Nancy Price

Phase I/II Trial 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 toxic- ities were observed despite escalation to the highest dose level. PSA response (z50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for z4 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 neutro- penia 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 con- sistent with previous studies of bortezomib alone or in combination with docetaxel. Further inves- tigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers. Recent therapeutic advances have, to some extent, modulated the nihilism historically associated with the management of patients with advanced prostate cancer. Standard first-line treatment of metastatic androgen-independent prostate cancer (AIPC)now includes docetaxel, based on findings from two prospective, randomized phase III trials (SWOG 9916 and TAX 327). These trials showed that patients treated with docetaxel- based chemotherapy had significantly improved survival compared with patients receiving mitoxantrone and prednisone (1, 2). Despite this important clinical advance, median survival in patients treated with docetaxel-based therapies remains in

The Development of Vitamin D-Based Therapies for Prostate Cancer

Rationale D is a hormone produced by the conversion of 7-dehydrocholesterol to pre–vitamin D in the skin followed by 2 more synthesis steps that take place in the liver and kidney, respectively, to produce 1,25 dihydroxycholecalciferol, or calcitriol, the activated form of vitamin D. Vitamin D and its metabolites are ligands for the vitamin D receptor (VDR), a member of the nuclear receptor super-family. The vitamin D receptor dimerizes with the retinoid X receptor (RXR), and the VDR/RXR heterodimer is known to associate with various coactivators and corepressors that modify its transcriptional activity. 1