Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3

Thomas Fischer, Richard M. Stone, Daniel J. DeAngelo, Ilene Galinsky, Elihu Estey, Carlo Lanza, Edward Fox, Gerhard Ehninger, Eric J. Feldman, Gary J. Schiller, Virginia M. Klimek, Stephen D. Nimer, D. Gary Gilliland, Catherine Dutreix, Alice Huntsman-Labed, Jodi Virkus, Francis J. Giles

Research output: Contribution to journalArticle

317 Scopus citations

Abstract

Purpose: Mutations leading to constitutive activation of the FMS-like tyrosine kinase 3 receptor (FLT3) occur in blasts of 30% of patients with acute myeloid leukemia (AML). Midostaurin (PKC412; N-benzoylstaurosporin) is a multitargeted tyrosine kinase inhibitor, with demonstrated activity in patients with AML/myelodysplastic syndrome (MDS) with FLT3 mutations. Patients and Methods: Ninety-five patients with AML or MDS with either wild-type (n = 60) or mutated (n = 35) FLT3 were randomly assigned to receive oral midostaurin at 50 or 100 mg twice daily. The drug was discontinued in the absence of response at 2 months, disease progression, or unacceptable toxicity. Response was defined as complete response, partial response (PR), hematologic improvement, or reduction in peripheral blood or bone marrow blasts by ≥ 50% (BR). Results: The rate of BR for the population in whom efficacy could be assessed (n = 92) was 71% in patients with FLT3-mutant and 42% in patients with FLT3 wild-type. One PR occurred in a patient with FLT3-mutant receiving the 100-mg dose regimen. Both doses were well-tolerated; there were no differences in toxicity or response rate according to the dose of midostaurin. Conclusion: These results suggest that midostaurin has hematologic activity in both patients with FLT3-mutant and wild-type. The degree of clinical activity observed supports additional studies that combine midostaurin and other agents such as chemotherapy especially in FLT3-mutant AML.

Original languageEnglish (US)
Pages (from-to)4339-4345
Number of pages7
JournalJournal of Clinical Oncology
Volume28
Issue number28
DOIs
StatePublished - Oct 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Fischer, T., Stone, R. M., DeAngelo, D. J., Galinsky, I., Estey, E., Lanza, C., Fox, E., Ehninger, G., Feldman, E. J., Schiller, G. J., Klimek, V. M., Nimer, S. D., Gilliland, D. G., Dutreix, C., Huntsman-Labed, A., Virkus, J., & Giles, F. J. (2010). Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. Journal of Clinical Oncology, 28(28), 4339-4345. https://doi.org/10.1200/JCO.2010.28.9678