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

doi:10.1016/j.ejca.2010.07.005

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 journal › Article › peer-review

49 Scopus citations

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 language	English (US)
Pages (from-to)	3287-3293
Number of pages	7
Journal	European Journal of Cancer
Volume	46
Issue number	18
DOIs	https://doi.org/10.1016/j.ejca.2010.07.005
State	Published - Dec 2010

Keywords

Brain stem neoplasms
Epidermal growth factor receptor
Gefitinib
Glioma
Radiotherapy
Supratentorial neoplasms

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ejca.2010.07.005

Cite this

Geyer, J. R., Stewart, C. F., Kocak, M., Broniscer, A., Phillips, P., Douglas, J. G., Blaney, S. M., Packer, R. J., Gururangan, S., Banerjee, A., Kieran, M. W., Kun, L. E., Gilbertson, R. J., & Boyett, J. M. (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, 46(18), 3287-3293. https://doi.org/10.1016/j.ejca.2010.07.005

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

@article{2cdc05142f90428d9ca5d31d3143bd7e,

title = "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 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.",

keywords = "Brain stem neoplasms, Epidermal growth factor receptor, Gefitinib, Glioma, Radiotherapy, Supratentorial neoplasms",

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

note = "Funding Information: 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. Funding Information: This study was sponsored by the US National Cancer Institute (NCI) and coordinated by the Pediatric Brain Tumour Consortium. This work was supported by NIH grant U01 CA81457 for the Pediatric Brain Tumour Consortium, NIH grant 5M01RR000188 (General Clinical Research Center for Texas Children{\textquoteright}s Cancer Center), AstraZeneca and the American Lebanese Syrian Associated Charities (ALSAC). The NCI provided input on the design of the trial and reviewed the final manuscript but had no role in the data collection, analysis and interpretation or decision to publish. Astrazeneca provided partial financial support for the conduct of the pharmacokinetic studies but no input into the study design or conduct. The GCRC and ALSAC had no role in the study design, data collection, data analysis, data interpretation or writing of the report. ",

year = "2010",

month = dec,

doi = "10.1016/j.ejca.2010.07.005",

language = "English (US)",

volume = "46",

pages = "3287--3293",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Limited",

number = "18",

}

TY - JOUR

T1 - A phase i and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas

AU - Geyer, J. Russell

AU - Stewart, Clinton F.

AU - Kocak, Mehmet

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.

N1 - Funding Information: 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. Funding Information: This study was sponsored by the US National Cancer Institute (NCI) and coordinated by the Pediatric Brain Tumour Consortium. This work was supported by NIH grant U01 CA81457 for the Pediatric Brain Tumour Consortium, NIH grant 5M01RR000188 (General Clinical Research Center for Texas Children’s Cancer Center), AstraZeneca and the American Lebanese Syrian Associated Charities (ALSAC). The NCI provided input on the design of the trial and reviewed the final manuscript but had no role in the data collection, analysis and interpretation or decision to publish. Astrazeneca provided partial financial support for the conduct of the pharmacokinetic studies but no input into the study design or conduct. The GCRC and ALSAC had no role in the study design, data collection, data analysis, data interpretation or writing of the report.

PY - 2010/12

Y1 - 2010/12

N2 - 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.

AB - 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.

KW - Brain stem neoplasms

KW - Epidermal growth factor receptor

KW - Gefitinib

KW - Glioma

KW - Radiotherapy

KW - Supratentorial neoplasms

UR - http://www.scopus.com/inward/record.url?scp=78649632132&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649632132&partnerID=8YFLogxK

U2 - 10.1016/j.ejca.2010.07.005

DO - 10.1016/j.ejca.2010.07.005

M3 - Article

C2 - 20708924

AN - SCOPUS:78649632132

SN - 0959-8049

VL - 46

SP - 3287

EP - 3293

JO - European Journal of Cancer

JF - European Journal of Cancer

IS - 18

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this