TY - JOUR
T1 - A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies
T2 - A pediatric brain tumor consortium study
AU - Fouladi, Maryam
AU - Stewart, Clinton F.
AU - Blaney, Susan M.
AU - Onar-Thomas, Arzu
AU - Schaiquevich, Paula
AU - Packer, Roger J.
AU - Goldman, Stewart
AU - Geyer, J. Russell
AU - Gajjar, Amar
AU - Kun, Larry E.
AU - Boyett, James M.
AU - Gilbertson, Richard J.
N1 - Funding Information:
Acknowledgments We acknowledge the clinical research assistant support of Helen Gallagher and Christopher Smith and the technical assistance of Inga Luckett and Radhika Thiruvenkatam. This study was supported in part by NIH Grant U01 CA81457 for the Pediatric Brain Tumor Consortium (JB), NCI Grant R21 CA114937 (MF) and American Lebanese Syrian Associated Charities.
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
KW - High-grade glioma
KW - Lapatinib
KW - Medulloblastoma
KW - Phase II trial
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UR - http://www.scopus.com/inward/citedby.url?scp=84885050035&partnerID=8YFLogxK
U2 - 10.1007/s11060-013-1166-7
DO - 10.1007/s11060-013-1166-7
M3 - Article
C2 - 23836190
AN - SCOPUS:84885050035
SN - 0167-594X
VL - 114
SP - 173
EP - 179
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 2
ER -