Ruxolitinib in Combination With Venetoclax With and Without Azacitidine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVE: I. To evaluate an maximum-tolerated dose (MTD) for ruxolitinib in combination with Ia. Venetoclax (Arm 1); Ib. Venetoclax and azacitidine (Arm 2). SECONDARY OBJECTIVES: I. To assess the efficacy of the study treatment. II. To assess the duration of clinical response. III. To assess the duration of clinical benefit. IV. To assess survival in the absence of treatment failure, hematologic relapse, or progressive disease. V. To assess overall survival. VI. To assess overall acute toxicity and tolerability. VII. To assess the effect of ruxolitinib in combination with azacitidine + venetoclax on quality of life (QOL). EXPLORATORY OBJECTIVES: I. To assess in vitro kinase inhibitor sensitivity using participants' bone marrow (or peripheral blood). II. To characterize changes in disease using molecular techniques (potentially including next-generation sequencing and/or BH3 profiling). III. To assess the impact of changes in molecular disease features. IV. To determine the in vivo pharmacokinetics (PK)/pharmacodynamics (PD) parameters of the study drugs (Arm 1 only). OUTLINE: This is a dose-escalation study of ruxolitinib in combination with fixed dose venetoclax with and without azacitidine. Patients are assigned to 1 of 2 arms. ARM 1 (COMPLETE 04/04/2025): Patients receive ruxolitinib orally (PO) twice daily (BID) and venetoclax PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of ruxolitinib and venetoclax at the discretion of the sponsor-investigator. Patients also undergo a skin punch biopsy and echocardiography (ECHO) at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study. ARM 2: Patients receive ruxolitinib PO BID, venetoclax PO QD, and azacitidine intravenously (IV) or subcutaneously (SC) on days 1-7 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study. After completion of study treatment, patients are followed up every 6 months for up to 2 years.