The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for midostaurin (PKC412) to treat acute myeloid leukemia (AML).
Midostaurin is a multi-targeted kinase inhibitor being developed for adults with newly diagnosed AML who are FLT3-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy.
Breakthrough therapy designation is intended to expedite the development and review of new medicines intended to treat serious or life-threatening conditions. The therapy must demonstrate substantial improvement over an available therapy on at least one clinically significant endpoint.
The designation includes all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.
Phase 3 trial
The breakthrough designation for midostaurin is primarily based on the results of the phase 3 RATIFY trial, which were presented at the 2015 ASH Annual Meeting.
The trial included 717 patients with newly diagnosed, FLT3-positive AML who were younger than 60 at enrollment. All of the patients received standard induction and consolidation therapy. Roughly half also received midostaurin (n=360), while the other half received placebo (n=357).
Patients who received midostaurin experienced a significant improvement in overall survival (hazard ratio=0.77, P=0.0074). The median overall survival was 74.4 months in the midostaurin arm and 25.6 months in the placebo arm.
The median event-free survival was 8 months in the midostaurin arm and 3.6 months in the placebo arm (P=0.0032). The 5-year event-free survival was 27.5% for midostaurin and 19.3% for placebo.
There was no significant difference between the treatment arms with regard to most non-hematologic grade 3/4 adverse events. The exception was rash/desquamation, which occurred in 13% of patients in the midostaurin arm and 8% of patients in the placebo arm (P=0.02).
Other grade 3/4 non-hematologic events occurring in 10% of patients or more included, in the midostaurin and placebo arms, respectively: febrile neutropenia (81%, 82%), infection (40%, 38%), diarrhea (15%, 16%), hypokalemia (13%, 17%), pain (13%, 13%), other infection (12%, 12%), ALT/SGPT (12%, 9%), and fatigue (9%, 11%).
There were 18 deaths (5%) in the midostaurin arm and 19 (5.3%) in the placebo arm during induction and consolidation.
Midostaurin development
Novartis has opened a Global Individual Patient Program (compassionate use program) and a US Expanded Treatment Protocol (ETP) to enable midostaurin access. Patients 18 years of age and older with newly diagnosed FLT3-mutated AML who are able to receive standard induction and consolidation therapy will be considered.
To help identify patients who may have a FLT3 mutation and potentially benefit from treatment with midostaurin, Novartis is collaborating with Invivoscribe Technologies, Inc. which is leading regulatory submissions for a companion diagnostic.
Midostaurin is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia.
