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Eur J Cancer. 2009 Sep;45(13):2333-41. Epub 2009 Jun 21.

Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers.

Soria JC, Massard C, Magné N, Bader T, Mansfield CD, Blay JY, Bui BN, Moussy A, Hermine O, Armand JP.

Département de Médecine, Institut Gustave Roussy, Université Paris XI, Service des Innovations Thérapeutiques Précoces, 94805 Villejuif, France.

BACKGROUND: Masitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting greater affinity and selectivity in vitro for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib.

METHODS: This dose-escalation study was conducted in patients with advanced and/or metastatic cancer to determine the maximum tolerated dose (MTD) for orally administered masitinib over a 12-week period. Secondary objectives were a clinical assessment of masitinib’s activity in cancer patients and establishment of a pharmacokinetic profile.

RESULTS: Forty patients with various solid tumours (predominantly GIST, 19 patients) were treated with masitinib at doses ranging between 0.7 and 17.2mg/kg/day. Although the MTD was not formally reached, an acceptable dose for chronic use was identified at 12 mg/kg/day. Treatment-related AEs were frequent (38/40 patients), however, the majority were grade 1 or 2 and demonstrated dose dependency at higher concentrations. Pharmacokinetic results showed a linear, dose-dependent increase of C(max) and AUC. One of two GIST patients with imatinib intolerance had a partial response at 11.1mg/kg/day. About 29% of the imatinib-resistant GIST population and 38% of the overall population had stable disease.

CONCLUSIONS: The safety profile of masitinib at 12 mg/kg/day b.i.d. for the treatment of solid cancers appears favourable and compatible with a long-term regimen. Tumour control rate in imatinib-resistant patients was encouraging, hence, the activity of masitinib in c-Kit expressing tumours, such as GIST, warrants further exploration as first-line anticancer therapy as well as for imatinib-resistant patients.

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