A PHASE-I AND PHARMACOKINETIC STUDY OF HIGH-DOSE TAMOXIFEN AND WEEKLYCISPLATIN IN PATIENTS WITH METASTATIC MELANOMA

BACKGROUND. The authors have previously demonstrated that tamoxifen (T AM) is synergistic with cisplatin (DDP) in patients with metastatic me lanoma. In vitro studies have demonstrated that TAM/DDP synergy is dep endent on a TAM effect that is currently under investigation. In an at tempt to improve the complete response rate of this regimen, the autho rs initiated a Phase I trial to determine the maximum tolerated dose ( MTD) of TAM that could be safely administered with weekly DDP. METHODS . TAM was started on Day 1 at a dose of 80 mg/day and was increased by 40 mg to the MTD in groups of 3 patients. DDP (80 mg/m(2)) was begun on Day 2 and repeated weekly for a total of 3 weeks. During Week 4, th e patients were not treated with DDP but instead evaluated for respons e. If disease stabilization or regression was documented, the patients received a second S-week cycle of DDP and were then reevaluated for r esponse. Patients with progressive disease were removed from the study . RESULTS. In 25 consecutive patients, the overall response rate was 2 0%. No responses were observed in patients treated with TAM at a dose of <240 mg/day. Among 13 patients treated at or above this dose, there were 2 complete responses, 3 partial responses, 2 mixed responses, an d 6 patients with progressive disease. The overall response rate for p atients treated with 240 mg of TAM or higher was 38.5%. Dose-limiting toxicity, which occurred at a TAM dose of 280 mg/day, was primarily he matologic and gastrointestinal in nature. There was one toxic death (d ue to septic neutropenia) at this dose. There were no episodes of thro mbosis. CONCLUSIONS, A TAM dose of 240 mg/day is the recommended Phase II dose. Based on the 38.5% overall response rate at this dose, the a uthors have initiated a Phase II study. (C) 1997 American Cancer Socie ty.