A Two Cohort, Randomized, Double-Blind, Placebo-Controlled, Phase II Multi-Center Signal-Finding Study of Venetoclax Combined With Reduced-Intensity Conditioning Followed by Allogeneic Hematopoietic Cell Transplantation Then Venetoclax Maintenance in Adult Patients With Acute Myeloid Leukemia in First Complete Remission: A MyeloMATCH Sub-Study
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 244
- 主要终点
- Event free survival (EFS)
研究概览
简要总结
This phase II MyeloMATCH treatment trial compares the effect of adding venetoclax or placebo to reduced intensity conditioning chemotherapy with fludarabine and busulfan or melphalan, with or without total body irradiation, followed by hematopoietic stem cell transplant and either venetoclax or placebo maintenance therapy after transplant, for the treatment of patients with acute myeloid leukemia (AML). 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. Giving chemotherapy and total body irradiation before a donor stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells. Adding venetoclax to conditioning therapy before, and giving it as maintenance therapy after, a hematopoietic stem cell transplant may be a more effective treatment option than the usual approach in patients with AML.
详细描述
PRIMARY OBJECTIVE:
I. To determine if venetoclax combined with reduced-intensity conditioned allogeneic hematopoietic cell transplantation improves 100-day event-free survival relative to placebo in adults with AML in first complete remission (complete remission [CR] or complete remission with incomplete hematologic recovery [CRi]).
SECONDARY OBJECTIVES:
I. To determine the post-transplant 30-day and 12-month event-free survival (EFS) rates in venetoclax and placebo arms.
II. To determine the post-transplant 12-month EFS in patients with minimal/measurable residual disease (MRD)-positive status first complete remission at transplant in venetoclax and placebo arms.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
This is a randomized, double-blind trial. Sites will be blinded to treatment assignment.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must be registered to the Master Screening and Reassessment Protocol (MSRP) and assigned to this protocol by the MATCHBox Treatment Verification Team
- •STEP 1: History of acute myeloid leukemia (AML) by World Health Organization (WHO) criteria in first complete remission with morphologic complete remission (CR) or CR with incomplete hematologic recovery (CRi) defined as less than 5% bone marrow blasts by morphology with no circulating leukemic myeloblasts and no known extramedullary disease
- •STEP 1: MRD status by MDNet must have been performed
- •STEP 1 COHORT 1: Human leukocyte antigen (HLA)-matched donor defined as one of the following:
- •Sibling donor must be a 6/6 match at HLA-A and -B (intermediate or higher resolution) and -DRB1 (at high resolution using deoxyribonucleic acid [DNA]-based typing)
- •Related donor other than sibling must be an 8/8 match for HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing
- •Unrelated donor must be an 8/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing
- •Age 40-75 years
- •STEP 1 COHORT 1: Not recommended for a myeloablative regimen by treating investigator
- •STEP 1 COHORT 2: Haploidentical or HLA-mismatched unrelated donor defined as one of the following:
- •Haploidentical donors: Related donor must be a haploidentical 3/6, 4/6, or 5/6 match at HLA-A and -B (intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based typing)
- •HLA-mismatched unrelated donors: Unrelated donor must be a 6/8 or 7/8 match at HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing, ideally age < 35
- •Age 18-75 years
- •STEP 1 COHORT 2: Not recommended for a myeloablative regimen by treating investigator
- •STEP 1: Prior venetoclax therapy is allowed unless there is evidence of progression or no response (failure to achieve remission) to venetoclax-based regimen < 2 months prior to registration
- •STEP 1: No prior allogeneic or autologous hematopoietic cell transplantation
- •STEP 1: Anti-leukemic therapy must be completed more than 14 days prior to registration with the exception of venetoclax
- •STEP 1: Karnofsky performance status ≥ 60
- •STEP 1: Total bilirubin < 2 x upper limit of normal (ULN)
- •STEP 1: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 3 x upper limit of normal (ULN)
- •STEP 1: Alkaline phosphatase ≤ 2.5 x upper limit of normal (ULN)
- •STEP 1: Pulmonary function diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) ≥ 40% and forced expiratory volume (FEV1) ≥ 50%
- •STEP 1: Calculated (Calc.) creatinine clearance ≥ 40 mL/min/based on the Cockcroft-Gault formula
- •STEP 1: Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required
- •STEP 1: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- •STEP 1: Patients with known HIV infection on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial
- •STEP 1: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- •STEP 1: Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- •STEP 1: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association (NYHA) Functional Classification. To be eligible for this trial, patients should have ejection fraction ≥ 40% and NYHA functional status class II or better
- •STEP 1: No history of liver cirrhosis
- •STEP 1: No history of sinusoidal occlusion syndrome of the liver
- •STEP 1: No known intolerance or allergy to any protocol-defined agents
- •STEP 1: No known medical condition causing an inability to swallow oral formulations of agents
- •STEP 2: Patient has completed the conditioning and transplantation regimens
- •STEP 2: Patient has no evidence of AML morphologic relapse
- •STEP 2: Patient does not have flow measurable/minimal residual disease by myeloMATCH central labs (MDNet) testing defined as ≥ 0.1% on day 100+ (between day 80+ and 110+) marrow
- •STEP 2: Absolute neutrophil count > 1,000/mcL (confirmed by a lab draw performed on two separate occasions [> 2 days apart])
- •STEP 2: Platelet count > 50,000/mcL
- •STEP 2: AST (SGOT)/ALT (SGPT) < 3 x upper limit of normal (ULN)
- •STEP 2: Total bilirubin < 2 mg/dL x upper limit of normal (ULN)
- •STEP 2: Calc. creatinine clearance ≥ 40 mL/min/based on the Cockcroft-Gault formula
- •STEP 2: Patient does not have active/current grade 3-4 acute GVHD
- •STEP 2: Patient does not have evidence of grade 3 or higher sinusoidal occlusion syndrome/veno-occlusive disease of the liver as defined by European Society for Blood and Marrow Transplantation (EBMT) criteria
排除标准
- 未提供
研究组 & 干预措施
Maintenance I (venetoclax)
Patients receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Biospecimen Collection (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Chest Radiography (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Multigated Acquisition Scan (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Echocardiography Test (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Melphalan (Drug)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Venetoclax (Drug)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Multigated Acquisition Scan (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Placebo Administration (Drug)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Computed Tomography (Procedure)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Chest Radiography (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Busulfan (Drug)
Maintenance I (venetoclax)
Patients receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Maintenance I (venetoclax)
Patients receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Maintenance I (venetoclax)
Patients receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Venetoclax (Drug)
Maintenance II (placebo)
Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Biospecimen Collection (Procedure)
Maintenance II (placebo)
Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Maintenance II (placebo)
Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Computed Tomography (Procedure)
Maintenance II (placebo)
Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Placebo Administration (Drug)
Maintenance II (placebo)
Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Biospecimen Collection (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Computed Tomography (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Echocardiography Test (Procedure)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Fludarabine (Drug)
Conditioning 1A (matched donors with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Biospecimen Collection (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Busulfan (Drug)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Chest Radiography (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Computed Tomography (Procedure)
Conditioning 1B (matched donor with placebo)
Patients receive placebo PO QD on days -10 to -2, fludarabine IV on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or BID on days -5 to -2 or melphalan IV on day -2. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Melphalan (Drug)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Biospecimen Collection (Procedure)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Echocardiography Test (Procedure)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Fludarabine (Drug)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Melphalan (Drug)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Multigated Acquisition Scan (Procedure)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Total-Body Irradiation (Radiation)
Conditioning 2A (haplo/mismatched donor with venetoclax)
Patients receive venetoclax PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Venetoclax (Drug)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Biospecimen Collection (Procedure)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Bone Marrow Biopsy (Procedure)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Chest Radiography (Procedure)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Computed Tomography (Procedure)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Echocardiography Test (Procedure)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Melphalan (Drug)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Multigated Acquisition Scan (Procedure)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Placebo Administration (Drug)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Positron Emission Tomography (Procedure)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Total-Body Irradiation (Radiation)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Allogeneic Hematopoietic Stem Cell Transplantation (Procedure)
Maintenance I (venetoclax)
Patients receive venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 1 year post transplant (9 cycles) in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Computed Tomography (Procedure)
Conditioning 2B (haplo/mismatched unrelated and placebo)
Patients receive placebo PO QD on days -10 to -2, melphalan IV on day -6, fludarabine IV on days -5 to -2 and undergo total body irradiation once on day -1. Patients then receive hematopoietic cell transplant IV on day 0. Treatment is given in the absence of disease progression or unacceptable toxicity. Patients undergo chest x-ray, echocardiography or MUGA during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo PET scan and/or CT scan throughout the study.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Event free survival (EFS)
时间窗: From randomization to minimal residual disease (MRD) persistence, MRD relapse, morphologic relapse, or death from any cause, assessed up to day +100
MRD positivity is defined as \>= 0.1% leukemic blasts by MyeloMatch flow cytometry. Day 100 is defined as 100 days (day +100 +/- 10 days) after hematopoietic cell infusion (day 0). The day 100 EFS rates will be compared between venetoclax versus placebo arms using a using a two-sided log-rank test.
次要结局
- Incidence of acute graft versus host disease (GVHD)(From date of randomization until date of death with acute GVHD)
- MRD conversion rate(At day +30)
- EFS(From the time of randomization to relapse or death, assessed at 12 months)
- Overall survival(From randomization to death from any cause, assessed up to 10 years)
- Relapse free survival(From randomization or re-randomization to morphologic relapse or death from any cause, assessed up to 10 years)
- Non relapse mortality(From randomization to death from any cause other than morphologic relapse, assessed up to 10 years)
- Cumulative incidence of morphologic relapse(From the date of achievement of a remission until the date morphologic relapse, assessed up to 10 years)
- Incidence of chronic GVHD(From date of randomization until date of death with chronic GVHD)
- Time of neutrophil engraftment(Up to 10 years)
- Time of platelet engraftment(Up to 10 years)
- Incidence of adverse events(Up to 10 years)