Thalidomide/estramustine/paclitaxel in metastatic androgen-independent prostate cancer.

BACKGROUND: This is a phase I/II trial of thalidomide with estramustine and paclitaxel in men with androgen-independent prostate cancer (AIPC) who underwent previous chemotherapy. PATIENTS AND METHODS: Men with progressive AIPC were treated with oral thalidomide (200 mg, 400 mg, or 600 mg daily), intravenous paclitaxel (100 mg/m2 over 3 hours on days 3 and 10), and oral estramustine (140 mg 3 times daily on days 1-5 and days 8-12) every 21 days. RESULTS: Phase I: first cycle dose-limiting toxicity occurred in 0 of 3 patients at 200 mg thalidomide daily, 0 of 3 at 400 mg daily, and 1 of 3 at 600 mg daily (the designated maximum tolerated dose). Phase II: twenty-nine of 38 evaluable patients (76%; 95% confidence interval, 67%-87%) experienced a 50% decrease in prostate-specific antigen level. Five of 18 patients (28%) with measurable disease exhibited an objective response. Nine of 14 patients (64%) with disease refractory to previous taxane therapy had 50% decreases in prostate-specific antigen level. Grade 3/4 adverse events included neutropenia (9 of 39 [23%]), fatigue (9 of 39 [23%]), dyspnea (8 of 39 [21%]), and thromboembolic events (7 of 39 [18%]). Cumulative dose-limiting toxicity rates were minimal (13%) with thalidomide at 200 mg daily. CONCLUSION: The profile of activity of thalidomide/paclitaxel/estramustine in taxane-refractory AIPC warrants further investigation.

Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer.

PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa). PATIENTS AND METHODS: Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)). RESULTS: A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.

Phase II study of capecitabine combined with gemcitabine in the treatment of androgen-independent prostate cancer previously treated with taxanes.

BACKGROUND: The primary objective of the current study was to evaluate the effectiveness of capecitabine and gemcitabine in the treatment of patients with androgen-independent prostate cancer (AIPCa) who experienced disease progression after taxane therapy. The secondary objective was to evaluate the safety and tolerability of the combination of capecitabine and gemcitabine in these patients. METHODS: Patients with AIPCa, either metastatic or unresectable disease, and prior taxane therapy were eligible. Patients were treated with 800 mg/m2 of capecitabine orally twice daily (1600 mg/m2 per day) for 14 days, and 800 mg/m2 of gemcitabine intravenously on Days 1 and 8. This regimen was repeated every 21 days. Response to therapy was determined by measuring prostate-specific antigen concentration. RESULTS: Sixteen patients participated in this study from June 2003 to January 2004. There were no responses as defined by a 50% decline in prostate-specific antigen. The study was terminated early because the response rate was not projected to exceed 30% (rejection error of 10%). Toxicities were notable: 3 patients had Grade 3 thrombocytopenia, 4 patients had Grade 3 neutropenia, and 3 patients had Grade 3 infections (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Eight patients (50%) required dose reduction or treatment interruption. CONCLUSIONS: The combination of capecitabine and gemcitabine for the salvage treatment of patients with AIPCa was associated with significant toxicities and was ineffective for induction of disease regression.