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

J. Russell Geyer, Clinton F. Stewart, Mehmet Kocak, Alberto Broniscer, Peter Phillips, James G. Douglas, Susan M. Blaney, Roger J. Packer, Sri Gururangan, Anu Banerjee, Mark W. Kieran, Larry E. Kun, Richard J. Gilbertson, James M. Boyett

Research output: Contribution to journalArticle

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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 100 mg/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 100 mg/m2/d, 1 of 10 at 250 mg/m2/d and 3 of 12 at 375 mg/m2/d. Subsequently a second patient at 250 mg/m2/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/m2/d was selected for the phase II trial.

Original languageEnglish (US)
Pages (from-to)3287-3293
Number of pages7
JournalEuropean Journal of Cancer
Volume46
Issue number18
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

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Glioma
Brain Stem
Radiation
Epidermal Growth Factor Receptor
Hemorrhage
Anticonvulsants
Radiotherapy
Pharmacokinetics
Maximum Tolerated Dose
gefitinib
Enzymes
Pharmacology
Pediatrics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

A phase i and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas. / Geyer, J. Russell; Stewart, Clinton F.; Kocak, Mehmet; Broniscer, Alberto; Phillips, Peter; Douglas, James G.; Blaney, Susan M.; Packer, Roger J.; Gururangan, Sri; Banerjee, Anu; Kieran, Mark W.; Kun, Larry E.; Gilbertson, Richard J.; Boyett, James M.

In: European Journal of Cancer, Vol. 46, No. 18, 01.12.2010, p. 3287-3293.

Research output: Contribution to journalArticle

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 2010, 'A phase i and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas', European Journal of Cancer, vol. 46, no. 18, pp. 3287-3293. https://doi.org/10.1016/j.ejca.2010.07.005
Geyer, J. Russell ; Stewart, Clinton F. ; Kocak, Mehmet ; Broniscer, Alberto ; Phillips, Peter ; Douglas, James G. ; Blaney, Susan M. ; Packer, Roger J. ; Gururangan, Sri ; Banerjee, Anu ; Kieran, Mark W. ; Kun, Larry E. ; Gilbertson, Richard J. ; Boyett, James M. / A phase i and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas. In: European Journal of Cancer. 2010 ; Vol. 46, No. 18. pp. 3287-3293.
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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 100 mg/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 100 mg/m2/d, 1 of 10 at 250 mg/m2/d and 3 of 12 at 375 mg/m2/d. Subsequently a second patient at 250 mg/m2/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/m2/d was selected for the phase II trial.",
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AU - Broniscer, Alberto

AU - Phillips, Peter

AU - Douglas, James G.

AU - Blaney, Susan M.

AU - Packer, Roger J.

AU - Gururangan, Sri

AU - Banerjee, Anu

AU - Kieran, Mark W.

AU - Kun, Larry E.

AU - Gilbertson, Richard J.

AU - Boyett, James M.

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