KRT-232 (AMG-232) and Decitabine in Treating Patients With Relapsed, Refractory, or Newly-Diagnosed Acute Myeloid Leukemia

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PRIMARY OBJECTIVE: I. To evaluate the toxicities of KRT-232 (AMG-232) in combination with decitabine (20 mg/m^2 for 10 days), and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of KRT-232 (AMG-232) in combination with a standard dose of decitabine. SECONDARY OBJECTIVES...

PRIMARY OBJECTIVE: I. To evaluate the toxicities of KRT-232 (AMG-232) in combination with decitabine (20 mg/m^2 for 10 days), and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of KRT-232 (AMG-232) in combination with a standard dose of decitabine. SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetic (PK) profiles of KRT-232 (AMG-232) and decitabine when used in combination. II. To evaluate tumor suppressor protein 53 (p53) signaling induced by KRT-232 (AMG-232) and decitabine as measured by macrophage inhibitory cytokine-1 (MIC-1) induction. III. To correlate KRT-232 (AMG-232) and decitabine exposure with pharmacodynamics endpoints (efficacy, toxicity, changes in p53 signaling). EXPLORATORY OBJECTIVES: I. To evaluate the response rate (RR) and progression free survival (PFS) of KRT-232 (AMG-232) and decitabine in acute myeloid leukemia (AML). II. To evaluate potential predictive biomarkers of response to KRT-232 (AMG-232) and decitabine in AML. III. To evaluate the pharmacodynamic (PD) effects of KRT-232 (AMG-232) and decitabine in AML blasts. IV. To determine the variability of decitabine incorporation into genomic deoxyribonucleic acid (DNA) and correlate with systemic pharmacokinetics and exposure-response relationships. OUTLINE: This is a dose-escalation study of MDM2 inhibitor KRT-232. Patients receive decitabine intravenously (IV) over 1 hour on days 1-10 and MDM2 inhibitor KRT-232 orally (PO) once daily (QD) on days 4-10. Treatment repeats every 28 days for up to 4 cycles in patients with evidence of persistent AML. Starting cycle 2, patients with no morphologic evidence of AML receive decitabine IV over 1 hour on days 1-5 and KRT-232 PO QD on days 4-10. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.

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