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Updated: Aug 31, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Pilot study of epothilone B analog (BMS-247550) and estramustine phosphate in patients with progressive metastatic
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%).
Insights
Combining estramustine phosphate (EMP) with the novel microtubule agent BMS-247550 showed a 92% decline in prostate-specific antigen (PSA) in metastatic prostate cancer patients. The maximum tolerated dose of BMS-247550 was determined to be 35 mg/m(2).
Area of Science:
- Oncology
- Pharmacology
- Cancer Therapeutics
Background:
- Estramustine phosphate (EMP) enhances response to microtubule agents in prostate cancer.
- BMS-247550, an epothilone B analog, shows activity in taxane-resistant tumors.
- Metastatic prostate cancer treatment benefits from novel therapeutic combinations.
Purpose of the Study:
- Determine the safe dose of BMS-247550 for combination therapy with EMP.
- Evaluate the efficacy and safety of BMS-247550 plus EMP in metastatic prostate cancer.
- Establish the maximum-tolerated dose (MTD) for this combination regimen.
Main Methods:
- Dose-escalation study in chemotherapy-naive patients with castrate-metastatic prostate cancer.
- Intravenous BMS-247550 combined with oral EMP (280 mg TID for 5 days) every 3 weeks.
- Patients treated at 35 mg/m(2) and 40 mg/m(2) dose levels of BMS-247550.
Main Results:
- Maximum-tolerated dose (MTD) established at 35 mg/m(2) due to grade 4 neutropenia at 40 mg/m(2).
- Significant peripheral neuropathy observed, dose-related and infusion rate-dependent.
- 92% of evaluable patients (11/12) achieved a >= 50% decline in prostate-specific antigen (PSA).
- Objective responses observed in 57% of soft tissue and 40% of bone metastases.
Conclusions:
- The recommended Phase II dose for BMS-247550 combined with EMP is 35 mg/m(2) over 3 hours every 3 weeks.
- This combination therapy is safe and well-tolerated in metastatic prostate cancer patients.
- High rates of PSA decline (92%) indicate significant clinical activity for this novel regimen.
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