Enasidenib in Combination With Cobimetinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES: I. Assess the safety and tolerability of cobimetinib in combination with enasidenib. II. Determine the maximum tolerated dose(s) (MTD) and recommended phase 2 dose (RP2D). SECONDARY OBJECTIVES: I. Obtain preliminary estimates of clinical activity as measured by the complete remission (complete response \[CR\], complete response with incomplete hematologic recovery \[CRi\], or complete response with partial hematologic recovery \[CRh\]) rate and minimal residual disease (MRD) rate. II. Obtain preliminary estimates of clinical activity as measured by overall response rate (CR, CRi, CRh, morphologic leukemia free state \[MLFS\], and partial response \[PR\]). III. Obtain preliminary estimates of median time to complete remission. IV. Obtain preliminary estimates of median time to first response. V. Obtain preliminary estimates of response duration in all participants and in those attaining CR/CRi/CRh. VI. Obtain preliminary estimates of median and 1-year event-free survival (EFS). VII. Obtain preliminary estimates of median and 1-year overall survival (OS). EXPLORATORY OBJECTIVES: I. Characterize the effects of the combination on cellular differentiation of leukemic cells as measured by flow cytometry performed at study entry and at serial timepoints throughout the study. II. Evaluate changes in promotor methylation patterns after treatment with combination therapy. III. Evaluate changes in gene expression of RAS pathway regulators as a result of the combination therapy. OUTLINE: This is dose-escalation study of cobimetinib followed by a dose-expansion study. Patients receive cobimetinib orally (PO) once daily (QD) on days 1-21 and enasidenib mesylate PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, and every 3 months for 1 year at last treatment dose.