednisolonum Prelone Prenilone Sterane .delta.1-Cortisone 1, 2-Dehydrocortisone Adasone Cortancyl Dacortin DeCortin Decortisyl Decorton Delta 1-Cortisone Delta-Dome Deltacortene Deltacortisone Deltadehydrocortisone Deltasone Deltison Deltra Econosone Lisacort Meprosona-F Metacortandracin Meticorten Ofisolona Orasone Panafcort Panasol-S Paracort Perrigo Prednisone PRED Predicor Predicorten Prednicen-M Prednicort Prednidib Prednilonga Predniment Prednisone Intensol Prednisonum Prednitone Promifen Rayos Servisone SK-Prednisone Aeroseb-HC Barseb HC Barseb-HC Cetacort Cort-Dome Cortef Cortenema Cortifan Cortisol Cortispray Cortril Dermacort Domolene Eldecort Hautosone Heb-Cort Hydrocortisone Hydrocortone Hytone Komed-HC Nutracort Proctocort Rectoid 2-Amino 6MP 2-Amino-1,7-dihydro-6H-purine-6-thione 2-Amino-6-mercaptopurine 2-Amino-6-purinethiol 2-Aminopurin-6-thiol 2-Aminopurine-6(1H)-thione 2-Aminopurine-6-thiol 2-Aminopurine-6-thiol Hemihydrate 2-Mercapto-6-aminopurine 6-Amino-2-mercaptopurine 6-Mercapto-2-aminopurine 6-Mercaptoguanine 6-TG 6H-Purine-6-thione, 2-amino-1,7-dihydro- (9CI) BW 5071 Lanvis Tabloid Thioguanine Hemihydrate Thioguanine Hydrate Tioguanin Tioguanine Wellcome U3B WR-1141 X 27 ABT 199 ABT-0199 ABT-199 ABT199 GDC 0199 GDC-0199 GDC0199 RG7601 Venclexta Venclyxto LCR Leurocristine VCR Vincrystine

Eligibility Criteria

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Inclusion Criteria

* All patients must be enrolled on APEC14B1 and consented to eligibility screening (part A) prior to treatment and enrollment on AALL2321
* Infants (aged 365 days or less) on the date of diagnosis are eligible; infants must be \> 36 weeks gestational age at the time of enrollment
* Patients must have newly diagnosed B-acute lymphoblastic leukemia (B-ALL, 2017 World Health Organization \[WHO\] classification), also termed B-precursor ALL, or acute leukemia of ambiguous lineage (ALAL), which includes mixed phenotype acute leukemia. For patients with ALAL, the immunophenotype of the leukemia must comprise at least 50% B lineage

* Diagnostic immunophenotype: Leukemia cells must express CD19

Exclusion Criteria

* Patients with Down Syndrome
* Patients with secondary B-ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy
* Patients must not have received any cytotoxic chemotherapy for either the current diagnosis of infant ALL or for any cancer diagnosis prior to the initiation of protocol therapy, with the exception of:

* Steroid pretreatment:

* PredniSONE, prednisoLONE, or methylPREDNISolone for ≤ 72 hours (3 days) in the 7 days prior to enrollment. The dose of predniSONE, prednisoLONE or methylPREDNISolone does not affect eligibility
* Inhaled and topical steroids are not considered pretreatment
* Note: Pretreatment with dexamethasone in the 28 days prior to initiation of protocol therapy is not allowed with the exception of a single dose of dexamethasone used during or within 6 hours prior to or after sedation to prevent or treat airway edema. However, prior exposure to ANY steroids that occurred \> 28 days before enrollment does not affect eligibility
* Intrathecal cytarabine or methotrexate:

* An intrathecal dose of cytarabine or methotrexate in the 7 days prior to enrollment does not affect eligibility
* Note: The preference is to defer the diagnostic lumbar puncture with intrathecal chemotherapy to day 1 of induction to allow for cytoreduction of circulating blasts and decrease the potential for central nervous system (CNS) contamination due to a traumatic tap. If done prior to day 1 of induction, these results will be used to determine CNS status
* Hydroxyurea:

* Pretreatment with ≤ 72 hours (3 days) of hydroxyurea in the 7 days prior to enrollment does not affect eligibility
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA) and National Cancer Institute (NCI) requirements for human studies must be met

Maximum Eligible Age

365 Days

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Erin H Breese

Role: PRINCIPAL_INVESTIGATOR

Children's Oncology Group

Identifier Type: REGISTRY

Identifier Source: secondary_id

AALL2321

Identifier Type: OTHER

Identifier Source: secondary_id

AALL2321

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA180886

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2024-01994

Identifier Type: -

Identifier Source: org_study_id