E-Newsletter - May 2016

calgb 10603 (ratify) study results lead to fda breakthrough therapy designation for investigational treatment for newly-diagnosed flt3-mutated aml

The United States Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to midostaurin (PKC412), an investigational treatment for 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. The Breakthrough Therapy designation for midostaurin is primarily based upon the positive results from the CALGB 10603 (RATIFY) phase III clinical trial.

AML is an aggressive cancer of the blood and bone marrow that prevents white blood cells from maturing, causing an accumulation of “blasts” which do not allow room for the normal blood cells. AML is the most common acute leukemia in adults, but also has the lowest survival rate. It accounts for approximately 25 percent of all adult leukemias worldwide. Mutations in specific genes are found in many cases of AML, and biomarker testing is considered standard of care for newly-diagnosed patients to help determine the best possible treatment option. FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase, a type of cell-surface receptor, which plays a role in the proliferation, or increase, in the number of certain blood cells.

In the study, patients who received midostaurin and standard induction and consolidation chemotherapy experienced a significant improvement in overall survival (OS) (hazard ratio = 0.77, P = 0.0074) compared to those who received standard induction and consolidation chemotherapy alone1. The median OS for patients in the midostaurin treatment group was 74.7 months (95 percent confidence interval [CI]: 31.7, not attained), versus 25.6 months (95 percent CI: 18.6, 42.9) for patients in the placebo group1. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic and non-hematologic adverse events in the midostaurin treatment group versus the placebo group1. A total of 37 deaths were reported, with no difference in treatment-related deaths observed between groups1.

According to the FDA, Breakthrough Therapy designation is intended to expedite the development and review of new medicines that treat serious or life-threatening conditions, if the therapy has demonstrated 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 program2.

In the United States, about 20,000 people were diagnosed with AML last year, the majority of whom were adults3. According to the latest research, approximately one-third of AML patients also harbor a FLT3 gene mutation4, which is associated with worse outcomes and shorter survival than in those without the mutation8. PKC412 (midostaurin) is the first drug targeting FLT3 to demonstrate an overall survival benefit in AML1.

Since midostaurin is investigational at this time and is expected to be submitted for FDA approval, Novartis (the agent's manufacturer) 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 and able to receive standard induction and consolidation therapy will be considered.

In order to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with midostaurin, Novartis is collaborating with Invivoscribe Technologies, Inc. who is leading regulatory submissions for a companion diagnostic.


1. Stone RM, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Presented at the 57th Annual Meeting of the American Society of Hematology.
2. US Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies. http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm341027.htm. Accessed May 2016.
3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. Ca Cancer J Clin. 2015;65(1):5–29.
4. Levis M. FLT3 mutations in acute myeloid leukemia: What is the best approach in 2013? Hematology Am Soc Hematol Educ Program. 2013;2013:220-6.


For other articles in the May issue of the Alliance E-News newsletter, see below.