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

J Clin Oncol. 2007 Jul 20;25(21):3137-43. doi: 10.1200/JCO.2006.09.4243.


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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Central Nervous System Neoplasms / drug therapy*
  • Central Nervous System Neoplasms / mortality*
  • Central Nervous System Neoplasms / pathology
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Enzyme Inhibitors / pharmacokinetics*
  • Enzyme Inhibitors / therapeutic use
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Female
  • Follow-Up Studies
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Maximum Tolerated Dose
  • Neoplasm Invasiveness / pathology*
  • Neoplasm Staging
  • Piperidines / pharmacokinetics*
  • Piperidines / therapeutic use
  • Pyridines / pharmacokinetics*
  • Pyridines / therapeutic use
  • Risk Assessment
  • Survival Analysis
  • Treatment Outcome


  • Enzyme Inhibitors
  • Piperidines
  • Pyridines
  • Farnesyltranstransferase
  • lonafarnib