Phase II trial of fenretinide (4-HPR) in recurrent ovarian and primary peritoneal carcinoma: A California Cancer Consortium trial

Abstract

5056 Background: 4-HPR is a synthetic retinoid that, in contrast to other retinoids is cytotoxic rather than a differentiation inducer. Induction of tumor cell ceramide and reactive oxygen species have both been implicated in 4-HPR cytotoxicity. 4-HPR inhibited the growth of ovarian cancer cell lines in vitro with 1–10 μmolar concentrations in a dose dependent manner. A recent phase I study achieved higher levels using an intermittent dosing schedule. Methods: We designed a phase II study to evaluate the activity, toxicity profile and pharmacokinetics of 4-HPR in recurrent ovarian cancer. 4-HPR was administered at a dose of 900 mg/m2 po bid for 7 days every 21 days. Patients were required to have bi-dimensionally measurable disease and could have received ≤ 3 prior chemotherapy regimens for recurrent disease. Results: 24 patients have been enrolled; 22 are evaluable for response. Median number of prior chemotherapy regimens is 3 (range: 1–3). Only 5 patients developed grade 3 or 4 toxicity: 1 grade 3 anemia, 1 grade 4 fatigue, 1 grade 3 diarrhea, 1 grade 3 nausea, and 1 with grade 3 vomiting, diarrhea and abdominal pain. There were no treatment related deaths. The median number of cycles was 2 (range 1–35). The median number of 4-HPR cycles was 2 (range 1–35). Pharmacokinetics obtained in 18 patients showed a day 7 mean Cmax of 7.8 ± 4.7 μM (range 0.61 to 14.6 μM). There have been no objective responses; 8 patients (33%) achieved stable disease. The median progression-free survival (PFS) was 1.5 months (95% CI 1.2–4.1) and the median survival was 9.2 months (CI 4.7–13.4). Six patients remained free of progression for more than 6 months (range 6–25); PFS at 6 months is 30% +/- 10%. Conclusions: The encouraging PFS at 6 months suggest 4-HPR may provide clinical benefit to a significant number of patients. 4-HPR was well tolerated and achieved expected plasma levels for the currently employed formulation. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Epimmune Corp.; Pfizer Ortho Biotech