Comparing Different Treatment Lengths for Venetoclax in Older People With Newly Diagnosed Acute Myeloid Leukemia (A MyeloMATCH Treatment Trial)

PRIMARY OBJECTIVES: I. To compare whether the proportion of participants with a measurable residual disease (MRD) negative complete remission (CR) at 180 days (6 months) is not more than 12% worse between participants randomized to venetoclax for 14 days versus 28 days per cycle (non-inferiority assessment). II. If 14 days of venetoclax is found to be non-inferior to 28 days, to test whether the proportion of participants with an MRD-negative CR at 180 days (6 months) after randomization is significantly higher in the 14 days per cycle compared to the 28-days per cycle (superiority assessment). SECONDARY OBJECTIVES: I. In each arm, to estimate the frequency and severity of toxicities. II. In each arm, to estimate CR rates, CR with incomplete count recovery (CRi) (CRi, with and without MRD) rates, event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) for each of the regimens. III. In each arm, to use the disease characteristics from MATCHBox to describe mechanisms of resistance (and disease sensitivity) across the treatment arms. IV. In each arm, to tabulate the number of cycles competed, percent of cycles with at least one dose reduction, and percent of cycles with at least one treatment delay at 180 days (6 months) after randomization. BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive decitabine and cedazuridine (ASTX727) orally (PO) once daily (QD) on days 1-5 and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or treatment discontinuation. Patients undergo bone marrow aspiration and blood sample collection throughout the study. ARM 2: Patients receive ASTX727 PO QD on days 1-5 and venetoclax PO QD on days 1-14 of each cycle. Cycles repeat every 28 days in the absence of disease progression or treatment discontinuation. Patients undergo bone marrow aspiration and blood sample collection throughout the study. After completion of study treatment, patients are followed up periodically for up to 5 years.