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Phase II Study of Extended-Dose Temozolomide in Patients With Melanoma

Petra Rietschel, Jedd D. Wolchok, Susan Krown, Scott Gerst, Achim A. Jungbluth, Klaus Busam, Katherine Smith, Irene Orlow, Katherine Panageas, Paul B. Chapman

From the Departments of Medicine, Radiology, Pathology, Clinical Laboratories, and Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY

Corresponding author: Paul B. Chapman, MD; Memorial Sloan-Kettering Cancer Center; 1275 York Ave, Room Z1402; New York, NY 10065; e-mail: chapmanp{at}mskcc.org

Purpose: We conducted a phase II trial of extended-dose temozolomide (TMZ) in patients with melanoma to test the hypothesis that the approximately 30% response rate observed in patients treated with extended-dose TMZ with antiangiogenic agents was caused by TMZ alone. We hypothesized that expression of methylguanine methyltransferase (MGMT) in the tumor would correlate with drug resistance to TMZ.

Patients and Methods: Patients with stage IV or unresectable stage III melanoma were treated with TMZ 75 mg/m²/d for 6 weeks followed by a 2-week rest period. Cycles were repeated until progression. Patients were stratified by M1c disease or not. The primary end point was objective response proportion. MGMT expression was assessed by methylation-specific pyrosequencing of the promoter and by immunohistochemistry.

Results: Forty-nine patients (25 with M1c disease) were assessable. Three patients (12.5%) in each cohort experienced partial responses; there were no complete responses. Ten patients (21%) had stable disease lasting more than 24 weeks. Median time to progression was 3.3 months. Median survival was 10.1 months; survival was similar in the two cohorts. The estimated 18-month survival was 27%. There was no correlation between response and either immunohistochemistry staining for MGMT or for MGMT promoter methylation. Seventy-five percent of patients developed CD4⁺ lymphopenia after three cycles.

Conclusion: Extended-dose TMZ therapy did not result in a 30% responses rate, which has been observed using extended-dose TMZ with antiangiogenic agents. Response did not correlate with MGMT expression or promoter methylation as a continuous variable, suggesting that other resistance mechanisms are important.

Supported by a grant from Schering-Plough Corp.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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