An Open-Label, Randomized Phase Iii Study Of Gilteritinib Versus Salvage Chemotherapy In Relapsed Or Refractory Flt3 Mutation-Positive Acute Myeloid Leukemia.

TPS7067 Background: FLT3 mutations occur in 30% of patients with acute myeloid leukemia (AML), most often as internal tandem duplications (FLT3-ITD) or point mutations at codon D835. FLT3-ITDs are associated with high relapse rates, short remission duration, and poor overall survival (OS); FLT3-D835 can confer resistance to other tyrosine kinase inhibitors (TKIs). Gilteritinib is a highly selective FLT3/AXL TKI with activity against both FLT3-ITD and FLT3-D835 mutations. A recent phase 1/2 study of gilteritinib (20–450 mg/d) in relapsed/refractory (R/R) AML showed favorable tolerability at doses ≤300 mg/d, and consistent, potent FLT3 inhibition at doses ≥80 mg/d. Patients with FLT3 mutation-positive (FLT3 mut+ ) AML receiving doses ≥80 mg/d had an ORR of 52% (CR/CRp/CRi = 41%, PR = 11%) and longer OS than historic experience in R/R AML with combination cytotoxic chemotherapy or other FLT3 TKIs as monotherapy. Given these results, we initiated a phase 3 trial of once-daily (QD) 120 mg gilteritinib. Methods: This randomized, open-label phase 3 study (NCT02421939) will enroll 369 adults with FLT3 mut+ AML in first relapse or refractory to front-line therapy. Patients who have not previously received FLT3 inhibitors, except sorafenib and midostaurin, will be randomized 2:1 to either 120 mg gilteritinib QD or the investigator’s pre-randomization specified salvage chemotherapy choice (LoDAC, Aza, MEC, FLAG-IDA), and stratified by prior chemotherapy response and salvage chemotherapy intensity. Gilteritinib or low-intensity chemotherapy cohorts will receive continuous 28-day treatment cycles until a discontinuation event occurs; the high-intensity chemotherapy cohort will receive ≤2 treatment cycles before response measurement. Primary objective is OS; key secondary objectives are event-free survival and CR rate. Other secondary objectives: leukemia-free survival, remission duration, composite CR rate, subsequent transplantation rate, patient-reported fatigue, and safety. A formal interim analysis is planned when ~50% of planned death events have occurred. Study enrollment began on Oct 23, 2015; as of Jan 20, 2017, 167 subjects have been randomized. Clinical trial information: NCT02421939.