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Annals of Oncology Advance Access published online on January 19, 2009
Annals of Oncology, doi:10.1093/annonc/mdn689
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

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

T. Li1,*, P. J. Christos2, J. A. Sparano1, D. L. Hershman3, S. Hoschander1, K. O'Brien2, J. J. Wright4 and L. T. Vahdat3

1 From the New York Cancer Consortium®, including the Montefiore-Einstein Cancer Center, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx
2 Weill Cornell Medical Center, Weill Cornell Medical College, New York
3 Columbia Presbyterian Medical College, New York
4 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, USA

* Correspondence to: Dr T. Li, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 1825 Eastchester Road, 2 South, Room 55, Bronx, NY 10461, USA. Tel: +1-718-904-2900; Fax: +1-718-904-2892; E-mail: tli{at}montefiore.org

Background: Fulvestrant produces a clinical benefit rate (CBR) of ~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.

farnesyltransferase inhibitor, fulvestrant, metastatic breast cancer, postmenopausal, selective estrogen receptor downregulator, tipifarnib

Received for publication September 22, 2008. Accepted for publication September 30, 2008.


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