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Type: Journal article
Title: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study
Author: Millward, M.
House, C.
Bowtell, D.
Webster, L.
Olver, I.
Gore, M.
Copeman, M.
Lynch, K.
Yap, A.
Wang, Y.
Cohen, P.
Zalcberg, J.
Citation: British Journal of Cancer, 2006; 95(7):829-834
Publisher: Nature Publishing Group
Issue Date: 2006
ISSN: 0007-0920
Statement of
M J Millward, C House, D Bowtell, L Webster, I N Olver, M Gore, M Copeman, K Lynch, A Yap, Y Wang, P S Cohen and J Zalcberg
Abstract: Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.
Keywords: protein kinase C; melanoma; midostaurin
Rights: © 2006 Cancer Research UK
RMID: 0020061554
DOI: 10.1038/sj.bjc.6603331
Appears in Collections:Earth and Environmental Sciences publications

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