title: Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group.
abstract: OBJECTIVE
  Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma.
  
  
  METHODS
  We randomly assigned chemotherapy-naïve patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m2) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival.
  
  
  RESULTS
  Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events.
  
  
  CONCLUSIONS
  The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.
authors.affiliation: University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Agop Y
authors.initials: AY
authors.lastname: Bedikian
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.forename: Hubert
authors.initials: H
authors.lastname: Pehamberger
authors.forename: Robert
authors.initials: R
authors.lastname: Conry
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.forename: Uwe
authors.initials: U
authors.lastname: Trefzer
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Ronald
authors.initials: R
authors.lastname: DeConti
authors.forename: Evan M
authors.initials: EM
authors.lastname: Hersh
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000627:therapeutic use*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D013873:Thionucleotides / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; D003606:Dacarbazine; C408162:oblimersen; D007770:L-Lactate Dehydrogenase