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Phase I clinical trial of the Src inhibitor dasatinib with dacarbazine in metastatic melanoma.

Author(s): Algazi AP, Weber JS, Andrews SC, Urbas P, Munster PN, Deconti RC, Hwang J, Sondak VK, Messina JL, McCalmont T, Daud AI

Affiliation(s): University of California, San Francisco, MTZ-A741, 1600 Divisadero Street, San Francisco, CA 94143, USA.

Publication date & source: 2011-11-29, Br J Cancer., [Epub ahead of print]

Background:Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma.Methods:Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations.Results:Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response.Conclusion:The recommended phase II dose is dasatinib70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.British Journal of Cancer advance online publication, 29 November 2011; doi:10.1038/bjc.2011.514 www.bjcancer.com.

Page last updated: 2011-12-09

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