A Study of Midostaurin Efficacy and Safety in Newly Diagnosed Patients With FLT3-mutated AML

This was a Phase II, multi-center trial consisting of two parts; Part 1: an open label, safety evaluation part in Japan only (minimum of three evaluable subjects) and Part 2: a double-blind, randomized, placebo-controlled part (60 subjects). Part 1 in Japan and Part 2 outside Japan were initiated simultaneously. Part 1 was conducted to evaluate the safety and tolerability of midostaurin in combination with daunorubicin/cytarabine induction and high-dose cytarabine consolidation in Japanese subjects and was a pre-requisite before allowing participation of Japan in Part 2. Data from Part 1 was reviewed by an Independent safety Committee (ISC) designated by the Sponsor. The ISC reviewed all available safety data in subjects from Japan up to the time of the safety review data cut-off date (6-Sep-2018). A meeting with the ISC was held on 25-Sep-2018: based on safety evaluation in three evaluable subjects, the ISC members recommended to start Part 2 in Japan.

Part 2 of the study included screening phase, treatment phase composed of up to 18 cycles of midostaurin/placebo treatment in combination with chemotherapy (daunorubicin and cytarabine) during induction and consolidation and alone during continuation and 30 days safety follow up from last dose of study treatment (daunorubicin or cytarabine or midostaurin/placebo); and follow up phase for continued remission and survival follow-up (until 36 months after Day 1 of the last subject). Subjects who provided written informed consent were screened for eligibility during the period up to 7 days immediately prior to starting chemotherapy (Day 1). The subject was randomized at Day 8 to receive either midostaurin or placebo only if FLT3 status was mutated. Treatment phase included induction, consolidation and continuation therapies.

Induction therapy: All screened subjects started induction therapy with chemotherapy from Day 1 to Day 7, while the FLT3 mutation status was being determined. Subjects who achieved CR already with induction Cycle 1 went directly to consolidation therapy without a second cycle of induction therapy. Subjects who did not achieve CR with one cycle of induction received a second induction cycle with same treatment as in Cycle 1. Subjects who did not achieve CR after induction 2 discontinued the study treatment and were followed in safety follow up and survival follow-up.

Consolidation therapy: Subjects who achieved a CR after 1 or 2 cycles of induction received consolidation therapy with 3 cycles of high-dose cytarabine for the Japan Adult Leukemia Study Group (JALSG) regimen and 4 cycles of high-dose cytarabine as tolerated for the Randomized AML Trial In FLT3+ subjects <60 Years old (RATIFY) regimen. Subjects received midostaurin/placebo, orally twice a day, on Days 8 to 21 of each cycle. Each consolidation cycle began within two weeks following hematopoietic recovery (ANC ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) but no sooner than four weeks from the beginning of the previous cycle.

Continuation therapy: After hematopoietic recovery (ANC ≥ 1.0 x 109/L, platelet count ≥ 100 x 109/L) following the final cycle of consolidation but no sooner than 14 days after the last dose of midostaurin/placebo during the last consolidation cycle, subjects who maintained a CR received up to 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice a day. Safety was assessed in this treatment phase for each subject until 30 days after the end of treatment (EOT) and included routine safety monitoring.

The follow-up phases included post treatment follow-up and survival follow-up. During post-treatment follow-up, all subjects continued to be assessed for relapse i.e. every 2 months during years 1 and 2, every 3 months on year 3 and 4 and then yearly and at time of relapse until relapse, withdrawal of consent, death, loss to follow up, or end of study, whichever was earlier following the end of study treatment for any reason other than persistent AML. Subjects who discontinued study treatment due to persistent AML or relapse and the post treatment follow-up phase due to relapse entered a survival follow-up period during which survival was recorded every 3 months. Survival information was obtained by clinical visits or telephone calls or other means until death, withdrawal of consent, lost to follow-up or end of study, whichever was earlier.