Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma.

Abstract

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/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.

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.

• Authors: Steven O'Day, Rene Gonzalez, David Lawson, Robert Weber, Laura Hutchins, Clay Anderson, Jonathan Haddad, Steven Kong, Anthony Williams, Eric Jacobson
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 32 Pg. 5452-8 (Nov 10 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19826135 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Hydrazines
• elesclomol
• Paclitaxel

Topics

• Adult
• Aged
• Aged, 80 and over
• Anemia (chemically induced)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Constipation (chemically induced)
• Cross-Over Studies
• Double-Blind Method
• Drug Administration Schedule
• Fatigue (chemically induced)
• Female
• Humans
• Hydrazines (administration & dosage, adverse effects)
• Infusions, Intravenous
• Kaplan-Meier Estimate
• Male
• Melanoma (drug therapy, pathology)
• Middle Aged
• Nausea (chemically induced)
• Neoplasm Metastasis
• Neoplasm Staging
• Paclitaxel (administration & dosage, adverse effects, therapeutic use)
• Treatment Outcome