Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

PRIMARY OBJECTIVES: I. To determine the maximum-tolerated dose (MTD) of venetoclax in combination with azacitidine and pevonedistat in patients with previously untreated secondary acute myeloid leukemia (AML). (Phase I) II. To determine the efficacy of the combination regimen, as defined by the rate of complete response (CR) plus complete response with incomplete bone marrow recovery (CRi) within 6 cycles of treatment. (Phase II \[AML\]) III. To determine the efficacy of the combination regimen, as defined by the rate of CR within 6 cycles of treatment. (Phase II \[myelodysplastic syndrome (MDS) Newly Diagnosed\]) IV. To determine the overall response rate (defined as CR + marrow CR \[mCR\] + partial remission \[PR\] + hematological improvement \[HI\]) within 6 cycles of treatment. (Phase II \[MDS/chronic myelomonocytic leukemia (CMML) post-hypomethylating agent (HMA) failure\]) SECONDARY OBJECTIVES: I. To determine efficacy outcomes, including CR rate, leukemia response rate (CR + CRi + partial response \[PR\] + morphologic leukemia free state \[MLFS\]), minimal residual disease (MRD) negativity by flow cytometry, duration of response, transformation to AML (in the MDS cohorts), relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS). II. To determine the safety of the combination regimen. OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study. Patients receive venetoclax orally (PO) once daily (QD) on days 1-28, azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7, and pevonedistat IV over 60 minutes on days 1, 3, and 5. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days, and then every 6 months thereafter.