Phase Ii and Pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma

Alberto Broniscer, Suzanne J. Baker, Clinton F. Stewart, Thomas E. Merchant, Fred H. Laningham, Paula Schaiquevich, Mehmet Kocak, E. Brannon Morris, Raelene Endersby, David W. Ellison, Amar Gajjar

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Abstract

Purpose: To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy, and to describe the pharmacokinetics of erlotinib and its metabolite OSI-420 in patients between 3 and 25 years with newly diagnosed high-grade glioma who did not require enzyme-inducing anticonvulsants. Experimental Design: Five dosage levels (70, 90,120,160, and 200 mg/m 2 per day) were planned in this phase I study. Dose-limiting toxicities (DLT) were evaluated during first 8 weeks of therapy. Local radiotherapy (dose between 54 and 59.4 Gy) and erlotinib started preferentially on the same day. Erlotinib was administered once daily for a maximum of 3 years. Pharmacokinetic studies were obtained after first dose and on day 8 of therapy. Mutational analysis of EGFR kinase domain, PIK3CA, and PTEN was done in tumor tissue. Results: Median age at diagnosis of 23 patients was 10.7 years (range, 3.7-22.5 years). MTD of erlotinib was 120 mg/m 2 per day. Skin rash and diarrhea were generally well controlled with supportive care. Dose-limiting toxicities were diarrhea (n = 1), increase in serum lipase (n = 1), and rash with pruritus (n = 1).The pharmacokinetic variables of erlotinib and OSI-420 in children were similar to those described in adults. However, there was no relationship between erlotinib dosage and drug exposure. No EGFR kinase domain mutations were observed. Two patients with glioblastoma harbored mutations in PIK3CA (n = 1) or PTEN (n = 1). Conclusions: Although the MTD of erlotinib in children with newly diagnosed high-grade glioma was 120 mg/m 2 per day, pharmacokinetic studies showed wide interpatient variability in drug exposure.

Original languageEnglish (US)
Pages (from-to)701-707
Number of pages7
JournalClinical Cancer Research
Volume15
Issue number2
DOIs
StatePublished - Jan 15 2009

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Glioma
Young Adult
Radiotherapy
Pharmacokinetics
Maximum Tolerated Dose
Exanthema
Diarrhea
Phosphotransferases
Mutation
Erlotinib Hydrochloride
Pruritus
Glioblastoma
Lipase
Pharmaceutical Preparations
Anticonvulsants
Research Design
Enzymes
Therapeutics
Serum
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Phase Ii and Pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma. / Broniscer, Alberto; Baker, Suzanne J.; Stewart, Clinton F.; Merchant, Thomas E.; Laningham, Fred H.; Schaiquevich, Paula; Kocak, Mehmet; Morris, E. Brannon; Endersby, Raelene; Ellison, David W.; Gajjar, Amar.

In: Clinical Cancer Research, Vol. 15, No. 2, 15.01.2009, p. 701-707.

Research output: Contribution to journalArticle

Broniscer, A, Baker, SJ, Stewart, CF, Merchant, TE, Laningham, FH, Schaiquevich, P, Kocak, M, Morris, EB, Endersby, R, Ellison, DW & Gajjar, A 2009, 'Phase Ii and Pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma', Clinical Cancer Research, vol. 15, no. 2, pp. 701-707. https://doi.org/10.1158/1078-0432.CCR-08-1923
Broniscer, Alberto ; Baker, Suzanne J. ; Stewart, Clinton F. ; Merchant, Thomas E. ; Laningham, Fred H. ; Schaiquevich, Paula ; Kocak, Mehmet ; Morris, E. Brannon ; Endersby, Raelene ; Ellison, David W. ; Gajjar, Amar. / Phase Ii and Pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 2. pp. 701-707.
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T1 - Phase Ii and Pharmacokinetic studies of erlotinib administered concurrently with radiotherapy for children, adolescents, and young adults with high-grade glioma

AU - Broniscer, Alberto

AU - Baker, Suzanne J.

AU - Stewart, Clinton F.

AU - Merchant, Thomas E.

AU - Laningham, Fred H.

AU - Schaiquevich, Paula

AU - Kocak, Mehmet

AU - Morris, E. Brannon

AU - Endersby, Raelene

AU - Ellison, David W.

AU - Gajjar, Amar

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N2 - Purpose: To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy, and to describe the pharmacokinetics of erlotinib and its metabolite OSI-420 in patients between 3 and 25 years with newly diagnosed high-grade glioma who did not require enzyme-inducing anticonvulsants. Experimental Design: Five dosage levels (70, 90,120,160, and 200 mg/m 2 per day) were planned in this phase I study. Dose-limiting toxicities (DLT) were evaluated during first 8 weeks of therapy. Local radiotherapy (dose between 54 and 59.4 Gy) and erlotinib started preferentially on the same day. Erlotinib was administered once daily for a maximum of 3 years. Pharmacokinetic studies were obtained after first dose and on day 8 of therapy. Mutational analysis of EGFR kinase domain, PIK3CA, and PTEN was done in tumor tissue. Results: Median age at diagnosis of 23 patients was 10.7 years (range, 3.7-22.5 years). MTD of erlotinib was 120 mg/m 2 per day. Skin rash and diarrhea were generally well controlled with supportive care. Dose-limiting toxicities were diarrhea (n = 1), increase in serum lipase (n = 1), and rash with pruritus (n = 1).The pharmacokinetic variables of erlotinib and OSI-420 in children were similar to those described in adults. However, there was no relationship between erlotinib dosage and drug exposure. No EGFR kinase domain mutations were observed. Two patients with glioblastoma harbored mutations in PIK3CA (n = 1) or PTEN (n = 1). Conclusions: Although the MTD of erlotinib in children with newly diagnosed high-grade glioma was 120 mg/m 2 per day, pharmacokinetic studies showed wide interpatient variability in drug exposure.

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