Milademetan Tosylate and Low-Dose Cytarabine With or Without Venetoclax in Treating Participants With Recurrent or Refractory Acute Myeloid Leukemia

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PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability. (Phase 1) II. To determine the recommended phase II dose. (Phase I) III. To evaluate the efficacy (by International Working Group [IWG] criteria - Phase 2) of the MDM2 inhibitor, milademetan tosylate (DS-3032b), in combination with low ...

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability. (Phase 1) II. To determine the recommended phase II dose. (Phase I) III. To evaluate the efficacy (by International Working Group [IWG] criteria - Phase 2) of the MDM2 inhibitor, milademetan tosylate (DS-3032b), in combination with low dose cytarabine (LDAC), with or without the addition of venetoclax in both the frontline and in relapsed/refractory (non-TP53 mutant) patient population. SECONDARY OBJECTIVES: I. Evaluation of time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR). II. Determine biomarkers that may be predictive of DS-3032b activity. III. Molecular profiling at screening, on study, and at relapse to determine genomic predictors of response and resistance. OUTLINE: This is a phase I, dose escalation study of milademetan tosylate, followed by a phase II study. Patients are assigned to 1 of 2 arms. ARM A: Patients receive low dose cytarabine subcutaneously (SC) twice daily (BID) on days 1-10 and milademetan tosylate orally (PO) once daily (QD) on days 8-14, 8-21, or 5-7 and 15-17. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive low dose cytarabine SC BID on days 1-10, milademetan tosylate PO QD on days 8-14, 8-21, or 5-7 and 15-17, and venetoclax PO QD on days 1-14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment participants are followed up at 30 days.

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