This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lebowitz, P. F. Articles by Zujewski, J. Search for Related Content PubMed PubMed Citation Articles by Lebowitz, P. F. Articles by Zujewski, J.

A Phase I Trial and Pharmacokinetic Study of Tipifarnib, a Farnesyltransferase Inhibitor, and Tamoxifen in Metastatic Breast Cancer

¹ Medical Oncology Clinical Research Unit, ² Pediatric Oncology Branch, and ³ Cell and Cancer Biology Branch, National Cancer Institute and ⁴ Diagnostic Radiology Department and ⁵ Biostatistics, NIH, Bethesda, Maryland

Requests for reprints: Peter F. Lebowitz, Medical Oncology Clinical Research Unit, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-496-7665; Fax: 301-402-0172; E-mail: peter.lebowitz{at}nih.gov.

Purpose: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed.

Patients and Methods: Patients with metastatic, hormone receptor–positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen.

Results: A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months.

Conclusions: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.

This article has been cited by other articles:

				D. Tripathy Capecitabine in Combination with Novel Targeted Agents in the Management of Metastatic Breast Cancer: Underlying Rationale and Results of Clinical Trials Oncologist, April 1, 2007; 12(4): 375 - 389. [Abstract] [Full Text] [PDF]

				B. C. Widemann, W. L. Salzer, R. J. Arceci, S. M. Blaney, E. Fox, D. End, A. Gillespie, P. Whitcomb, J. S. Palumbo, A. Pitney, et al. Phase I Trial and Pharmacokinetic Study of the Farnesyltransferase Inhibitor Tipifarnib in Children With Refractory Solid Tumors or Neurofibromatosis Type I and Plexiform Neurofibromas J. Clin. Oncol., January 20, 2006; 24(3): 507 - 516. [Abstract] [Full Text] [PDF]

				A. D. Basso, P. Kirschmeier, and W. R. Bishop Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors J. Lipid Res., January 1, 2006; 47(1): 15 - 31. [Abstract] [Full Text] [PDF]