A completed phase I trial of 13-cis retinoic acid, alpha interferon, docetaxel, and estramustine (R.I.T.E.) for the treatment of hormone refractory prostate cancer (HRPC) and other advanced malignancies and effect on BCL-2 expression

Abstract

4740 Background: To test the hypothesis that 13-cis retinoic acid (R) and interferon alpha (I), which have been shown to decrease the expression of Bcl-2, are capable of improving the results of standard chemotherapy with docetaxel (T) and estramustine (E), we conducted a phase I study in patients (pts) with HRPC and other advanced malignancies. Methods: Pts received retinoic acid 1 mg/kg and interferon 6 million units/m2 on days 1–4, estramustine 280mg, orally tid on days 1–5, with escalating doses of docetaxel (0, 40, 50, 60 mg/m2) on day 2. Ttreatment was repeated every 21 days. Each pt had peripheral blood mononuclear cells (PBMCs) obtained prior to therapy and on days 1–4 of cycle 1 to assess the effect of therapy on Bcl-2 by immunoblot. Results: Sixteen pts (HRPC-13, larynx-1, colon-1, ovarian-1) with mean age of 67 were enrolled. Of the 13 pts with HRPC, nine had prior chemotherapy (seven pts had ≥ 2 prior chemotherapy regimens and eight pts had prior docetaxel). Of the 3 pts with non-prostate solid tumors, 2 had received prior paclitaxel. The mean number of cycles administered was 5.2 (range 2–10), with 2 pts in cohort 2 continuing to receive treatment. Therapy was well tolerated on this study. Grade 3 fatigue occurred during the first cycle in two pts in cohort 3 and one pt in cohort 4, defining a DLT, and occurred in 3 pts after cycle 1. Fatigue resolved with interferon dose reduction per protocol. Of 13 pts with HRPC, 4 pts had a response of a >50% reduction in PSA. Five additional pts had confirmed stable disease over a median of 5 cycles and 2 pts continue on therapy. All pts with non-prostate solid tumors progressed on therapy. In 11 evaluable pts, the ratio of BCL-2 to actin in PBMCs was significantly decreased on days 2–4 of therapy, compared to baseline (p<0.05 via signed rank test). Conclusions: R.I.T.E. therapy was well tolerated and active in HRPC. The MTD of taxotere is 40mg/2. The R.I.T.E. regimen significantly downregulates PBMC Bcl-2 expression. These data support further studies to determine the activity of this regimen and to determine the validity of PBMC BCL-2 as a marker of drug effect. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis