Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer

Purpose: Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer. Methods: Eligible women were treated with POH four times daily at 1,200-1,500 mg m^-2 dose ^-1 on a 28-day cycle. Patients tolerating 1,200 mg m^-2 day^-1 four times daily after one cycle were dose-escalated to 1,500 mg/m². The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations. Results: Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m². Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29-123 days). Median overall survival was 389 days (95% CI, 202-776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-β1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability. Conclusions: Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.