A Phase 3, Open-Label, Randomized Study Of The Flt3 Inhibitor Gilteritinib Versus Salvage Chemotherapy In Adults With First Relapse Or Primary Refractory Flt3 Mutation-Positive Acute Myeloid Leukemia.

TPS7072 Background: FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML) and FLT3 internal tandem duplication (ITD) mutations are associated with high relapse rates, short remission durations, and poor overall survival (OS). Gilteritinib (ASP2215) is a highly selective FLT3 tyrosine kinase inhibitor with activity against FLT3-ITD mutations. It also inhibits FLT3-D835 mutations that can confer clinical resistance to other FLT3 inhibitors. A phase 1/2 study of gilteritinib in relapsed/refractory AML showed favorable tolerability across a wide dose range and consistent, potent, FLT3 inhibition in correlative assays. Cohort expansion in FLT3-mutated patients generated an overall response rate of 55% (CR/CRp/CRi = 44%, PR = 11%) and survival that was longer than in prior reports of cytotoxic chemotherapy or other FLT3 inhibitors. Therefore, a phase 3 trial was initiated. Methods: This randomized phase 3 study (NCT02421939) will enroll 369 adult AML subjects at ~140 centers across North America, Europe, and Asia. Subjects must be in first relapse or refractory to frontline therapy and have a centrally confirmed FLT3 mutation. Subjects will be randomized 2:1 to treatment with either 120 mg gilteritinib QD or to investigator’s pre-randomization choice of specified salvage chemotherapy. Randomization will be stratified by prior chemotherapy response and salvage chemotherapy regimen intensity. Subjects randomized to gilteritinib or low-intensity chemotherapy will receive continuous 28-day cycles until a discontinuation event occurs; high-intensity chemotherapy subjects will receive up to 2 cycles before response measurement. The primary objective is OS; key secondary objectives are event-free survival and complete remission (CR) rate. Other secondary objectives include leukemia-free survival, remission duration, composite CR rate, subsequent transplantation rate, patient-reported fatigue, and overall safety. A formal interim analysis is planned after ~50% of deaths have occurred. Study enrollment began October 23, 2015; as of February 1, 2016, 10 subjects have been randomized. Clinical trial information: NCT02421939.