Safety and efficacy of midostaurin in patients with newly diagnosed FLT3-mutated AML

Abstract

Background: Activating mutations in fms‐like tyrosine kinase 3 (FLT3) occur in more than 30% of patients with newly diagnosed acute myeloid leukemia (AML). Midostaurin is an oral multikinase inhibitor with activity in AML with FLT3 mutations. The phase 3, randomized, placebo‐controlled CALGB 10603 (RATIFY) trial, conducted in North America and Europe, showed that overall survival was significantly longer in the midostaurin plus standard chemotherapy group than in the placebo plus standard chemotherapy group (hazard ratio for death, 0.78; one‐sided P = 0.009), as was event‐free survival (EFS) (hazard ratio for event or death, 0.78; one‐sided P = 0.002) (Stone R, et al. N Engl J Med. 2017). These results led to regulatory approval in the United States, Europe, and other regions. We are now performing a trial in countries that did not participate in RATIFY. Trial design: The phase 2, multicenter CPKC412A2220 trial (NCT03280030) enrolls patients aged < 65 years with newly diagnosed AML in Japan, South Korea, Hong Kong, Taiwan, and Russia. In part 1 (open label), midostaurin plus daunorubicin/cytarabine induction and highdose cytarabine consolidation is evaluated in Japanese patients (n = 3‐6) regardless of FLT3 mutation status (primary objective: safety). In part 2 (double blind), patients with FLT3‐ mutated AML (all countries, n = 60) are randomized to either midostaurin or placebo and stratified by mutation status and chemotherapy regimen‐the JALSG regimen (Ohtake S, et al. Blood. 2011)or the RATIFY regimen (Stone R, et al. N Engl J Med. 2017). After 1‐2 induction cycles, patients achieving complete remission (CR) proceed to consolidation plus midostaurin or placebo. Single‐agent midostaurin or placebo maintenance therapy is given to patients with continued CR following consolidation. The primary endpoint, EFS, will be analyzed after 36 documented EFS events (≈ 21 months after randomization of the first patient). Other endpoints include OS, CR rate, cumulative incidence of relapse, safety, pharmacokinetics parameters, and exploratory endpoints (including biomarkers and patient‐reported outcomes). The first patient was enrolled into part 1 in April 2018 and enrollment is ongoing in part 2).