title: A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours.
abstract: OBJECTIVE
  To evaluate the safety, efficacy and pharmacokinetics of imatinib in children with recurrent or refractory central nervous system (CNS) tumours expressing KIT and/or PDGFRA.
  
  
  METHODS
  Nineteen patients aged 2-18 years, with recurrent or refractory CNS tumours expressing either of the target receptors KIT and/or PDGFRA (by immunohistochemistry) were eligible. Participants received imatinib orally at a dose of 440 mg/m(2)/day and toxicities and tumour responses were monitored. Serial blood and cerebrospinal fluid samples for pharmacokinetics were obtained in a subset of consenting patients. Frozen tumour samples were analysed retrospectively for KIT and PDGFRA gene amplification in a subset of patients for whom samples were available.
  
  
  RESULTS
  Common toxicities were lymphopaenia, neutropaenia, leucopaenia, elevated serum transaminases and vomiting. No intratumoural haemorrhages were observed. Although there were no objective responses to imatinib, four patients had long-term stable disease (SD) (38-104 weeks). Our results suggest a possible relationship between KIT expression and maintenance of SD with imatinib treatment; KIT immunopositivity was seen in only 58% (11/19) of study participants overall, but in 100% of patients with SD at 38 weeks. All patient tumours showed PDGFRA expression. Pharmacokinetic data showed a high interpatient variability, but corresponded with previously reported values.
  
  
  CONCLUSIONS
  Imatinib at 440 mg/m(2)/day is relatively safe in children with recurrent CNS tumours, but induced no objective responses. Demonstration of SD in previously progressing patients (KIT-expressing) suggests cytostatic activity of imatinib.
authors.affiliation: Department of Paediatrics Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada. sylvain.baruchel@sickkids.ca
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
authors.forename: Julia R
authors.initials: JR
authors.lastname: Sharp
authors.forename: Ute
authors.initials: U
authors.lastname: Bartels
authors.forename: Juliette
authors.initials: J
authors.lastname: Hukin
authors.forename: Isaac
authors.initials: I
authors.lastname: Odame
authors.forename: Carol
authors.initials: C
authors.lastname: Portwine
authors.forename: Doug
authors.initials: D
authors.lastname: Strother
authors.forename: Chris
authors.initials: C
authors.lastname: Fryer
authors.forename: Jackie
authors.initials: J
authors.lastname: Halton
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Rui Manuel
authors.initials: RM
authors.lastname: Reis
authors.forename: Olga
authors.initials: O
authors.lastname: Martinho
authors.forename: Diana
authors.initials: D
authors.lastname: Stempak
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: Janet
authors.initials: J
authors.lastname: Gammon
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001549:Benzamides; D002170:Canada; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha