Ignite Creation Date:
2024-05-06 @ 8:15 PM
Last Modification Date:
2024-10-26 @ 3:24 PM
Study NCT ID:
NCT06317662
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-07-03
First Post:
2024-03-16
Brief Title:
Testing the Addition of the Anti-cancer Drug Venetoclax andor the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia
Sponsor:
National Cancer Institute NCI
Organization:
National Cancer Institute NCI
Study Overview
Official Title:
A Phase 2 Study of Blinatumomab in Combination With Chemotherapy for Infants With Newly Diagnosed Acute Lymphoblastic Leukemia With Randomization of KMT2A-Rearranged Patients to Addition of Venetoclax
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This phase II trial tests the addition of venetoclax andor 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 andor 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 andor blinatumomab to chemotherapy for the treatment of infants with KMT2A-R or KMT2A-G ALL
Detailed Description:
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 compare event free survival EFS rates of infants with KMT2A-R ALL treated on arm B to those treated on arm A
II To compare 3-year EFS of infants with KMT2A-R ALL treated on arm A to historical controls
III To determine the feasibility of treating infants with KMT2A-G ALL with a Childrens Oncology Group COG high-risk ALL chemotherapy backbone and two cycles of blinatumomab and describe their outcomes
IV To characterize the pharmacokinetics PK of venetoclax in infants
EXPLORATORY OBJECTIVES
I To describe 3-year EFS of infants with KMT2A-R ALL treated on arm B II To describe 3-year EFS of infants with KMT2A-G ALL treated on arm C III To evaluate the use of high-throughput sequencing HTS for MRD detection in infant ALL compared to centralized flow cytometry
IV To characterize the PK of calaspargase pegol-mknl in infants with ALL V To report the incidence of CD19 negative relapse and myeloid switch relapse with protocol therapy
VI To evaluate the impact of venetoclax in combination with chemotherapy on T-cell subsets and function
VII 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
VIII To determine predictors of response and resistance to venetoclax and overall protocol therapy
IX 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 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 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 intravenously 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 pegaspargase intramuscularly IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 750uL and platelets 75000uL
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 pegaspargase IM or IV over 2 hours of calaspargase pegol IV over 1-2 hours on days 15 and 43 Patients who are MRD 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
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 pegaspargase IM or IV over 2 hours or 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 750uL and platelets 75000uL
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 pegaspargase IM or IV over 2 hours on days 2 and 22 or 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 750uL and platelets 75000uL
MAINTENANCE Patients receive methotrexate IT on day 1 of each cycle vincristine IV on day 1 of each cycle prednisone or prednisolone PO NG or 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 and collection of blood samples throughout the trial and undergo ECHO or MUGA at screening and end of therapy Patients may undergo CT MRI FDG-PET andor lumbar puncture if clinically indicated
After completion of study treatment patients are followed up for up to 3 years
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 compare event free survival EFS rates of infants with KMT2A-R ALL treated on arm B to those treated on arm A
II To compare 3-year EFS of infants with KMT2A-R ALL treated on arm A to historical controls
III To determine the feasibility of treating infants with KMT2A-G ALL with a Childrens Oncology Group COG high-risk ALL chemotherapy backbone and two cycles of blinatumomab and describe their outcomes
IV To characterize the pharmacokinetics PK of venetoclax in infants
EXPLORATORY OBJECTIVES
I To describe 3-year EFS of infants with KMT2A-R ALL treated on arm B II To describe 3-year EFS of infants with KMT2A-G ALL treated on arm C III To evaluate the use of high-throughput sequencing HTS for MRD detection in infant ALL compared to centralized flow cytometry
IV To characterize the PK of calaspargase pegol-mknl in infants with ALL V To report the incidence of CD19 negative relapse and myeloid switch relapse with protocol therapy
VI To evaluate the impact of venetoclax in combination with chemotherapy on T-cell subsets and function
VII 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
VIII To determine predictors of response and resistance to venetoclax and overall protocol therapy
IX 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 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 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 intravenously 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 pegaspargase intramuscularly IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 500uL and platelets 50000uL
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 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
DELAYED INTENSIFICATION Patients receive pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL
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 pegaspargase IM or IV over 2 hours or 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 500uL and platelets 50000uL 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 750uL and platelets 75000uL
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 pegaspargase IM or IV over 2 hours of calaspargase pegol IV over 1-2 hours on days 15 and 43 Patients who are MRD 001 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 750uL and platelets 75000uL
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 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 500uL and platelets 50000uL
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 750uL and platelets 75000uL
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 pegaspargase IM or IV over 2 hours or 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 750uL and platelets 75000uL
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 pegaspargase IM or IV over 2 hours on days 2 and 22 or 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 750uL and platelets 75000uL
MAINTENANCE Patients receive methotrexate IT on day 1 of each cycle vincristine IV on day 1 of each cycle prednisone or prednisolone PO NG or 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 and collection of blood samples throughout the trial and undergo ECHO or MUGA at screening and end of therapy Patients may undergo CT MRI FDG-PET andor lumbar puncture if clinically indicated
After completion of study treatment patients are followed up for up to 3 years
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| AALL2321 | OTHER | None | None |
| NCI-2024-01994 | REGISTRY | None | None |
| AALL2321 | OTHER | None | None |
| U10CA180886 | NIH | CTEP | httpsreporternihgovquickSearchU10CA180886 |