title: 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.
  
  
  CONCLUSIONS
  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.
authors: University of California, San Francisco, MTZ-A741, 1600 Divisadero Street, San Francisco, CA 94143, USA.
authors: A P
authors: AP
authors: Algazi
authors: J S
authors: JS
authors: Weber
authors: S C
authors: SC
authors: Andrews
authors: P
authors: P
authors: Urbas
authors: P N
authors: PN
authors: Munster
authors: R C
authors: RC
authors: DeConti
authors: J
authors: J
authors: Hwang
authors: V K
authors: VK
authors: Sondak
authors: J L
authors: JL
authors: Messina
authors: T
authors: T
authors: McCalmont
authors: A I
authors: AI
authors: Daud
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000009:adverse effects; D000069439:Dasatinib; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011743:Pyrimidines / Q000009:adverse effects; D016019:Survival Analysis; D013844:Thiazoles / Q000009:adverse effects; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D011743:Pyrimidines; D013844:Thiazoles; D003606:Dacarbazine; D019061:src-Family Kinases; D000069439:Dasatinib