A phase I/II study of weekly paclitaxel and 3 days of high dose oral estramustine in patients with hormone-refractory prostate carcinoma

BACKGROUND. The maximum tolerated dose (MTD) and efficacy of weekly 1-hour paclitaxel with 3 days of high dose oral estramustine were evaluated in patients with hormone-refractory prostate carcinoma. METHODS. Patients enrolled in cohorts of three received two cycles of six weekly treatments with 1 week of rest: Cohort I received paclitaxel 40 mg/m² and estramustine 600 mg/m², and Cohorts II-IV received paclitaxel 60 mg/m², 75 mg/m², or 90 mg/m², respectively, and estramustine 900 mg/m², Toxicity was assessed weekly, and response was measured by serum prostate specific antigen (PSA), abdominal computed tomography scans, and bone scans at Week 13. RESULTS. Eighteen patients were enrolled, with 12 in Cohorts III and IV. Four patients did not complete treatment Grade 3 toxicity included one patient with nausea and diarrhea in Cohort III and one patient each with neutropenia and edema followed by Grade 4 thromboembolism in Cohort IV. Grade 1-2 anemia or myelotoxicity were not observed; 3 patients had neuropathy, 5 patients had hair loss, and 8 patients had gastrointestinal symptoms. A decline in the serum PSA level ≥ 50% occurred in none of three patients, one of three patients, four of six patients, and four of six patients in Cohorts I-IV, respectively. An intent-to-treat analysis showed responses in 9 of 18 patients (50%) in Cohorts I-IV, with 9 of 15 responders (60%) in Cohorts II-IV. Seven patients achieved declines in serum PSA levels > 75%. The median duration of PSA response was 16.7 weeks. Response was observed in one of three patients with measurable disease. CONCLUSIONS. The MTD for 1 -hour weekly paclitaxel was 90 mg/m² with 3 days of 900 mg/m² estramustine. Hematologic and neurotoxicity were reduced markedly, and gastrointestinal symptoms were ameliorated, but thromboembolic events were unaffected. PSA response rates were within the expected 60% range for these agents.