title: Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma.
abstract: OBJECTIVE
  Elesclomol, an investigational first-in-class compound, induces oxidative stress, triggers mitochondrial-induced apoptosis in cancer cells, and shows synergy with taxanes in tumor models. Following completion of a phase II trial of elesclomol in combination with paclitaxel that met its primary end point of progression-free survival (PFS), this randomized, double-blind, controlled phase III study was conducted to confirm the efficacy and tolerability of elesclomol in combination with paclitaxel versus paclitaxel alone in patients with advanced melanoma.
  
  
  METHODS
  Patients with stage IV chemotherapy-naive melanoma (n = 651) were randomly assigned 1:1 to paclitaxel 80 mg/m(2) either alone or in combination with elesclomol 213 mg/m(2) administered weekly for 3 weeks of a 4-week cycle. Patients were stratified by prior systemic treatment, M1 subclass, and baseline lactate dehydrogenase (LDH) levels. The primary end point was PFS.
  
  
  RESULTS
  The study did not achieve its PFS end point (hazard ratio, 0.89; P = .23). The study was stopped when an early overall survival data analysis indicated an imbalance in total deaths favoring paclitaxel, predominantly in patients with high LDH levels. A prospectively defined subgroup analysis revealed a statistically significant improvement in median PFS for the combination in patients with normal baseline LDH.
  
  
  CONCLUSIONS
  The addition of elesclomol to paclitaxel did not significantly improve PFS in unselected patients with advanced melanoma. The association between baseline LDH and clinical outcomes suggests that LDH may be a predictive factor for treatment with this combination, consistent with recent findings on the association between elesclomol anticancer activity and cellular metabolic state.
authors: Los Angeles Skin Cancer Institute, The Beverly Hills Cancer Center, 8900 Wilshire Blvd, Beverly Hills, CA 90211, USA. stevenjoday@gmail.com
authors: Steven J
authors: SJ
authors: O'Day
authors: Alexander M M
authors: AM
authors: Eggermont
authors: Vanna
authors: V
authors: Chiarion-Sileni
authors: Richard
authors: R
authors: Kefford
authors: Jean Jacques
authors: JJ
authors: Grob
authors: Laurent
authors: L
authors: Mortier
authors: Caroline
authors: C
authors: Robert
authors: Jacob
authors: J
authors: Schachter
authors: Alessandro
authors: A
authors: Testori
authors: Jacek
authors: J
authors: Mackiewicz
authors: Philip
authors: P
authors: Friedlander
authors: Claus
authors: C
authors: Garbe
authors: Selma
authors: S
authors: Ugurel
authors: Frances
authors: F
authors: Collichio
authors: Wei
authors: W
authors: Guo
authors: Joelle
authors: J
authors: Lufkin
authors: Safi
authors: S
authors: Bahcall
authors: Vojo
authors: V
authors: Vukovic
authors: Axel
authors: A
authors: Hauschild
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006834:Hydrazines; C512195:elesclomol; D007770:L-Lactate Dehydrogenase; D017239:Paclitaxel