title: A phase 2 trial of dasatinib in advanced melanoma.
abstract: BACKGROUND
  Inhibiting src kinases (non-receptor tyrosine kinase signaling intermediates) reduces melanoma cell proliferation and invasion. Dasatinib inhibits c-kit, PDGFβR, and EPHA2 and src kinases c-src, c-Yes, Lck, and Fyn. A phase 2 trial of dasatinib in melanoma was conducted to assess response rate (RR), progression-free survival (PFS), and toxicity.
  
  
  METHODS
  Adults with stage 3/4 chemotherapy-naïve unresectable melanoma were eligible. Dasatinib was initially administered at 100 mg twice daily continuously to 17 patients. Due to toxicity, the starting dosage was decreased to 70 mg twice daily. Tumor assessments occurred every 8 weeks.
  
  
  RESULTS
  Thirty-nine patients were enrolled, 36 of whom were evaluable for activity and toxicity. Five, 4, and 3 patients had acral-lentiginous, ocular, or mucosal primaries, respectively. Two patients had confirmed partial responses lasting 64 and 24 weeks (RR 5%). Three patients had minor responses lasting 136, 64, and 28 weeks, and 1 patient who was responding discontinued due to noncompliance. The median PFS was 8 weeks; the 6-month PFS rate was 13%. One patient with an exon-13 c-kit mutation had a partial response, whereas disease in another patient with an exon-11 c-kit mutation progressed. Common toxicities were fatigue, dyspnea, and pleural effusion.
  
  
  CONCLUSIONS
  Daily dasatinib has minimal activity in unselected melanoma patients, excluding those with c-kit mutations. The study did not meet the prespecified endpoints of 30% response rate or 6-month PFS. Dasatinib was poorly tolerated overall, often requiring dose reduction or interruption. Because activity was observed in a small subset without c-kit mutations, identifying predictive biomarkers is important for future development of dasatinib in melanoma alone or in combination trials.
authors.affiliation: Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA. harriet.kluger@yale.edu
authors.forename: Harriet M
authors.initials: HM
authors.lastname: Kluger
authors.forename: Arkadiuz Z
authors.initials: AZ
authors.lastname: Dudek
authors.forename: Carrie
authors.initials: C
authors.lastname: McCann
authors.forename: Jean
authors.initials: J
authors.lastname: Ritacco
authors.forename: Nadine
authors.initials: N
authors.lastname: Southard
authors.forename: Lucia B
authors.initials: LB
authors.lastname: Jilaveanu
authors.forename: Annette
authors.initials: A
authors.lastname: Molinaro
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069439:Dasatinib; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib