title: A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas.
abstract: OBJECTIVE
  To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ⩽21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG.
  
  
  METHODS
  Three strata were identified: stratum 1A--BSG; stratum IB--incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II--incompletely resected STMG receiving EIACD. Dose escalation using a modified 3+3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100mg/m(2)/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients.
  
  
  RESULTS
  Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100mg/m(2)/d, 1 of 10 at 250 mg/m(2)/d and 3 of 12 at 375 mg/m(2)/d. Subsequently a second patient at 250 mg/m(2)/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples.
  
  
  CONCLUSIONS
  This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m(2)/d was selected for the phase II trial.
authors: Seattle Children's Hospital, Seattle, WA, USA.
authors: J Russell
authors: JR
authors: Geyer
authors: Clinton F
authors: CF
authors: Stewart
authors: Mehmet
authors: M
authors: Kocak
authors: Alberto
authors: A
authors: Broniscer
authors: Peter
authors: P
authors: Phillips
authors: James G
authors: JG
authors: Douglas
authors: Susan M
authors: SM
authors: Blaney
authors: Roger J
authors: RJ
authors: Packer
authors: Sri
authors: S
authors: Gururangan
authors: Anu
authors: A
authors: Banerjee
authors: Mark W
authors: MW
authors: Kieran
authors: Larry E
authors: LE
authors: Kun
authors: Richard J
authors: RJ
authors: Gilbertson
authors: James M
authors: JM
authors: Boyett
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy / Q000379:methods; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D015173:Supratentorial Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib