title: Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma.
abstract: OBJECTIVE
  Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma.
  
  
  METHODS
  We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m(2) plus paclitaxel 80 mg/m(2) (E + P) or to paclitaxel 80 mg/m(2) alone at a 2:1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc).
  
  
  RESULTS
  At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated.
  
  
  CONCLUSIONS
  E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.
authors.affiliation: Angeles Clinic and Research Institute, Santa Monica, CA 90404, USA. soday@theangelesclinic.org
authors.forename: Steven
authors.initials: S
authors.lastname: O'Day
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
authors.forename: David
authors.initials: D
authors.lastname: Lawson
authors.forename: Robert
authors.initials: R
authors.lastname: Weber
authors.forename: Laura
authors.initials: L
authors.lastname: Hutchins
authors.forename: Clay
authors.initials: C
authors.lastname: Anderson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Haddad
authors.forename: Steven
authors.initials: S
authors.lastname: Kong
authors.forename: Anthony
authors.initials: A
authors.lastname: Williams
authors.forename: Eric
authors.initials: E
authors.lastname: Jacobson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003248:Constipation / Q000139:chemically induced; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D006834:Hydrazines; C512195:elesclomol; D017239:Paclitaxel