A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic hormone refractory prostate cancer: results of ECOG 3899

Abstract

4594 Background: Additional options of chemotherapy are limited for hormone refractory prostate cancer (HRPC), making the study of novel agents and combinations critical. We tested two novel regimens in HRPC. Given data demonstrating that retinoids and interferon reduce Bcl-2 expression, the effect of therapy on Bcl-2 was tested in peripheral blood mononuclear cells (PBMC). Methods: Patients (pts) received 10 mg/m2 mitoxantrone on d2, 280 mg bid estramustine on d1–5 and 25 mg/m2 vinorelbine on d2 and 9 (MEN) q3 wks (Arm A), or 1 mg/kg 13 cis-retinoic acid, 6 million U/m2 alpha interferon on d1 and 2, and 75 mg/m2 paclitaxel on d2 (RIT) weekly for 6 out of 8 weeks (Arm B). PBMCs were obtained on day 1 and 3 to assess the effect on Bcl-2 by immunoblot. Results: Seventy pts with HRPC, without prior chemotherapy, were entered. PSA at entry was 165 ng/ml in arm A and 234 ng/ml in arm B. In arm A, grade > 2 toxicities included neutropenia in 77%, with only 3% febrile neutropenia, thrombosis in 16%, and fatigue in 22%. In arm B, grade > 2 toxicities included neutropenia in 13%, with no pts having febrile neutropenia, thrombosis in 3%, and fatigue in 23%. Biochemical response, defined as a decrease in PSA >/= 50%, occurred in 50% (13/26) and 17% (4/24) of evaluable pts in arm A and B respectively. Partial tumor response was documented in 2/10 pts in arm A and 2/12 pts in B with measurable disease. Stable measurable disease occurred in 5/10 and 6/12 pts in arm A and B respectively. Median overall survival was 18.4 and 11.5 months in arm A and B respectively. Bcl-2 expression in PBMCs deceased significantly during therapy only in arm B (p=0.03). There was no association with the decreased expression of Bcl-2 and response, but power is limited for comparison. Assessment of Bax is ongoing. Conclusion: MEN and RIT are well tolerated in pts with HRPC. Therapy with MEN offers an active non-taxane combination that may warrant further study in pts after progression on taxane therapy. The activity of RIT is not enough to warrant study in phase III trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Glaxo Aventis; Bristol-Myers Squibb