The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study.
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Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J
The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study.
Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12.
- PubMed ID
- 16969355 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Midostaurin Mast/stem cell growth factor receptor Kit Protein Humans UnknownAntagonistInhibitorDetails Midostaurin Platelet-derived growth factor receptor alpha Protein Humans YesAntagonistInhibitorDetails Midostaurin Platelet-derived growth factor receptor beta Protein Humans YesAntagonistInhibitorDetails Midostaurin Protein kinase C alpha type Protein Humans YesAntagonistInhibitorDetails Midostaurin Receptor-type tyrosine-protein kinase FLT3 Protein Humans YesAntagonistInhibitorDetails Midostaurin Vascular endothelial growth factor receptor 2 Protein Humans YesAntagonistInhibitorDetails