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 Papadimitrakopoulou, V. Articles by Khuri, F. Search for Related Content PubMed PubMed Citation Articles by Papadimitrakopoulou, V. Articles by Khuri, F.

Phase I Study of the Farnesyltransferase Inhibitor BMS-214662 Given Weekly in Patients with Solid Tumors

Authors' Affiliations: ¹ The University of Texas M.D. Anderson Cancer Center, Houston, Texas, ² National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, Maryland, and ³ Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia

Requests for reprints: Vali Papadimitrakopoulou, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Unit 432, 1515 Holcombe Boulevard, Houston 77030, TX. Phone: 713-792-6363; Fax: 713-7968655; E-mail: vpapadim{at}mdanderson.org.

Purpose: A phase I trial of BMS-214662, a selective farnesyltransferase inhibitor with significant preclinical antitumor activity in which drug was given as a weekly 1-hour infusion for four of six weeks, was conducted to evaluate the tolerability, pharmacokinetics, and pharmacodynamic effect on farnesyltransferase activity in peripheral blood mononuclear cells.

Experimental Design: BMS-214662 was given to 27 patients with solid tumors at 10 escalating dose levels (28-220 mg/m²) allowing intrapatient dose escalation; pharmacokinetics and pharmacodynamics were done at the first seven dose levels.

Results: Grade 4 neutropenia (four patients) was the most common dose-limiting toxicity followed by aminotransferase elevation (grade 3 alanine aminotransferase and grade 4 aspartate aminotransferase) and grade 3 dehydration. Most frequent toxicities were neutropenia in 11 (14%), anemia in 15 (19%), fatigue in 9 (12%), and nausea and diarrhea in 6 (8%) of courses, respectively. One minor response lasting 18 weeks in a patient with non–small cell lung cancer, serum calcitonin level reduction accompanied by disease stabilization in two of four patients with medullary thyroid carcinoma, and stable disease in 16 of 25 evaluable patients was seen. No correlation was observed between dose and C_max, total body clearance (mean, 26.15 ± 10.88 L per hour per m²), volume of distribution at steady state (mean, 39.51 ± 17.91 L/m²), or half-life (mean, 2.63 ± 1.81 hours); a moderate correlation existed between dose given and systemic drug exposure (AUC). Substantial inhibition of peripheral blood mononuclear cell farnesyltransferase activity but near complete recovery by 24 hours was seen.

Conclusion: BMS-214667 was well tolerated as a weekly 1-hour i.v. infusion for four of six weeks with evidence of pharmacodynamic effect. The study was terminated before maximum tolerated dose was reached. Alternative schedules of drug administration might result in improved pharmacodynamic profile.

Key Words: clinical trials • farnesyl transferase inhibitor • pharmacokinetics

This article has been cited by other articles:

				M. Copland, F. Pellicano, L. Richmond, E. K. Allan, A. Hamilton, F. Y. Lee, R. Weinmann, and T. L. Holyoake BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors Blood, March 1, 2008; 111(5): 2843 - 2853. [Abstract] [Full Text] [PDF]

				H. H. Bailey, D. B. Alberti, J. P. Thomas, D. L. Mulkerin, K. A. Binger, M. M. Gottardis, R. E. Martell, and G. Wilding Phase I Trial of Weekly Paclitaxel and BMS-214662 in Patients with Advanced Solid Tumors Clin. Cancer Res., June 15, 2007; 13(12): 3623 - 3629. [Abstract] [Full Text] [PDF]

				R. T. Eastman, F. S. Buckner, K. Yokoyama, M. H. Gelb, and W. C. Van Voorhis Thematic review series: Lipid Posttranslational Modifications. Fighting parasitic disease by blocking protein farnesylation J. Lipid Res., February 1, 2006; 47(2): 233 - 240. [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]