Originally published as JCO Early Release 10.1200/JCO.2008.17.1579 on October 13 2009

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Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma

From the Angeles Clinic and Research Institute, Santa Monica; St Francis Memorial Hospital, San Francisco, CA; University of Colorado Health Sciences Center, Aurora, CO; Emory Winship Cancer Institute, Atlanta, GA; University of Arkansas for Medical Sciences, Little Rock, AR; Ellis Fischel Cancer Center/University of Missouri, Columbia, MO; and Synta Pharmaceuticals, Lexington, MA.

Corresponding author: Steven O'Day, MD, Angeles Clinic and Research Institute; 2001 Santa Monica Blvd, Ste 560W; Santa Monica, CA 90404; e-mail: soday{at}theangelesclinic.org.

Purpose 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.

Patients and Methods We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m² plus paclitaxel 80 mg/m² (E + P) or to paclitaxel 80 mg/m² 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.

Conclusion 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.

Supported by Synta Pharmaceuticals, Lexington, MA.

Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL; the 33rd European Society of Medical Oncology Congress, September 12-16, 2008, Stockholm, Sweden; the 12th Perspectives in Melanoma, October 2-4, 2008, The Hague, the Netherlands; the 1st World Meeting of Interdisciplinary Melanoma/ Skin Cancer Centers, September 5-8, 2007, Barcelona, Spain; the 44th Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; the 11th Perspectives in Melanoma, October 3-4, 2007 Huntington Beach, CA; and the 14th ECCO 14 European Cancer Conference, September 23-27, 2007, Barcelona, Spain.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00084214 [ClinicalTrials.gov] .

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