Phase I Study of AR-42 and Decitabine in Acute Myeloid Leukemia

PRIMARY OBJECTIVES: I. To determine the biologic effective and tolerable dose (BETD) of AR-42 (histone deacetylase [HDAC] inhibitor AR-42) in combination with a 10 day schedule of decitabine in acute myeloid leukemia (AML) in adults (Stratum 1) and children (Stratum 2). II. To define the specific toxicities and the dose limiting toxicity (DLT) of AR-42 in combination with a 10 day schedule of decitabine in adults and children. SECONDARY OBJECTIVES: I. To describe biologic activity of the combination of AR-42 and decitabine (changes in micro ribonucleic acid [RNA] [miR]-29b expression; specificity protein 1 [Sp1], deoxyribonucleic acid [DNA] (cytosine-5-)-methyltransferase [DNMT]1, 3A and 3B, KIT and FMS-like tyrosine kinase 3 [FLT3] RNA and protein levels). II. To provide preliminary data for clinical response with the combination of AR-42 and decitabine in adults and in children. III. To provide preliminary data on correlation of biologic endpoints and clinical response (particularly miR-29b expression). OUTLINE: This is a dose-escalation study of HDAC inhibitor AR-42. INDUCTION THERAPY: Patients receive HDAC inhibitor AR-42 orally (PO) daily on days 1, 3, and 5 or 1, 3, 4, 5 and decitabine intravenously (IV) over 1 hour on days 6-15. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients achieving complete remission (CR) or morphologic CR with incomplete blood count recovery (CRi) receive HDAC inhibitor AR-42 as in Induction Therapy and decitabine IV over 1 hour on days 6-10. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.