Venetoclax or Placebo in Combination With Reduced-Intensity Conditioning Hematopoietic Cell (Bone Marrow/Blood Stem Cell) Transplant and as Maintenance Therapy After Transplant in Patients With Acute Myeloid Leukemia (A MyeloMATCH Treatment Trial)

PRIMARY OBJECTIVE:

1. 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:

1. 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.

III. To determine the post-transplant 100-day and 12-month overall survival (OS) rate in venetoclax and placebo arms.

IV. To determine the post-transplant 100-day and 12-month cumulative incidence rates (CIR) of morphologic relapse in venetoclax and placebo arms.

1. To determine the post-transplant 100-day and 12-month non-relapse mortality (NRM) rates in venetoclax and placebo arms.

VI. To determine the post-transplant 12-month relapse-free survival rate (RFS), OS, cumulative incidence of relapse (CIR), and cumulative incidence of NRM from start of maintenance in venetoclax and placebo arms.

VII. To determine the post-transplant 100-day and 12-month cumulative incidence of grade 2-4 acute graft versus host disease (GVHD) and 12-month cumulative incidence of chronic GVHD.

VIII. To determine neutrophil engraftment at day 30 and platelet engraftment at days 30 and 60 post-transplant.

IX. To determine the incidence of primary and secondary graft failure within 12 months of hematopoietic stem cell transplant (HCT).

1. To assess toxicity and tolerability of the combination of reduced intensity conditioned allogeneic hematopoietic cell transplantation and venetoclax.

EXPLORATORY OBJECTIVES:

1. To determine the post-transplant 30-day MRD clearance rates in venetoclax and placebo arms.

II. To assess patterns of immune reconstitution per standard of care (SOC) site testing for venetoclax and placebo arms.

III. To assess patterns of marrow and peripheral blood chimerism per SOC site testing for venetoclax and placebo arms.

IV. To assess graft-versus-host relapse-free survival for venetoclax and placebo arms.

1. To assess clinical flow and genetic MRD concordance rate (using Myelomatch available MRD tools) and to associate MRD negativity with clinical outcomes for venetoclax and placebo arms.

VI. Compare rate of cytokine release syndrome after hematopoietic cell infusion. (Cohort 2 only)

OUTLINE: Patients with matched donors are randomized to conditioning 1A or 1B. Patients with haploidentical or mismatched unrelated donors are randomized to conditioning 2A or 2B.

CONDITIONING 1A: Patients receive venetoclax orally (PO) once daily (QD) on days -10 to -2, fludarabine intravenously (IV) on days -6 or -5 to -2 and busulfan IV on days -3 to -2 or twice daily (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.

CONDITIONING 1B: 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.

CONDITIONING 2A: 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.

CONDITIONING 2B: 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.

MAINTENANCE: All patients without evidence of relapse at day +100 are re-randomized to maintenance I or II.

MAINTENANCE I: 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.

MAINTENANCE II: 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 chest x-ray, echocardiography or multigated acquisition scan (MUGA) during screening, and bone marrow biopsy and blood, urine and buccal swab collection throughout the study. Patients may also undergo positron emission tomography (PET) scan and/or computed tomography (CT) scan throughout the study.

After completion of study treatment, patients are followed up at 30 days, every 3 months for up to 1 year and then every 6 months for up to 10 years.