Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML.

7008 Background: We investigated the clinical activity, PK, safety and resistance mechanisms to single-agent crenolanib patients (pts) with refractory/relapsed acute myeloid leukemia (R/R AML) with FLT3 ITD. Methods: From Aug 2012 to May 2015, 69 pts (65 evaluable) with R/R FLT3+ AML (29 ITD, 11 D835, 29 ITD+D835) were treated with crenolanib 100 mg TID (42) or 200 mg/m2/d in 3 divided doses (27). Results: Crenolanib therapy resulted in a 39% CRi and 11% PR amongst the 18 pts (6 D835, 9 ITD, 3 ITD+D835) with R/R FLT3 AML who had not received prior FLT3 inhibitors (Cohort A). OS was 234d (238d in pts with ≤ 2 prior therapies and 133d in ≥ 3 prior therapies). Activity was seen in FLT3 ITD (OS 238d), TKD (OS 185d), and TKD+ITD (128d). Pts < 60 had a higher survival (OS 234d) than those ≥ 60 (OS 185d). 36 pts received crenolanib after progressing on prior TKIs (Cohort B), sorafenib (28), quizartinib (11), midostaurin (3), pexidartinib (4), gilteritinib (2) and FLX-925 (1). 10 pts had received ≥ 2 prior TKIs. FLT3-TKD mutations were acquired in 25 pts following TKI exposure: 19/36 had dual mutations with FLT3-ITD and FLT3-D835 (15 ITD, 2 D835). Overall RR was 31% (6 CRi, 5 PRs). OS was 94d in this cohort (158d in ITD, 63d in the dual ITD+D835 mutants). Cohort C consisted of 11 pts who developed FLT3+ AML after prior MDS (8 pts), and 1 pt each after prior myelofibrosis, polycythemia vera and systemic mastocytosis. These pts had only transient benefit from crenolanib, with OS of 55d. Crenolanib had predictable PKs (tmax 2 hrs, T1/2 7.5 hrs), with no accumulation seen with repeated dosing. Median Day 15 trough level was 352 nM documenting therapeutic drug levels. Common AEs included nausea/vomiting, transaminitis and fluid retention (majority Grade 1/2). Only 2 pts discontinued crenolanib due to related AEs. No pt acquired a secondary FLT3 mutation at the time of relapse following crenolanib. Conclusions: Encouraging single-agent activity, safety and PK is observed with crenolanib in multiply relapsed FLT3+ AML (including 40 pts with FLT3 D835 mutations). Crenolanib isnow being assessed in combination with standard chemotherapy in newly diagnosed and R/R AML. Clinical trial information: NCT01657682 and NCT01522469.