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The U.S. Food and Drug Administration has granted breakthrough therapy designation to PKC412 (midostaurin) for the treatment of adults with newly-diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy. PKC412 is an investigational, oral, multi-targeted kinase inhibitor.

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The breakthrough therapy designation, enacted as part of the FDA's 2012 Safety and Innovation Act, was created to expedite the development and review time of a potential new drug for serious or life-threatening disease where early clinical evidence suggests the drug may demonstrate substantial improvement compared with existing therapies.


This designation for PKC412 is based on data from the Phase III RATIFY (CALGB 10603) clinical trial (OT 1/25/16 issue). The trial included 717 patients with FLT3-mutated AML who were randomized to receive either PKC412 (360 patients) or placebo (357 patients) in addition to standard chemotherapy, daunorubicin and cytarabine, for induction therapy, followed by high-dose cytarabine for consolidation chemotherapy. Patients who achieved a complete remission after consolidation chemotherapy continued treatment with PKC412 or placebo as a single agent for up to one year.


Median overall survival for the patients who received PKC412 was 74.7 months compared with 25.6 months for the patients receiving the placebo. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events for patients receiving PKC412 versus patients receiving the placebo.


PKC412 is also being investigated for the treatment of aggressive systemic mastocytosis/mast cell leukemia, according to the drug's developer, Novartis. Novartis is collaborating with Invivoscribe Technologies, Inc., who is leading regulatory submissions for a companion diagnostic to identify patients with a FLT3 mutation.