Originally published as JCO Early Release 10.1200/JCO.2005.04.9114 on June 12 2006

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Targeted Inhibition of Farnesyltransferase in Locally Advanced Breast Cancer: A Phase I and II Trial of Tipifarnib Plus Dose-Dense Doxorubicin and Cyclophosphamide

Joseph A. Sparano, Stacy Moulder, Aslamuzzaman Kazi, Linda Vahdat, Tianhong Li, Christine Pellegrino, Pam Munster, Mokenge Malafa, David Lee, Shira Hoschander, Una Hopkins, Dawn Hershman, John J. Wright, Said M. Sebti

From the New York Phase II Consortium, including the Albert Einstein Cancer Center, Montefiore Medical Center, Bronx; Weill Cornell Medical Center; Columbia Presbyterian Medical Center, New York, NY; Breast Oncology Program and Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL; and the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD

Address reprint requests to Joseph A. Sparano, MD, Montefiore Medical Center-Weiler Division, Department of Oncology, 2 S, Room 47-48, 1825 Eastchester Rd, Bronx, NY 10461; e-mail: jsparano{at}montefiore.org

PURPOSE: To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo.

PATIENTS AND METHODS: Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m²) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination.

RESULTS: When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33%) of 21 patients (95% CI, 15% to 55%) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib.

CONCLUSION: Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.

Supported by the US Department of Health and Human Service Contract No. N01 CM-17103 (Scott Wadler, MD) and Grant No. RO1CA98473 (S.M.S.).

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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• Lately, It Occurs to Me What a Long, Strange Trip It's Been for the Farnesyltransferase Inhibitors
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  JCO 2006 24: 2981-2984 [Full Text]

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