Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205

Abstract

Background: Fulvestrant produces a clinical benefit rate (CBR) of approximately 45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib-fulvestrant combination in HR-positive MBC.

Patients and methods: Postmenopausal women with no prior chemotherapy for metastatic disease received i.m. fulvestrant 250 mg on day 1 plus oral tipifarnib 300 mg twice daily on days 1-21 every 28 days. The primary end point was CBR.

Results: The CBR was 51.6% [95% confidence interval (CI) 34.0% to 69.2%] in 31 eligible patients and 47.6% (95% CI 26.3% to 69.0%) in 21 patients with AI-resistant disease. A futility analysis indicated that it was unlikely to achieve the prespecified 70% CBR. Tipifarnib dose modification was required in 8 of 33 treated patients (24%).

Conclusions: The target CBR of 70% for the tipifarnib-fulvestrant combination in HR-positive MBC was set too high and was not achieved. The 48% CBR in AI-resistant disease compares favorably with the 32% CBR observed with fulvestrant alone in prior studies and merit further clinical and translational evaluation.

Trial registration: ClinicalTrials.gov NCT00082810.

Figures

Figure 1.

Waterfall plot of magnitude of tumor response in targeted lessions after 6-month treatment of fulvestrant and tipifarnib in all eligible patients (N=31).

Figure 2.

Kaplan–Meier plots of (A) time to progression (TTP) and (B) overall survival (OS) in all eligible patients. The ranges of 95% confidence interval for the median TTP or OS are included in the graphs.