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.

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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 28 Issue 28 Pg. 4339-45 (Oct 01 2010) ISSN: 1527-7755 [Electronic] United States
• PMID: 20733134 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Receptor Protein-Tyrosine Kinases
• fms-Like Tyrosine Kinase 3
• Staurosporine
• midostaurin

Topics

• Administration, Oral
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• Female
• Humans
• Leukemia, Myeloid, Acute (drug therapy, enzymology, genetics)
• Male
• Mutation
• Myelodysplastic Syndromes (drug therapy, enzymology, genetics)
• Receptor Protein-Tyrosine Kinases (genetics)
• Staurosporine (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
• Treatment Outcome
• fms-Like Tyrosine Kinase 3 (genetics)