A phase I trial of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in hormone-receptor positive metastatic breast cancer

Abstract

644 Background: Farnesyltransferase inhibitors (FTIs) were initially developed to target oncogenic Ras and have clinical activity in a number of malignancies. Preclinically, FTIs have synergistic activity when used with tamoxifen in breast cancer cell lines. We conducted a phase I trial using tipifarnib with tamoxifen in patients with hormone-receptor positive breast cancer to determine acute and chronic toxicities and to identify a chronic dose for phase II testing. Methods: Patients with hormone-receptor positive metastatic breast cancer, performance status 0–1, and adequate organ function were entered in the study. Tipifarnib was administered at 2 dose levels (200 mg po BID and 300 mg po BID) for 21 out of 28 days. Tamoxifen (20 mg daily) was started after 1 week of tipifarnib alone thereby allowing comparison of pharmacokinetics and other correlative studies with tipifarnib alone versus tipifarnib and tamoxifen. Results: Pharmacokinetic analysis (n=9) demonstrated a median AUC of 3514 ng.hr/ml (range 1829–4803) with tipifarnib alone and 3093 ng.hr/ml (range 1417–3747) with tipifarnib and tamoxifen. Farnesyltransferase activity, measured at steady state in peripheral blood mononuclear cells (n=6), decreased by a median of 30% (range 14–57%) with tipifarnib alone, and by 41% (range 23–59%) with tipifarnib and tamoxifen. Grade 2 or 3 toxicities included diarrhea (1), nausea/vomiting (3), constipation (2), hot flashes (3), fatigue (1), and rash (1). Hematologic toxicities included grade 2 neutropenia (6), thrombocytopenia (1), and anemia (1). One patient had a pulmonary embolism. All patients treated at the 300 mg BID dose level had the tipifarnib dose decreased due to ≥ grade 2 toxicities. Although not a primary objective of the study, 4 of 11 (36%) evaluable patients had clinical benefit. Partial tumor responses were seen in 3 of 11 patients and one patient has stable disease at 8 months. Conclusions: The combined regimen of tipifarnib and tamoxifen is well-tolerated and exhibits promising initial clinical activity. A phase II trial is currently in progress using tipifarnib 200 mg BID and tamoxifen 20 mg QD. No significant financial relationships to disclose.