PRIMARY OBJECTIVES:
I. To determine and compare the preliminary efficacy of venetoclax +ASTX727 versus (vs.) standard anthracycline induction therapy ('7+3') with a primary endpoint of event-free survival (EFS).
SECONDARY OBJECTIVES:
I. To determine the complete response (complete response \[CR\] + complete response with incomplete bone marrow recovery \[CRi\]) rate in patients with treatment naive FLT3 wild type (WT) acute myeloid leukemia (AML) treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3').
II. To determine the duration of response (DoR) in patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3').
III. To determine the progression free survival (PFS) of patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3').
IV. To determine the overall response rate (ORR) in patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3').
V. To determine the overall survival (OS) of patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3').
VI. To determine the proportion of patients receiving stem cell transplantation (SCT) in patients with treatment naive FLT3WT AML treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3').
VII. To identify mutational burdens in venetoclax +ASTX727 sensitive vs. resistant AML leukemia initiating cells (LICs).
EXPLORATORY OBJECTIVES:
I. To identify transcriptomic signatures in venetoclax +ASTX727 sensitive vs. resistant AML LICs.
II. Determine the utility of high-throughput phenotype-based assessment of drug efficacy for predicting patient response to venetoclax +ASTX727.
III. Determine if treatment failure is a function of therapy sequence or results in resistance to the alternative therapy by conducting a co-clinical trial via patient-derived xenograft (PDX).
IV. To characterize the pharmacokinetics of venetoclax. V. To determine the morphologic leukemia-free state (MLFS) rate in patients with treatment naïve FLT3WT AML treated with venetoclax and ASTX727 vs. 7+3 therapy.
OUTLINE: This is a phase Ib dose de-escalation study followed by a phase II randomized study.
PHASE Ib: Patients receive ASTX727 (decitabine and cedazuridine) orally (PO) once daily (QD) on days 1-4 or 1-5 of each cycle and venetoclax PO QD on days 1-28 or days 1-21 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy and collection of blood samples throughout the trial.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive ASTX727 PO QD at the recommended phase II dose and venetoclax PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy and collection of blood samples throughout the trial.
ARM II: Patients receive cytarabine intravenously (IV) over 24 hours on days 1-7 of each cycle and daunorubicin IV over 10-30 minutes on days 1-3 of each cycle. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy throughout the trial.
After completion of study treatment, patients are followed up every 3 months for up to 2 years.
