Testing Oral Decitabine and Cedazuridine (ASTX727) in Combination With Venetoclax for Higher-Risk Acute Myeloid Leukemia Patients

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PRIMARY OBJECTIVES: I. To determine the recommended safe phase 2 dose of venetoclax + decitabine and cedazuridine (ASTX727) defined as the highest dose level in which one or fewer dose limiting toxicities (DLTs) are experienced among six patients. (Phase Ib) II. To determine and compare the prelimin...

PRIMARY OBJECTIVES: I. To determine the recommended safe phase 2 dose of venetoclax + decitabine and cedazuridine (ASTX727) defined as the highest dose level in which one or fewer dose limiting toxicities (DLTs) are experienced among six patients. (Phase Ib) II. 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). (phase II) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. (Phase Ib) II. To determine the complete response (complete response [CR] + complete response with incomplete bone marrow recovery [CRi]) rate in patients with treatment naive FLT3WT acute myeloid leukemia (AML) treated with venetoclax and ASTX727 vs. standard anthracycline induction therapy ('7+3'). (Phase II) III. 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'). (Phase II) IV. 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'). (Phase II) V. 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'). (Phase II) VI. 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'). (Phase II) VII. To identify mutational burdens in venetoclax +ASTX727 sensitive vs. resistant AML leukemia initiating cells (LICs). (Phase II) 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 and venetoclax PO QD on days 1-28 or days 1-21. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. 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. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive cytarabine intravenously (IV) over 24 hours on days 1-7 and daunorubicin IV over 10-30 minutes on days 1-3. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 5 years.

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