Phase I Study of Temozolomide and Thalidomide in the Treatment of Metastatic Melanoma.
Wen-Jen Hwu, Katherine s Panageas, Suan E Krown, Paul B Chapman, Phillip o Livingston, Linda J Williams, Carolyn J Quinn, Essai Mahalingan, Alan N Houghton, Memorial Sloan-Kettering Cancer Center, New York, NY.

Temozolomide (TMZ) is an active cytotoxic agent in the treatment of metastatic melanoma. Thalidomide is a biologic modulator that influences several cellular activities that may be important for control of melanoma metastases. This study is designed to assess toxicity of escalating doses of TMZ and thalidomide in combination and to determine the maximum tolerated dose (MTD). Method: Thalidomide was administered at 200 mg/d for 2 weeks, increased by 100 mg/d at 2-week intervals until a maximum of 400 mg/d was reached. Elderly patients (70y) were started at a lower thalidomide dose (100 mg/d) and doses were escalated in 50 mg increments every 2 weeks to a maximum of 250 mg/d. TMZ was administered at 4 dose levels: Level 1- 50 mg/m[sup2]/d for 6 weeks followed by a 4-week rest; Level 2- 75 mg/m[sup2]/d for 6 weeks with a 4-week rest; Level 3-75 mg/m[sup2]/d for 6 weeks with a 3-week rest; Level 4- 75 mg/m[sup2]/d for 6 weeks with a 2-week rest. Results: Twelve chemotherapy-naïve patients (3 female, 9 male; median age 69.5, range 47-75) were treated; 3 at each dose level. All 12 patients could be evaluated for toxicity. There were no treatment related grade 3 or 4 toxicities. Grade 2 toxicities, which were primarily attributed to thalidomide, included peripheral neuropathy, constipation, dry skin, nausea, vomiting, and headache. Thus, the MTD was determined to be dose level 4. Of 9 patients whose response can currently be evaluated, 1 has shown partial response (at dose level 2), 3 showed minor response (1 at level 2 and 2 at level 3), 1 showed mixed response (at level 2), 2 showed stable disease (1 each at levels 1 and 3), and 2 showed progression (both at level 1). Conclusion: The phase I study indicates that the combination of TMZ and thalidomide is well-tolerated and has antitumor activity in patients with metastatic melanoma. The ongoing phase II study will establish the efficacy of this combination.