Phase I Trial of Oral Estramustine and 3-hr Infusional Paclitaxel for the Treatment of Hormone Refractory Prostate Cancer

Abstract

Precis. Estramustine 600 mg/m² can be administered safely with 225 mg/m² of paclitaxel if administered as a 3-hr infusion for the treatment of hormone refractory prostate cancer. Significant anti-tumor activity has been reconfirmed despite the change in schedule of administration of the paclitaxel.

Purpose. This phase I study was conducted to identify the maximum tolerated dosage of paclitaxel administered as a 3-hr infusion combined with a stable dosage of estramustine capsules daily in men with hormone refractory prostate cancer. A secondary endpoint was to assess anti-tumor efficacy in this targeted patient population.

Patients and methods. Twenty-six male patients, all with hormone refractory prostate cancer were enrolled in this trial. Estramustine was administered at a dosage of 600 mg/m² daily, and paclitaxel was dose-escalated in cohorts from 125 to 250 mg/m² administered as an infusion over 3 hr every 21 days. Patients were treated until maximum response was achieved, or toxicity or progressive disease precluded further treatment. Toxicity to determine maximum tolerated dose was assessed only during the first 3-week cycle.

Results. The maximum tolerated dose of paclitaxel on this schedule was 225 mg/m² based on unacceptable dose-limiting fatigue observed at the next higher dosage level. Other grade 3 or 4 events included myelosuppression, left ventricular dysfunction, elevated liver function tests, deep venous thrombosis, vomiting, and development of depression. Using a response criteria of prostate specific antigen decline of >50% persisting for a minimum of 6 weeks, eight of 26 patients responded (30.8%). Two of seven patients with documented soft-tissue disease experienced >50% reductions in size of lesions or number of sites. The median response duration was 6 months, and the median survival time was 16 months.

Conclusion. The recommended phase II dose of paclitaxel is 225 mg/m² when administered over 3 hr in combination with estramustine. This regimen has an acceptable toxicity profile, is a convenient schedule, and results in significant anti-tumor activity even in a heavily pre-treated population of patients.