A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas.


Journal Article

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.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.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.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.

Full Text

Cited Authors

  • Geyer, JR; Stewart, CF; Kocak, M; Broniscer, A; Phillips, P; Douglas, JG; Blaney, SM; Packer, RJ; Gururangan, S; Banerjee, A; Kieran, MW; Kun, LE; Gilbertson, RJ; Boyett, JM

Published Date

  • December 2010

Published In

Volume / Issue

  • 46 / 18

Start / End Page

  • 3287 - 3293

PubMed ID

  • 20708924

Pubmed Central ID

  • 20708924

Electronic International Standard Serial Number (EISSN)

  • 1879-0852

International Standard Serial Number (ISSN)

  • 1879-0852

Digital Object Identifier (DOI)

  • 10.1016/j.ejca.2010.07.005


  • eng