A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies

A pediatric brain tumor consortium study

Maryam Fouladi, Clinton F. Stewart, Susan M. Blaney, Arzu Onar-Thomas, Paula Schaiquevich, Roger J. Packer, Stewart Goldman, J. Russell Geyer, Amar Gajjar, Larry E. Kun, James M. Boyett, Richard J. Gilbertson

Research output: Contribution to journalArticle

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Abstract

High expression of ERBB2 has been reported in medulloblastoma and ependymoma; EGFR is amplified and over-expressed in brainstem glioma suggesting these proteins as potential therapeutic targets. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor ERBB signaling and sustained responses by lapatinib in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, ependymoma, and high-grade glioma (HGG) undergoing resection were stratified and randomized to pre-resection treatment with lapatinib 900 mg/m2 dose bid for 7-14 days or no treatment. Western blot analysis of ERBB expression and pathway activity in fresh tumor obtained at surgery estimated ERBB receptor signaling inhibition in vivo. Drug concentration was simultaneously assessed in tumor and plasma. In the phase II study, patients, stratified by histology, received lapatinib continuously, to assess sustained response. Eight patients, on the MB trial (four medulloblastomas, four ependymomas), received a median of two courses (range 1-6+). No intratumoral target inhibition by lapatinib was noted in any patient. Tumor-to-plasma ratios of lapatinib were 10-20 %. In the 34 patients (14 MB, 10 HGG, 10 ependymoma) in the phase II study, lapatinib was well-tolerated at 900 mg/m2 dose bid. The median number of courses in the phase II trial was two (range 1-12). Seven patients (three medulloblastoma, four ependymoma) remained on therapy for at least four courses range (4-26). Lapatinib was well-tolerated in children with recurrent or CNS malignancies, but did not inhibit target in tumor and had little single agent activity.

Original languageEnglish (US)
Pages (from-to)173-179
Number of pages7
JournalJournal of Neuro-Oncology
Volume114
Issue number2
DOIs
StatePublished - Sep 1 2013

Fingerprint

Brain Neoplasms
Ependymoma
Molecular Biology
Medulloblastoma
Pediatrics
Neoplasms
Glioma
Therapeutics
lapatinib
Brain Stem
Histology
Western Blotting
Pharmaceutical Preparations
Proteins

Keywords

  • High-grade glioma
  • Lapatinib
  • Medulloblastoma
  • Phase II trial

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

Fouladi, M., Stewart, C. F., Blaney, S. M., Onar-Thomas, A., Schaiquevich, P., Packer, R. J., ... Gilbertson, R. J. (2013). A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: A pediatric brain tumor consortium study. Journal of Neuro-Oncology, 114(2), 173-179. https://doi.org/10.1007/s11060-013-1166-7

A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies : A pediatric brain tumor consortium study. / Fouladi, Maryam; Stewart, Clinton F.; Blaney, Susan M.; Onar-Thomas, Arzu; Schaiquevich, Paula; Packer, Roger J.; Goldman, Stewart; Geyer, J. Russell; Gajjar, Amar; Kun, Larry E.; Boyett, James M.; Gilbertson, Richard J.

In: Journal of Neuro-Oncology, Vol. 114, No. 2, 01.09.2013, p. 173-179.

Research output: Contribution to journalArticle

Fouladi, M, Stewart, CF, Blaney, SM, Onar-Thomas, A, Schaiquevich, P, Packer, RJ, Goldman, S, Geyer, JR, Gajjar, A, Kun, LE, Boyett, JM & Gilbertson, RJ 2013, 'A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: A pediatric brain tumor consortium study', Journal of Neuro-Oncology, vol. 114, no. 2, pp. 173-179. https://doi.org/10.1007/s11060-013-1166-7
Fouladi, Maryam ; Stewart, Clinton F. ; Blaney, Susan M. ; Onar-Thomas, Arzu ; Schaiquevich, Paula ; Packer, Roger J. ; Goldman, Stewart ; Geyer, J. Russell ; Gajjar, Amar ; Kun, Larry E. ; Boyett, James M. ; Gilbertson, Richard J. / A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies : A pediatric brain tumor consortium study. In: Journal of Neuro-Oncology. 2013 ; Vol. 114, No. 2. pp. 173-179.
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