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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. Br J
Cancer. 2006 Oct 9;95(7):829-34
The multikinase inhibitor midostaurin (PKC412) lacks
activity in metastatic melanoma: a phase IIA clinical and
biologic study.
Peter MacCallum Cancer Institute, Melbourne, Victoria,
Australia.
millward@cyllene.uwa.edu.au
Midostaurin (PKC412), 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.
PMID: 16969355 |
