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 Patnaik, A. Articles by Rowinsky, E. K. Search for Related Content PubMed PubMed Citation Articles by Patnaik, A. Articles by Rowinsky, E. K.

A Phase I, Pharmacokinetic, and Biological Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with Gemcitabine in Patients with Advanced Malignancies

Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229 [A. P., S. G. E., E. I., A. A. T., L. A. H., C. H. T., H. M., A. G., E. K. R.]; Brooke Army Medical Center, San Antonio, Texas 78234-6200 [G. S.]; Kumamoto University School of Medicine, Kumamoto, Japan 860-8556 [M. M., K. T.]; and Johnson and Johnson Pharmaceutical Research and Development, Titusville, New Jersey 08560 [L. G., M-E. R., H. R., S. Z.]

Purpose: To assess the feasibility of administering tipifarnib, an oral nonpeptidomimetic competitive inhibitor of farnesyltransferase, in combination with gemcitabine and recommend doses for disease-directed clinical trials. The study also sought to identify drug-drug pharmacokinetic interactions, evaluate effects on protein farnesylation, and seek preliminary evidence for clinical activity.

Experimental Design: Patients with advanced solid malignancies were treated with tipifarnib at doses of 100, 200, and 300 mg twice daily continuously and 1000 mg/m² gemcitabine i.v. on days 1, 8, and 15 every 4 weeks. To identify pharmacokinetic interactions, the treatment and plasma sampling schemes were designed to permit comparisons of the pharmacokinetic behavior of each agent administered alone and together. The proportions of unfarnesylated and farnesylated HDJ2, a chaperone protein that undergoes farnesylation, were measured in peripheral blood mononuclear cells.

Results: Nineteen evaluable patients were treated with 74 courses of tipifarnib/gemcitabine (mg/mg/m²). Myelosuppression was the principal toxicity. Dose-limiting myelosuppression occurred in 2 of 5 patients at the 300/1000 dose level, whereas 2 of 11 evaluable patients at the 200/1000 dose level experienced dose-limiting toxicity. There was no evidence of clinically relevant pharmacokinetic interactions between tipifarnib and gemcitabine. Inhibition of farnesylation of HDJ2, a potential surrogate for Ras and/or other potentially relevant farnesylated proteins, was demonstrated in peripheral blood mononuclear cells at all dose levels. Partial responses were noted in patients with advanced pancreatic and nasopharyngeal carcinomas.

Conclusions: On the basis of the results of this study, the tipifarnib/gemcitabine dose level of 200/1000 is recommended for disease-directed studies. At this dose level, biologically relevant plasma concentrations of tipifarnib that consistently inhibit protein farnesylation in vitro are achieved and drug-induced inhibition of protein farnesylation is measured in most patients.

This article has been cited by other articles:

				N. E. Ready, A. Lipton, Y. Zhu, P. Statkevich, E. Frank, D. Curtis, and R. M. Bukowski Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Weekly Paclitaxel in Patients with Solid Tumors Clin. Cancer Res., January 15, 2007; 13(2): 576 - 583. [Abstract] [Full Text] [PDF]

				L Gore, S. Holden, R. Cohen, M Morrow, A. Pierson, C. O'Bryant, M Persky, D Gustafson, C Mikule, S Zhang, et al. A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors Ann. Onc., November 1, 2006; 17(11): 1709 - 1717. [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]

				H. Mo and C. E. Elson Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention Experimental Biology and Medicine, July 1, 2004; 229(7): 567 - 585. [Abstract] [Full Text] [PDF]