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 Adjei, A. A. Articles by Kaufmann, S. H. Search for Related Content PubMed PubMed Citation Articles by Adjei, A. A. Articles by Kaufmann, S. H.

A Phase I Trial of the Farnesyl Protein Transferase Inhibitor R115777 in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer¹

Mayo Clinic and Foundation, Departments of Oncology and Medicine, Rochester, Minnesota 55905 [A. A. A., G. A. C., C. E., R. S. M., J. M. R., J. A. S., H. C. P., S. R. A., R. M. G., L. J. H., L. M. B., P. A., S. H. K.], and Janssen Research Foundation, Titusville, New Jersey 92008 [A. T., P. A. P.]

Purpose: This Phase I study was undertaken to define the toxicity, pharmacodynamics, and maximum tolerated dose of the combination of R115777, a farnesyl transferase inhibitor, with gemcitabine and cisplatin in patients with advanced solid tumors.

Patients and Methods: Thirty patients with solid tumors received a median of 2.5 cycles (range 1–30+) through five dose levels. R115777 was administered p.o. twice daily for 14 days. Gemcitabine was infused 15 min after the ingestion of R115777 on days 1 and 8. Cisplatin was administered starting 30 min after completion of the gemcitabine infusion on day 1. Cycles were repeated every 21 days. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for each treatment cycle. At the maximum tolerated dose, accumulation of prelamin A in buccal mucosa cells of patients was evaluated as a marker of farnesyl transferase inhibition by R115777.

Results: Neutropenia and thrombocytopenia were the most common toxicities. Dose-limiting toxicity in cycle 1 was myelosuppression with thrombocytopenia alone (4 patients), neutropenia alone (1 patient), or a combination of both (3 patients). Common nonhematologic toxicities were anorexia, rash, nausea, vomiting, and fatigue, none of which was dose limiting in the first cycle. At the maximum tolerated dose, defined as R115777 300 mg twice daily p.o., 1000 mg/m² gemcitabine, and 75 mg/m² cisplatin, inhibition of prelamin A farnesylation in buccal mucosa cells of patients was demonstrated, confirming that R115777 inhibits protein farnesylation in vivo. Nine objective responses (one complete response and eight partial responses) were documented in 27 evaluable patients.

Conclusion: The combination of R115777 with gemcitabine and cisplatin was well tolerated and showed evidence of antitumor activity. The maximum tolerated dose of R115777 successfully inhibits farnesyltransferase in patients in vivo. This combination warrants further evaluation in a number of tumor types.

This article has been cited by other articles:

				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]

				L. G. Fong, D. Frost, M. Meta, X. Qiao, S. H. Yang, C. Coffinier, and S. G. Young A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria Science, March 17, 2006; 311(5767): 1621 - 1623. [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]

				S. G. Young, L. G. Fong, and S. Michaelis Thematic Review Series: Lipid Posttranslational Modifications. Prelamin A, Zmpste24, misshapen cell nuclei, and progeria--new evidence suggesting that protein farnesylation could be important for disease pathogenesis J. Lipid Res., December 1, 2005; 46(12): 2531 - 2558. [Abstract] [Full Text] [PDF]

				N. M.G.M. Appels, J. H. Beijnen, and J. H.M. Schellens Development of Farnesyl Transferase Inhibitors: A Review Oncologist, September 1, 2005; 10(8): 565 - 578. [Abstract] [Full Text] [PDF]

				J. Larghero, N. Gervais, B. Cassinat, J.-D. Rain, M.-H. Schlageter, R. A. Padua, C. Chomienne, and P. Rousselot Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells Blood, May 1, 2005; 105(9): 3743 - 3745. [Abstract] [Full Text] [PDF]

				G. K. Dy, L. M. Bruzek, G. A. Croghan, S. Mandrekar, C. Erlichman, P. Peethambaram, H. C. Pitot, L. J. Hanson, J. M. Reid, A. Furth, et al. A Phase I Trial of the Novel Farnesyl Protein Transferase Inhibitor, BMS-214662, in Combination with Paclitaxel and Carboplatin in Patients with Advanced Cancer Clin. Cancer Res., March 1, 2005; 11(5): 1877 - 1883. [Abstract] [Full Text] [PDF]