Safety and Efficacy of Midostaurin in Patients With Newly Diagnosed FLT3-Mutated AML

Date 24 November 2018
Event ESMO Asia 2018 Congress
Session Poster display - Cocktail
Topics Leukaemia
Anticancer Agents
Personalised/Precision Medicine
Presenter Po-Nan Wang
Citation Annals of Oncology (2018) 29 (suppl_9): ix87-ix93. 10.1093/annonc/mdy437
Authors P. Wang1, A.Y.H. Leung2, J.H. Jang3, S. Voloshin4, L. O'Sullivan-Djentuh5, K. Suzuki6, S. Ifrah7, G. Le Gouadec7, T. Kakizume6, H. Kitagawa6, K. Malek5, Y. Miyazaki8
  • 1Division Of Hematology, Chang Gung Memorial Hospital, 333 - Taoyuan City/TW
  • 2Li Ka Shing Faculty Of Medicine, The University of Hong Kong, Hong Kong/CN
  • 3Internal Medicine, Seoul National University Hospital, Seoul/KR
  • 4Hematology, Institute of Hematology and Transfusiology of the FMBA, St Petersburg/RU
  • 5Oncology, Novartis Pharma AG, Basel/CH
  • 6Oncology, Novartis Pharma KK, Tokyo/JP
  • 7Oncology, Novartis Pharma S.A.S., Rueil-Malmaison/FR
  • 8Department Of Hematology, Nagasaki University Hospital, Nagasaki/JP



Activating mutations in fms-like tyrosine kinase 3 (FLT3) occur in more than 30% of patients with newly diagnosed acute myeloid leukemia (AML). Midostaurin is an oral multikinase inhibitor with activity in AML with FLT3 mutations. The phase 3, randomized, placebo-controlled CALGB 10603 (RATIFY) trial, conducted in North America and Europe, showed that overall survival was significantly longer in the midostaurin plus standard chemotherapy group than in the placebo plus standard chemotherapy group (hazard ratio for death, 0.78; one-sided P = 0.009), as was event-free survival (EFS) (hazard ratio for event or death, 0.78; one-sided P = 0.002) (Stone R, et al. N Engl J Med. 2017). These results led to regulatory approval in the United States, Europe, and other regions. We are now performing a trial in countries that did not participate in RATIFY.

Trial design

The phase 2, multicenter CPKC412A2220 trial (NCT03280030) enrolls patients aged < 65 years with newly diagnosed AML in Japan, South Korea, Hong Kong, Taiwan, and Russia. In part 1 (open label), midostaurin plus daunorubicin/cytarabine induction and high-dose cytarabine consolidation is evaluated in Japanese patients (n = 3-6) regardless of FLT3 mutation status (primary objective: safety). In part 2 (double blind), patients with FLT3-mutated AML (all countries, n = 60) are randomized to either midostaurin or placebo and stratified by mutation status and chemotherapy regimen—the JALSG regimen (Ohtake S, et al. Blood. 2011)or the RATIFY regimen (Stone R, et al. N Engl J Med. 2017). After 1-2 induction cycles, patients achieving complete remission (CR) proceed to consolidation plus midostaurin or placebo. Single-agent midostaurin or placebo maintenance therapy is given to patients with continued CR following consolidation. The primary endpoint, EFS, will be analyzed after 36 documented EFS events (≈ 21 months after randomization of the first patient). Other endpoints include OS, CR rate, cumulative incidence of relapse, safety, pharmacokinetics parameters, and exploratory endpoints (including biomarkers and patient-reported outcomes). The first patient was enrolled into part 1 in April 2018 and enrollment is ongoing in part 2).

Editorial acknowledgement

Medical editorial assistance was provided by Pamela Tuttle, PhD, of ArticulateScience LLC, which was funded by Novartis Pharmaceuticals Corporation.

Clinical trial identification

CPKC412A2220. (NCT03280030); release date 16 Jun 2017.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.


Novartis Pharmaceuticals Corporation.


J.H. Jang: Advisory board member, Member of the Study Steering Committee for the CPKC412A2220 trial: Novartis Pharmaceuticals. S. Voloshin: Consultancy, Member of the Study Steering Committee for the CPKC412A2220 trial: Novartis Pharmaceuticals. L. O\'Sullivan-Djentuh, K. Malek: Employment: Novartis AG. K. Suzuki, T. Kakizume: Employment: Novartis Pharma KK. S. Ifrah, G. Le Gouadec: Employment: Novartis Pharma S.A.S. H. Kitagawa: Employment: Novartis Pharma KK; Stock ownership: GSK: Y. Miyazaki: Honoraria, Participation on an advisory board: Novartis; Honoraria: Astellas, Daiichi Sankyo, Dainippon-Sumitomo, Participation on an advisory board: Abbvie. All other authors have declared no conflicts of interest.