Phase I I S tudy o f T emozolomide P lus T halidomide f or t he Treatment o f M etastatic M elanoma

Purpose: To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases. Patients and Methods: Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary end point was response rate. Patients received temozolomide (75 mg/m 2 / d 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/d with dose escalation to 400 mg/d for patients 70 years old). Treatment was continued until unacceptable toxicity or disease progression occurred. Results: Thirty-eight patients (median age, 62 years) with stage IV (three patients with M1a, eight with M1b, and 26 with M1c) or stage IIIc (one patient) melanoma and a median of four metastatic sites were enrolled, and received a median of two cycles of therapy. Twelve patients (32%) had an objective tumor response, including one with an ongoing complete response of 25 months’ duration and 11 with partial responses. Five patients achieving partial response with a more than 90% reduction of disease were converted to a complete response with surgery. Treatment was generally well tolerated. Median survival was 9.5 months (95% confidence interval, 6.05 to 19.38 months), with a median follow-up among survivors of 24.3 months. Conclusion: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study. J Clin Oncol 21:3351-3356. © 2003 by American Society of Clinical Oncology. A DVANCED-STAGE METASTATIC melanoma is associated with a poor prognosis, with 10-year survival rates of only 2.5% to 15.7%. 1 In 2002, an estimated 7,400 patients in the United States died of melanoma. 2 Current treatment options have provided no improvement in overall survival. Standard therapies include dacarbazine- (DTIC-) based chemotherapy regimens (eg, Dartmouth regimen) and biochemotherapy. Standard chemotherapy regimens produce response rates of only 10% to 20% with very few complete or durable responses, 3 and the Dartmouth regimen does not improve survival compared with DTIC alone. 4 The addition of biologic therapy with agents such as interleukin-2 and interferon alfa increases response rates at the expense of increased toxicity, but it has not been shown to provide a significant survival advantage compared with standard chemotherapy regimens in randomized trials. 5-7 Treatment failure in the CNS is a clinically important problem in patients with advanced melanoma. Temozolomide is a well-tolerated oral alkylating agent with excellent CNS penetration 8,9 that has demonstrated activity in patients with recurrent gliomas, and has been shown to improve progression-free survival compared with DTIC alone in patients with metastatic melanoma. 10 Temozolomide may also reduce the incidence of CNS relapse in patients with metastatic melanoma. 11,12 Myelosuppression is the primary toxicity associated with temozolomide, but it is noncumulative, and manageable in the majority of patients and infrequently causes dose delays or discontinuation. Temozolomide is typically administered for 5 consecutive days every 28 days at a dose of 150 to 200 mg/m 2 /d, but can also be safely administered on an extended daily regimen at a dose of 75 mg/m 2 /d. 13