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

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

Conflict of interest statement

Conflict of interest statement

Dr. Stewart received research funding from Astrazeneca for the conduct of the pharmacokinetic studies. Dr. Gururangan disclosed a consultant or advisory role with Boehringer Ingelheim Pharma. No other conflicts of interest have been declared.

Copyright © 2010 Elsevier Ltd. All rights reserved.

Figures

FIGURE 1

a. Graph summarizing percent of tumour cells expressing epidermal growth factor receptor (EGFR) according to EGFR copy number status. b. Top panel: EGFR immunohistochemistry showing intense membrane staining in the sample in which 90% of cells express EGFR. Bottom panel: FISH analysis confirming high-level EGFR amplification in this same tumour.