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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.

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