Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic prostate cancer following castration.

BACKGROUND Several trials have demonstrated that the response proportions to microtubule agents in patients with prostate cancer are increased by the addition of estramustine phosphate (EMP). The epothilone B analog BMS-247550 is a novel microtubule agent that has shown activity in taxane-resistant tumors. We conducted a dose-escalation study to determine a safe dose of BMS-247550 to combine with EMP in patients with metastatic prostate cancer. PATIENTS AND METHODS Chemotherapy-naive patients with castrate-metastatic prostate cancer were treated with intravenous BMS-247550 and oral EMP (280 mg three times daily for 5 days) every 3 weeks. RESULTS Thirteen patients were treated at two dose levels (35 and 40 mg/m(2)). Three of six patients treated at 40 mg/m(2) developed grade 4 neutropenia, establishing 35 mg/m(2) as the maximum-tolerated dose. Significant peripheral neuropathy (grade >/= 2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of >/= 50% was seen in 11 of 12 evaluable patients (92%) (95% confidence interval 76% to 100%). There were objective responses in soft tissue (57%) and bone metastasis (40%). CONCLUSIONS The phase II dose of BMS-247550 combined with EMP is 35 mg/m(2) over 3 h every 3 weeks. This combination is safe and >/= 50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).