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Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study

Mark W. Kieran, Roger J. Packer, Arzu Onar, Susan M. Blaney, Peter Phillips, Ian F. Pollack, J. Russell Geyer, Sri Gururangan, Anu Banerjee, Stewart Goldman, Christopher D. Turner, Jean B. Belasco, Alberto Broniscer, Yali Zhu, Emily Frank, Paul Kirschmeier, Paul Statkevich, Antoine Yver, James M. Boyett, Larry E. Kun

From the Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA; Children's National Medical Center, Washington, DC; St Jude Children's Research Hospital, Memphis, TN; Baylor College of Medicine, Houston, TX; The Children's Hospital of Philadelphia, Philadelphia; Children's Hospital of Pittsburgh, Pittsburgh, PA; Children's Hospital and Regional Medical Center, Seattle, WA; Duke University Medical Center, Durham, NC; University of California at San Francisco, San Francisco, CA; Children's Memorial Hospital, Chicago, IL; and Schering-Plough Research Institute, Kenilworth, NJ

Address reprint requests to Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute, Pediatric Neuro-Oncology, 44 Binney St, Room SW331, Boston, MA 02115; e-mail: mark_Kieran{at}dfci.Harvard.edu

Purpose: A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured.

Patients and Methods: Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m²/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment.

Results: Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m²/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m²/dose levels resulted in a recommended phase II dose of 115 mg/m²/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer.

Conclusion: Although the estimated MTD by the CRM model was 98.5 mg/m²/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m²/dose administered twice daily by mouth with concurrent loperamide.

Supported in part by National Institutes of Health Grant No. U01 CA81457 for the Pediatric Brain Tumor Consortium and the American Lebanese Syrian Associated Charities.

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

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