Date: 2016-06-29
Type of
information: Publication of results in a medical journal
phase: 2
Announcement: publication of results in The New English Journal of Medicine
Company: Novartis (Switzerland)
Product: Rydapt®(midostaurin - PKC412)
Action
mechanism: kinase inhibitor. PKC412 (midostaurin) is an oral, multi-targeted kinase inhibitor in development for the treatment of patients with newly-diagnosed acute myeloid leukemia who are FLT3 mutation-positive, as detected by an FDA-approved test, and who are eligible to receive standard induction and consolidation chemotherapy. In order to help identify patients who may have a FLT3 mutation and potentially benefit from treatment with PKC412 (midostaurin), Novartis is collaborating with Invivoscribe Technologies for the development and FDA approval of the FLT3 companion diagnostic. The same test is being CE marked in Europe. Regulatory submissions for the companion diagnostic are being led by IVS.
Disease: advanced systemic mastocytosis
Therapeutic
area: Rare diseases
Country: Australia, Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Norway, Poland, Turkey, UK, USA
Trial
details: This study has investigated if the drug midostaurin taken orally twice daily is effective and safe in treating patients with aggressive systemic mastocytosis or mast cell leukemia with or without an additional hematological neoplasm. (NCT00782067)
Latest
news:
- • On June 29, 2016, Novartis announced that The New England Journal of Medicine published data for PKC412 (midostaurin) demonstrating an overall response rate, defined as a major or partial response, of 60% (95% confidence interval [CI], 49-70%; P<0.001) in patients with advanced systemic mastocytosis (Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016;374(26):2530-2541). The median duration of response for all responders in the primary efficacy population was 24.1 months (95% CI, 10.8-not estimated [NE]).
- The pivotal Phase II study, CPKC412D2201, was the largest and longest-running prospective trial ever conducted in this rare disorder. Jason Gotlib, MD, of Stanford University School of Medicine and Stanford Cancer Institute, served as lead author of the study, which enrolled 116 people with advanced systemic mastocytosis. Eligibility and responses were reviewed by a Study Steering Committee and 89 patients were eligible for inclusion in the primary efficacy population. Patients received single-agent, oral PKC412 (midostaurin) until disease progression or unacceptable toxicity. Results demonstrated a median overall survival (OS) of 28.7 months (95% CI, 18.1-NE). Improvements in both bone marrow mast cell burden and serum tryptase levels - a marker for mast cell burden - were seen in 78% of patients, and were associated with disease regression.
- The most frequent side effects were gastrointestinal. With the exception of nausea and vomiting, all 32 symptoms self-reported with the Memorial Symptom Assessment Scale significantly decreased with treatment (P<0.001). Quality of life, assessed by the 12-item Short Form Health Survey (SF-12), was also significantly increased with PKC412 (midostaurin) treatment, compared to baseline values: improvement was shown by a 26% (P<0.001) increase in mental health scores and a 29% (P<0.001) increase in physical health scores.
- The Phase II study results are also reinforced in a letter published in the same issue of NEJM by the French Reference Centre of Mastocytosis (CEREMAST) regarding a compassionate use program for PKC412 (midostaurin) in advanced systemic mastocytosis. After a median follow-up time of 18.5 (3-36) months, the overall response rate to treatment was 71%. After a similar follow-up time, the overall survival (OS) rate was 42.7%, compared with 14.9% in a matched historic control group (P=0.03). A more than twofold higher risk of death was also observed in the control group (HR 2.2; P=0.02)[6]. The most frequent side effects were nausea/vomiting in 89% of patients (leading to failure/discontinuation in 18%), lymphocytopenia in 61% without opportunistic infection and photosensitivity in 25%. The authors concluded that PKC412 (midostaurin) is effective in advanced systemic mastocytosis.
Is
general: Yes
