PS1065 OPEN‐LABEL STUDY OF GILTERITINIB, GILTERITINIB PLUS AZACITIDINE, OR AZACITIDINE ALONE IN NEWLY DIAGNOSED FLT3‐MUTATED AML PATIENTS INELIGIBLE FOR INTENSIVE CHEMOTHERAPY: RESULTS FROM THE SAFETY COHORT
Authors: J. Esteve, R. Schots, T. Bernal Del Castillo, J.‐H. Lee, E. Wang, S. Dinner, M. Minden, O. Salamero, J. Sierra, G. Yoshimoto, K. Laribi, J. Halka, P. Montesinos, S. Liu, E. Rich, E. Bahceci
Journal: HemaSphere (2019)

Background: The FLT3 inhibitor, gilteritinib, showed antileukemic activity and favorable tolerability in patients (pts) with FLT3 ‐mutated ( FLT3 mut+ ) relapsed/refractory AML. Gilteritinib plus azacitidine (AZA) induced apoptosis and inhibited MV4–11 cell and tumor growth. A clinical trial investigating gilteritinib plus AZA vs either agent alone in pts with newly diagnosed (ND) FLT3 mut+ AML ineligible for intensive induction chemotherapy was initiated; we present data from the Safety Cohort, which evaluated combination therapy. Aims: A clinical trial investigating gilteritinib plus AZA vs either agent alone in pts with newly diagnosed (ND) FLT3 mut+ AML ineligible for intensive induction chemotherapy was initiated; we present data from the Safety Cohort, which evaluated combination therapy. Methods: Adults with ND FLT3 mut+ AML are being enrolled in this clinical trial (NCT02752035). To determine the appropriate gilteritinib dose for combination therapy prior to the randomized portion of the study, a Safety Cohort was initiated, in which pts received 80 or 120 mg/day gilteritinib (Days 1–28) plus subcutaneous/intravenous AZA (75 mg/m 2 /day; Days 1–7) and were observed for dose‐limiting toxicities (DLTs) through Cycle 1. Treatment continued until lack of clinical benefit or unacceptable toxicity. Safety/tolerability and antileukemic response were assessed. Results: Fifteen pts (median age, 76 years [range: 65–86]) were enrolled into the Safety Cohort (n = 9, 80 mg gilteritinib; n = 6, 120 mg gilteritinib); 14 were FLT3 mut+ (ITD alone, n = 10; TKD alone, n = 3; ITD and TKD, n = 1). As of 25 June 2018, 56% (n = 8/15; Figure) of pts had been treated for &gt;6 mo, 9 discontinued, and 6 remained on treatment. A DLT (tumor lysis syndrome) occurred in a pt who received 80 mg gilteritinib plus AZA; no DLTs occurred in the 120 mg gilteritinib plus AZA cohort. All 15 pts had ≥1 AE; 12 (80%) experienced treatment‐related AEs. Common AEs were anemia (n = 7), febrile neutropenia and nausea (n = 6 each), increased ALT/AST, constipation, diarrhea, neutropenia, thrombocytopenia, and pyrexia (n = 5 each), and decreased appetite, fatigue, increased blood creatinine, and hypocalcemia (n = 4 each). Common grade ≥3 AEs were febrile neutropenia (n = 6), anemia and neutropenia (n = 5 each), and thrombocytopenia (n = 4). Serious AEs in &gt;2 pts were febrile neutropenia (n = 5), and anemia and pyrexia (n = 3 each). Eight pts had fatal AEs; none were treatment‐related and 3 occurred early in treatment: septic shock (Day 2), respiratory failure (Day 6), and cerebral hemorrhage in the setting of acute kidney injury and uremia (Day 17). Of 13 pts with post‐baseline laboratory data, none had clinically significant AST/ALT or total bilirubin values or maximum post‐baseline QTcF interval &gt;500 msec. The composite complete remission rate was 67% (n = 10/15); complete remission and complete remission with incomplete hematologic recovery was achieved in 4 and 6 pts, respectively (Figure); 2 pts (13%) achieved a partial response, giving an overall response rate of 80%. One DLT from the 11 DLT‐evaluable pts (ie, pts who experienced a DLT, or in the absence of DLT, received ≥23 of 28 gilteritinib doses and ≥5 of 7 AZA doses during DLT observation) informed the decision to proceed to randomization at 120 mg/day gilteritinib for combination treatment. Summary/Conclusion: In ND FLT3 mut+ AML pts unfit to receive standard induction chemotherapy, gilteritinib and AZA were well tolerated, and induced antileukemic responses. Based on these results, enrollment into the randomized portion of the study has begun and pts in the combination arm will receive 120 mg gilteritinib. image