Background: Despite the approval of multi-targeted protein kinase inhibitor midostaurin for use in combination with chemotherapy which improves 5-year survival in newly diagnosed (NDx) acute myeloid leukemia (AML) associated with FLT3 mutations; the cumulative incidence of relapse in FLT3 mutant AML remains high, with progression often characterized by secondary FLT3-TKD mutations. Crenolanib is a potent pan-FLT3 inhibitor that has shown promising efficacy and tolerability in combination with chemotherapy in Phase 1/2 trials for AML patients with FLT3-ITD or -TKD mutations. This is the first globally initiated, randomized Phase 3 trial comparing the efficacy of two FLT3-TKIs, crenolanib and midostaurin, combined with intensive chemotherapy in NDx FLT3-mutated AML patients. Methods: This Phase 3, randomized, multi-center trial will be conducted at multiple sites worldwide, with a target enrollment of 510 subjects. Patient inclusion was modified to match the midostaurin RATIFY criteria to enroll NDx FLT3-mutated AML (18 – 60 yo), who are eligible for intensive chemotherapy; with the addition of any FLT3-ITD and/or -TKD mutations being eligible. All subjects will receive TKI treatment and will be randomized in a 1:1 ratio to receive either crenolanib (arm A) or the active-control, midostaurin (arm B). All patients will be treated with 7+3 (100 mg/m² IV cytarabine; 90 mg/m² IV daunorubicin) and can initiate treatment while awaiting FLT3 results prior to randomization. Consolidation could include chemotherapy (3000 mg/m² IV HiDAC) for up to 4 cycles and/or Allo-HSCT, depending on patient condition. During induction and consolidation patients on arm A will take crenolanib (100 mg TID) from d9 until 72h prior to the next cycle, and patients on arm B will take midostaurin (50 mg BID) on d8 to d21 of each cycle. Following consolidation or HSCT, patients may receive up to 12 months of FLT3-TKI maintenance. Maintenance efficacy will be evaluated over time using single-cell sequencing to assess MRD. Primary endpoint is event-free survival. Interim analyses will occur at approximately 178 and 267 events, and primary analysis at 356 events. Enrollment is underway as of January 31, 2019. Clinical trial information: NCT03258931