Phase I trial of weekly paclitaxel plus oral estramustine phosphate in patients with hormone-refractory prostate cancer

Objectives. To exploit the favorable dose intensity and safety profile of w eekly paclitaxel, we conducted a Phase I trial of paclitaxel by 3-hour infu sion in combination with estramustine phosphate (EM) in men with hormone-re fractory prostate cancer (HRPC). The antimicrotubule drug combination of pa clitaxel by 96-hour infusion plus EM is active in HRPC. Methods, Twenty-four patients with metastatic HRPC and progressive tumor af ter antiandrogen withdrawal were enrolled in this study. Oral EM was taken at a dose of 600 mg/m(2) daily for the initial 21 patients and on a reduced schedule of 280 mg twice daily for the final 3 patients. Paclitaxel was es calated from 60 to 118 mg/m(2). Results. The major toxicities were gastrointestinal and thromboernbolic com plications related to daily oral dosing of EM. Of the first 21 patients, on e third (n = 7) discontinued therapy within 4 weeks because of protracted n ausea and/or thrombotic complications. Dose-limiting toxicities at 118 mg/m (2) paclitaxel were fatigue and hepatotoxicity. Of 13 patients with measura ble soft-tissue lesions, 6 had objective partial regressions, and 9 (37.5%) of 24 patients (95% confidence interval 19.1% to 59.1%) with elevated pros tate-specific antigen levels had a 50% or greater decline of at least 4 wee ks' duration. Conclusions. Weekly paclitaxel at doses of 60 to 107 mg/m(2) were feasible in combination with oral EM, but daily oral EM produced unacceptable toxici ty. On the basis of these results, a Phase II trial of weekly paclitaxel wi th the reduced dose and schedule of EM was initiated by the Eastern Coopera tive Oncology Group to assess further the benefits and risks of this treatm ent in men with metastatic HRPC. UROLOGY 58: 59-64, 2001. (C) 2001, Elsevie r Science Inc.