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A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study.

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.

journal_name

J Neurooncol

journal_title

Journal of neuro-oncology

authors

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

doi

10.1007/s11060-013-1166-7

subject

Has Abstract

pub_date

2013-09-01 00:00:00

pages

173-9

issue

eissn

0167-594X

issn

1573-7373

journal_volume

114

pub_type

杂志文章,随机对照试验

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A molecular biology and phase II trial of lapatinib in children with refractory CNS malignancies: a pediatric brain tumor consortium study.