A Phase I Study of Midostaurin and Azacitidine in Relapsed and Elderly AML Patients

A phase I study of azacitidine 75 mg/m(2) intravenously on days 1 to 7 and escalating doses of midostaurin, an oral Fms-like tyrosine kinase 3 (FLT3) kinase inhibitor, on days 8 to 21 was conducted in untreated acute myeloid leukemia (AML) in older patients and/or relapsed AML. Midostaurin, at a dose of 75 mg orally twice daily, was safe and tolerable. Three of 17 patients enrolled achieved a complete remission and 2 had hematologic improvement. Background: Midostaurin is a novel, orally available Fms-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor that induces cell cycle arrest and apoptosis of leukemic cells expressing mutant and wild type FLT3 receptors, and has} shown potential synergism with cytotoxic chemotherapy. Patients and Methods: We conducted a phase I study of azacitidine (intravenous 75 mg/m(2) daily for 7 days) with escalating doses of oral midostaurin (25 mg twice per day [b.i.d.], 50 mg b.i.d., and 75 mg b.i.d.) on days 8 to 21 of a 28-day cycle in untreated acute myeloid leukemia (AML) in older patients and/or relapsed AML. Patients were eligible regardless of FLT3 mutation status. Trough blood samples for pharmacokinetics were obtained on days 8, 15, and 21 before midostaurin dosing. Results: Seventeen patients with a median age of 73 (range,, 57-83) years were enrolled; 5 patients had previous conventional treatment and none of the patients had FLT3 mutations. Dose-limiting toxicities were not observed. Hospitalizations, primarily for infections, occurred in one-third of treatment cycles. Fourteen patients were evaluable for response: 3 attained complete remission and 2 had hematologic improvement. Median (range) survival from enrollment was 6 (1 to >= 19) months. Three patients died within 60 days of enrollment (2 progressive disease, 1 non dose-limiting toxicity, treatment-related). Pharmacokinetic data at 75 mg orally b.i.d. showed increased trough levels of midostaurin during cycle 2 compared with cycle 1 and persistent and increasing levels of its active metabolite, CGP52421. Conclusion: The combination of sequential azacitidine and midostaurin is safe and tolerable with response rates comparable with azacitidine alone and should be studied further in FLT3 mutation-positive AML. (C) 2015 Elsevier Inc. All rights reserved.