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
Top Cited Papers
- 1 October 2010
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 28 (28), 4339-4345
- https://doi.org/10.1200/jco.2010.28.9678
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.Keywords
This publication has 23 references indexed in Scilit:
- FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AMLBlood, 2010
- An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AMLBlood, 2008
- A Mechanism-Based Population Pharmacokinetic Model for Characterizing Time-Dependent Pharmacokinetics of Midostaurin and its Metabolites in Human SubjectsClinical Pharmacokinetics, 2008
- Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitorsBlood, 2006
- Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domainBlood, 2005
- Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412Blood, 2005
- Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid LeukemiaJournal of Clinical Oncology, 2003
- New designs for phase 2 clinical trialsBlood, 2003
- Role of FLT3 in leukemiaCurrent Opinion in Hematology, 2002
- A bayesian strategy for screening cancer treatments prior to phase ii clinical evaluationStatistics in Medicine, 1993