Phase I/II trial of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer

Abstract

4654 Background: Docetaxel is a microtubule stabilizing agent with documented clinical activity in patients with advanced prostate cancer. Bortezomib (Velcade, formerly PS-341) is a small molecule that is a potent and reversible proteasome inhibitor with evidence of anti-tumor activity in prostate cancer models. Following completion of the phase I portion of this study during which MTD was not reached, we evaluated two dose levels in expanded phase II cohorts. We report the results from the low expanded cohort. Methods: From 6/02 to 4/03, 31 patients (pts) were enrolled. Eligible pts had androgen-independent prostate cancer with radiologic and/or biochemical evidence of progression following antiandrogen withdrawal with castrate testosterone levels, KPS ≥ 60% and adequate organ function; prior systemic therapy was permitted. Docetaxel with standard dexamethasone premedication was given at 40 mg/m2 IV over 30 minutes on days 1 and 8. Bortezomib was given 24 hours after docetaxel at of dose of 1.3 mg/m2 IV push on days 2 and 9. Treatment was repeated every 21 days. Results: Median age was 67 (53–81), median KPS was 85% (60–90%), and median pre-therapy PSA value was 270. Nineteen pts had prior chemotherapy, 14 with a taxane containing regimen. Therapy was well tolerated with grade 3 diarrhea, peripheral neuropathy, hyperglycemia, neutropenia and fatigue seen in less than 5% of patients. Twenty-two patients are currently evaluable for response. Eight of 22 (36%) (90% CI 20–56) had a ≥ 50% decline in PSA from baseline and 5 of the 8 had a 90% or greater decline. Two of 12 (17%) patients with measurable disease achieved a partial response. Conclusions: Docetaxel + bortezomib was well tolerated at this dose and schedule, and showed promising activity in this population. Evaluation of a cohort receiving docetaxel at 40 mg/m2 + bortezomib 1.6 mg/m2 is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Millennium Pharmacueticals Glaxo Aventis; Celgene AstraZeneca; Aventis; Genentech; Millennium