Abstract
8571 Background: Temozolomide (TMZ) and Lomustine (CCNU) are alkylating and active cytotoxic agents for metastatic melanoma (MM). The DNA repair enzyme O6-alkylguinine-DNA alkyltransferase (ATase), is the major cause of drug resistance for alkylating agents. Depletion of ATase by continuous dosing of TMZ may improve the anti-tumor activity of alkylating agents. This Phase I study is designed to establish a safe and tolerated regimen of oral cytotoxic agents, TMZ and CCNU in combination with a cytostatic agent, thalidomide (TLD), in patients with MM in the brain. Methods: Patients (pts) with stage IV MM in the brain with or without extracranial metastasis were entered successively onto 3 treatment cohorts: level 1, CCNU 30 mg/m2on day 1; level 2, CCNU 45 mg/m2on day 1; level 3, CCNU 60 mg/m2 on day 1. CCNU was administered at a flat dose of 30 mg/m2 on day 29 for all cohorts. TMZ was administered at 75mg/m2/d x 6 weeks followed by a 2-week break. TLD was administered at 200 mg/m2/d to the first 3 patient in level 1, then 200 mg/d in all other patients. Safety was assessed at weeks 2, 4, 6, 8 and every 4 weeks thereafter; tumor response was evaluated every 8 weeks. Results: Seventeen pts were enrolled, 7 pts each in levels 1 and 2, and 3 pts in level 3. . The MTD was determined to be dose level 2: CCNU 45 mg/m2on day 1. Three pts had a deep venous thrombosis. The most common adverse events were fatigue, constipation and myelosuppression. Of 16 pts assessable for disease response: 2 experienced a partial response, 2 stable disease and 2 mixed response. Disease response in brain and visceral organs were observed in dose levels 1 and 2. Conclusions: The combination therapy of TMZ, TLD and CCNU is safe and well tolerated in patients with MM in the brain. Clinical activity was seen at both levels 1 and 2. Further study of this oral drug combination therapy in these patients with extremely poor prognosis and lack of effective therapy is warranted.
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