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/m2 as the maximum-tolerated dose. Significant peripheral neuropathy (grade greater than or equal to2) was related to dose level and infusion rate. A decline in prostate-specific antigen (PSA) of greater than or equal to50% 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 greater than or equal to50% post-therapy declines in PSA were seen in 11 of 12 patients (92%).