title: 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.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA 02115, USA. mark_Kieran@dfci.Harvard.edu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.forename: Arzu
authors.initials: A
authors.lastname: Onar
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Peter
authors.initials: P
authors.lastname: Phillips
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: J Russell
authors.initials: JR
authors.lastname: Geyer
authors.forename: Sri
authors.initials: S
authors.lastname: Gururangan
authors.forename: Anu
authors.initials: A
authors.lastname: Banerjee
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Turner
authors.forename: Jean B
authors.initials: JB
authors.lastname: Belasco
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhu
authors.forename: Emily
authors.initials: E
authors.lastname: Frank
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: Paul
authors.initials: P
authors.lastname: Statkevich
authors.forename: Antoine
authors.initials: A
authors.lastname: Yver
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.forename: Larry E
authors.initials: LE
authors.lastname: Kun
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020714:Maximum Tolerated Dose; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D010880:Piperidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome; D003986:Dibenzocycloheptenes
chemical_list: D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes