Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme

North central cancer treatment group study N0177

Paul D. Brown, Sunil Krishnan, Jann N. Sarkaria, Wenting Wu, Kurt A. Jaeckle, Joon H. Uhm, Francois J. Geoffroy, Robert Arusell, Gaspar Kitange, Robert B. Jenkins, John W. Kugler, Roscoe F. Morton, Kendrith M. Rowland, Paul Mischel, William H. Yong, Bernd W. Scheithauer, David Schiff, Caterina Giannini, Jan C. Buckner

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Abstract

Purpose: Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods: Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results: Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Conclusion: Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

Original languageEnglish (US)
Pages (from-to)5603-5609
Number of pages7
JournalJournal of Clinical Oncology
Volume26
Issue number34
DOIs
StatePublished - Dec 1 2008

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temozolomide
Glioblastoma
Radiotherapy
Epidermal Growth Factor Receptor
Neoplasms
Survival
Phosphoric Monoester Hydrolases
Drug Therapy
Therapeutics
National Cancer Institute (U.S.)
Erlotinib Hydrochloride
Exanthema
Anticonvulsants
Canada
Diarrhea

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Brown, Paul D. ; Krishnan, Sunil ; Sarkaria, Jann N. ; Wu, Wenting ; Jaeckle, Kurt A. ; Uhm, Joon H. ; Geoffroy, Francois J. ; Arusell, Robert ; Kitange, Gaspar ; Jenkins, Robert B. ; Kugler, John W. ; Morton, Roscoe F. ; Rowland, Kendrith M. ; Mischel, Paul ; Yong, William H. ; Scheithauer, Bernd W. ; Schiff, David ; Giannini, Caterina ; Buckner, Jan C. / Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme : North central cancer treatment group study N0177. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 34. pp. 5603-5609.
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title = "Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North central cancer treatment group study N0177",
abstract = "Purpose: Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods: Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results: Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Conclusion: Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.",
author = "Brown, {Paul D.} and Sunil Krishnan and Sarkaria, {Jann N.} and Wenting Wu and Jaeckle, {Kurt A.} and Uhm, {Joon H.} and Geoffroy, {Francois J.} and Robert Arusell and Gaspar Kitange and Jenkins, {Robert B.} and Kugler, {John W.} and Morton, {Roscoe F.} and Rowland, {Kendrith M.} and Paul Mischel and Yong, {William H.} and Scheithauer, {Bernd W.} and David Schiff and Caterina Giannini and Buckner, {Jan C.}",
year = "2008",
month = "12",
day = "1",
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language = "English (US)",
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pages = "5603--5609",
journal = "Journal of Clinical Oncology",
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}

Brown, PD, Krishnan, S, Sarkaria, JN, Wu, W, Jaeckle, KA, Uhm, JH, Geoffroy, FJ, Arusell, R, Kitange, G, Jenkins, RB, Kugler, JW, Morton, RF, Rowland, KM, Mischel, P, Yong, WH, Scheithauer, BW, Schiff, D, Giannini, C & Buckner, JC 2008, 'Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North central cancer treatment group study N0177', Journal of Clinical Oncology, vol. 26, no. 34, pp. 5603-5609. https://doi.org/10.1200/JCO.2008.18.0612

Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme : North central cancer treatment group study N0177. / Brown, Paul D.; Krishnan, Sunil; Sarkaria, Jann N.; Wu, Wenting; Jaeckle, Kurt A.; Uhm, Joon H.; Geoffroy, Francois J.; Arusell, Robert; Kitange, Gaspar; Jenkins, Robert B.; Kugler, John W.; Morton, Roscoe F.; Rowland, Kendrith M.; Mischel, Paul; Yong, William H.; Scheithauer, Bernd W.; Schiff, David; Giannini, Caterina; Buckner, Jan C.

In: Journal of Clinical Oncology, Vol. 26, No. 34, 01.12.2008, p. 5603-5609.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme

T2 - North central cancer treatment group study N0177

AU - Brown, Paul D.

AU - Krishnan, Sunil

AU - Sarkaria, Jann N.

AU - Wu, Wenting

AU - Jaeckle, Kurt A.

AU - Uhm, Joon H.

AU - Geoffroy, Francois J.

AU - Arusell, Robert

AU - Kitange, Gaspar

AU - Jenkins, Robert B.

AU - Kugler, John W.

AU - Morton, Roscoe F.

AU - Rowland, Kendrith M.

AU - Mischel, Paul

AU - Yong, William H.

AU - Scheithauer, Bernd W.

AU - Schiff, David

AU - Giannini, Caterina

AU - Buckner, Jan C.

PY - 2008/12/1

Y1 - 2008/12/1

N2 - Purpose: Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods: Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results: Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Conclusion: Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

AB - Purpose: Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods: Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results: Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Conclusion: Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

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