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Clinical Trial
. 2010 Oct 1;28(28):4339-45.
doi: 10.1200/JCO.2010.28.9678. Epub 2010 Aug 23.

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  1 , 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
Affiliations
Clinical Trial

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 et al. J Clin Oncol. .

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.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
CONSORT diagram.
Fig 2.
Fig 2.
Kaplan-Meier plot of overall survival according to FMS-like tyrosine kinase 3 receptor (FLT3) mutation status. All reported deaths that occurred in the efficacy population after first dose of study drug are included. Censoring (26 patients) took place within a period of 9 months from study completion with a mean post-treatment follow-up of 41 days (standard deviation, 75).
Fig 3.
Fig 3.
Plasma concentrations of midostaurin and metabolites. Median trough plasma concentration-time profiles of midostaurin and its metabolites, CGP62221 and CGP52421, after oral dose of (A) 50 mg (n = 45) and (B) 100 mg (n = 42) midostaurin twice a day in patients with wild-type or mutated FMS-like tyrosine kinase 3 receptor acute myeloid leukemia.
See this image and copyright information in PMC

References

    1. Burnett AK, Goldstone AH, Stevens RM, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: Results of MRC AML 10 trial: UK Medical Research Council Adult and Children's Leukaemia Working Parties. Lancet. 1998;351:700–708. - PubMed
    1. Stone RM. The difficult problem of acute myeloid leukemia in the older adult. CA Cancer J Clin. 2002;52:363–371. - PubMed
    1. Breitenbuecher F, Schnittger S, Grundler R, et al. Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor. Blood. 2009;113:4074–4077. - PubMed
    1. Kayser S, Schlenk RF, Londono MC, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114:2386–2392. - PubMed
    1. Gilliland DG, Griffin JD. Role of FLT3 in leukemia. Curr Opin Hematol. 2002;9:274–281. - PubMed

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