Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer

Purpose: To evaluate the toxicity, efficacy, and pharmacokinetics of docetaxel when combined with oral estramustine and dexamethasone in a phase I study in patients with progressive metastatic androgen-independent prostate cancer. Patients and Methods: Thirty-four men were stratified into minimally pretreated (MPT) and extensively pretreated (EPT) groups. Estramustine 280 mg PO tid was administered 1 hour before or 2 hours after meals on days i through 5, with escalated doses of docetaxel from 40 to 80 mg/m² on day 2. Treatment was repeated every 21 days. Results: Thirty-four patients were assessable for toxicity and 33 for response. In the MPT patients, dose- limiting myelosuppression was reached at 80 mg/m², with six patients experiencing grade 3/4 granulocytopenia. In EPT patients, escalation above 70 mg/m² was not attempted. Fourteen MPT (70%) and six EPT (50%) patients had a ≥ 50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. The overall 50% PSA response rate was 63% (95% confidence interval [CI], 28% to 81%). Of the 18 patients with bidimensionally measurable disease, five (28%; 95% CI, 11% to 54%) achieved a partial response. At the time of entry onto the study, 15 patients required narcotic analgesics for bone pain; after treatment, eight (53%) discontinued their pain medications. The area under the curve for docetaxel increased linearly from 40 to 70 mg/m². At 80 mg/m², the measured area under the curve was 8.37 (standard deviation, 0.724), which was significantly higher than the previously reported values. Conclusion: The recommended phase II dose of docetaxel combined with estramustine is 70 mg/m² in MPT patients and 60 mg/m² in EPT patients. This combination is active in men with androgen- independent prostate cancer.