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

Abstract

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 dasatinib 70 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.

Figure 1

(A) Best percent changes in overall RECIST score by treatment group. ^*Progression of non-targets. ^aMarked clinical progression at 3 weeks. ^bDasatinib dose (mg) and frequency. ^cDacarbazine dose (mg m⁻²). (B) Exploratory analysis: best RECIST response by tumour mutation status. ^†This patient with an NRAS mutation had marked clinical progression at 3 weeks follow-up. ^*Progression of non-targets at first restaging.