Dose escalation of oral vinorelbine in combination with estramustine in hormone-refractory adenocarcinoma of the prostate

BACKGROUND. The primary objective of the current study was to identify the tolerable dose level of oral vinorelbine when given in combination with estramustine to men with hormone-refractory prostate cancer (HRPC).The secondary objectives were to describe the toxicities of the combined regimen in patients with HRPC and to estimate the efficacy of oral vinorelbine in combination with estramustine based on the prostate-specific antigen (PSA) response. METHODS. Thirty-three patients with HRPC were treated on a 28-day cycle with estramustine at a dose of 140 mg orally 3 times a day on Days 1-3 and 8-10. Vinorelbine was given orally on Days 2 and 9. The initial dose of vinorelbine was 50 mg/m(2) and was escalated to 70 mg/m(2) using the time-to-event continual reassessment method. RESULTS. Three of 17 patients experienced dose-limiting toxicity at the 70 mg/m(2) dose level of oral vinorelbine. One patient experienced dose-limiting toxicity at a dose of 60 mg/m(2) and no dose-limitig toxicities were reported at the 50 mg/m(2) dose. The overall response rate by >= 50% reduction in PSA was 17.2%, (95% confidence interval, 5.9-35.8%). CONCLUSIONS. Oral vinorelbine at doses of 70 mg/m(2) may be safely combined with estramustine. The combination appears to have modest activity in men with advanced prostate cancer. The trial design employed the time-to-event continual reassessment method, which potentially allows for rapid accrual, a more complete assessment of toxicities, and a larger fraction of patients to be treated at an effective dose. More active regimens are needed to further evaluate the utility of this clinical trial design in patients with prostate cancer.