Phase 3b Study Assessing the Safety and Efficacy of Midostaurin in Younger and Older Patients with Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML) Who Are Eligible for 7+3 or 5+2 Chemotherapy

Background: Midostaurin, a multikinase inhibitor that directly inhibits FLT3, is approved for the treatment of adult patients (pts) with newly diagnosed, FLT3-mutated AML. In the phase 3 RATIFY study (NCT00651261), younger adults (aged ≤ 60 y) who received midostaurin plus standard chemotherapy (CT) had significant improvements in survival compared with those that received placebo plus standard CT. To further evaluate the safety and efficacy of midostaurin in FLT3-mutated AML, a phase 3b (NCT03379727) study was initiated that allowed enrollment of younger and older (aged > 60 y) pts and variations in CT regimens, including idarubicin or daunorubicin for 7+3 or 5+2. Methods: This is an open-label, single-arm, multicenter study in adults fit for CT with newly diagnosed AML, ECOG performance status (PS) ≤ 2, and a documented FLT3 ITD or TKD mutation. Pts must start their first induction cycle with 7+3 (cytarabine [Ara-C] 100-200 mg/m2/d on days 1-7 + daunorubicin 60-90 mg/m2/d or idarubicin 12 mg/m2/d on days 1-3) or 5+2 (a reduced-dose regimen with these agents) per investigator’s discretion and enroll by day 7 of the first induction cycle. Pts are assigned to the 7+3 group if their Ara-C duration is ≥ 7 days, independent of daunorubicin/idarubicin duration, and to the 5+2 group in other cases. Pts may not switch once started on 7+3 or 5+2. Pts receive Ara-C consolidation (dose per investigator’s choice). Midostaurin 50 mg bid is administered on days 8-28 of each 28-day induction/consolidation cycle and daily for ≤ 12 cycles of maintenance. Pts are discontinued from the study if not in either complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the end of induction, relapse during consolidation/maintenance, receive a stem cell transplant (SCT), or experience toxicities leading to discontinuation. The primary and secondary endpoints are safety and the proportion of pts achieving CR/CRi, respectively. Results: Pts were recruited throughout Europe; study enrollment was closed January 28th, 2020, with 318 pts screened and 17 screen failures. Safety and efficacy analyses focused on 301 pts who received treatment and 300 pts who met all study criteria, respectively. The median age (range) was 59 (19-85) y, and 47.2% were aged > 60 y. Most pts had a FLT3-ITD mutation (82.7%), with 17.6% having a FLT3-TKD mutation. At data cut-off on March 31st, 2020, 63 pts were still receiving treatment. All 301 pts entered induction, 69% entered consolidati