Temozolomide and cisplatin (TP) vs temozolomide (T) in patients with advanced melanoma. A randomized phase II of the Hellenic Cooperative Oncology Group

7545 Background: Temozolomide (T) is an oral alkylating agent that produces methyl adducts at the 0.6 position of guanine. The methyl adducts are removed by the DNA repair enzyme AGAT. As demonstrated by in vitro studies, cisplatin (P) is able to down regulate the AGAT activity, so enhancing the antitumor activity of T. From previous phase I study the recommended doses of T were 200 mg/m2 daily on days 1 to 5 and 75 mg/m2 of P on day 1, respectively, every 4 weeks. We designed a randomized phase II study to evaluate and compare the activity and safety profile of the combination vs single agent T, in patients with advanced melanoma. Patients and Methods: From January 2000 to April 2002, 127 patients were enrolled on the study. Patient and tumor characteristics were well balanced between the 2 arms. Patients with cerebral metastases were included. Patients received T 200mg/m2 /day po for 5 consecutive days every 4 weeks or T+P 200 mg/m2 daily on days 1 to 5 and 75 mg/m2 of P on day 1. Results: Tumor responses (CR and PR) were seen in 16 patients (26%) in arm A and 19 patients (29%) in arm B. The median time to progression (TTP) was 3.6 months in arm A and 5.8 months in arm B. The median survival (OS) was 14.6 months in arm A and 12.4 months in arm B. The difference between treatment arms regarding objective response rates, TTP, OS were not statistically significant. Toxicity was comparable between the two arms for anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, constipation and arthralias-myalgias. There was significantly more grade 3 and 4 emesis in the combination arm. Conclusion: No clear benefit in terms of response rates, median time to progression or overall survival was shown with the combination of T+P. Additionally, the combination was associated with higher incidence of grade 3 and 4 emesis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Pfizer