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

J Clin Oncol. 2013 Mar 20;31(9):1211-8. doi: 10.1200/JCO.2012.44.5585. Epub 2013 Feb 11.

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00522834.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / therapeutic use*
  • Disease-Free Survival
  • Double-Blind Method
  • Humans
  • Hydrazines / administration & dosage*
  • L-Lactate Dehydrogenase / blood
  • Melanoma / drug therapy*
  • Melanoma / mortality
  • Paclitaxel / administration & dosage*
  • Paclitaxel / therapeutic use*
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / mortality
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Phytogenic
  • Hydrazines
  • elesclomol
  • L-Lactate Dehydrogenase
  • Paclitaxel

Associated data

  • ClinicalTrials.gov/NCT00522834