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

Purpose: To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent prostate cancer.

Experimental Design: Two bortezomib doses (1.3 and 1.6 mg/m(2)/dose) in combination with four docetaxel doses (25-40 mg/m(2)/dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in Solid Tumors guidelines.

Results: Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (>or=50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for >or=4 weeks in 14 patients (21%). According to Response Evaluation Criteria in Solid Tumors guidelines, 11% achieved a partial response, and an additional 67% had stable disease. The degree of proteasome inhibition was similar to that reported with single-agent bortezomib. Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred.

Conclusions: The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m(2) bortezomib plus 40 mg/m(2) docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.