This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Widemann, B. C. Articles by Balis, F. M. Search for Related Content PubMed Articles by Widemann, B. C. Articles by Balis, F. M.

Phase I Trial and Pharmacokinetic Study of the Farnesyltransferase Inhibitor Tipifarnib in Children With Refractory Solid Tumors or Neurofibromatosis Type I and Plexiform Neurofibromas

From the Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; Children's Hospital and Medical Center, Cincinnati, Cincinnati, OH; Texas Children's Cancer Center, Houston, TX; and Janssen Research Foundation, Beerse, Belgium.

Address reprint requests to Brigitte C. Widemann, MD, Pediatric Oncology Branch, National Cancer Institute, 10 Center Dr, Building 10 CRC, Room 1-5750, MSC 1101, Bethesda, MD 20892; e-mail: widemanb{at}mail.nih.gov

Purpose: This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1) –related plexiform neurofibromas.

Patients and Methods: Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m²/dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m²/dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation.

Results: Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m²/dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m²/dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m²/dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs.

Conclusion: Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m²/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.

Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

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

This article has been cited by other articles:

				M. Case, E. Matheson, L. Minto, R. Hassan, C. J. Harrison, N. Bown, S. Bailey, J. Vormoor, A. G. Hall, and J. A.E. Irving Mutation of Genes Affecting the RAS Pathway Is Common in Childhood Acute Lymphoblastic Leukemia Cancer Res., August 15, 2008; 68(16): 6803 - 6809. [Abstract] [Full Text] [PDF]

				J. W. Wojtkowiak, F. Fouad, D. T. LaLonde, M. D. Kleinman, R. A. Gibbs, J. J. Reiners Jr., R. F. Borch, and R. R. Mattingly Induction of Apoptosis in Neurofibromatosis Type 1 Malignant Peripheral Nerve Sheath Tumor Cell Lines by a Combination of Novel Farnesyl Transferase Inhibitors and Lovastatin J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 1 - 11. [Abstract] [Full Text] [PDF]

				A. Kim, E. Fox, K. Warren, S. M. Blaney, S. L. Berg, P. C. Adamson, M. Libucha, E. Byrley, F. M. Balis, and B. C. Widemann Characteristics and Outcome of Pediatric Patients Enrolled in Phase I Oncology Trials Oncologist, June 1, 2008; 13(6): 679 - 689. [Abstract] [Full Text] [PDF]

				B. Hegedus, D. Banerjee, T.-H. Yeh, S. Rothermich, A. Perry, J. B. Rubin, J. R. Garbow, and D. H. Gutmann Preclinical Cancer Therapy in a Mouse Model of Neurofibromatosis-1 Optic Glioma Cancer Res., March 1, 2008; 68(5): 1520 - 1528. [Abstract] [Full Text] [PDF]

				T. Raz, V. Nardi, M. Azam, J. Cortes, and G. Q. Daley Farnesyl transferase inhibitor resistance probed by target mutagenesis Blood, September 15, 2007; 110(6): 2102 - 2109. [Abstract] [Full Text] [PDF]

				Y. Qiu, X. Liu, W. Zou, P. Yue, S. Lonial, F. R. Khuri, and S.-Y. Sun The Farnesyltransferase Inhibitor R115777 Up-regulates the Expression of Death Receptor 5 and Enhances TRAIL-Induced Apoptosis in Human Lung Cancer Cells Cancer Res., May 15, 2007; 67(10): 4973 - 4980. [Abstract] [Full Text] [PDF]

				E. Dombi, J. Solomon, A. J. Gillespie, E. Fox, F. M. Balis, N. Patronas, B. R. Korf, D. Babovic-Vuksanovic, R. J. Packer, J. Belasco, et al. NF1 plexiform neurofibroma growth rate by volumetric MRI: Relationship to age and body weight Neurology, February 27, 2007; 68(9): 643 - 647. [Abstract] [Full Text] [PDF]