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Erschienen in: Journal of Neuro-Oncology 3/2016

27.06.2016 | Clinical Study

A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study

verfasst von: Ralph Salloum, Trent R. Hummel, Shiva Senthil Kumar, Kathleen Dorris, Shaoyu Li, Tong Lin, Vinay M. Daryani, Clinton F. Stewart, Lili Miles, Tina Young Poussaint, Charles Stevenson, Stewart Goldman, Girish Dhall, Roger Packer, Paul Fisher, Ian F. Pollack, Maryam Fouladi, James Boyett, Rachid Drissi

Erschienen in: Journal of Neuro-Oncology | Ausgabe 3/2016

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Abstract

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m2, 12–24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m2. Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.
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Metadaten
Titel
A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study
verfasst von
Ralph Salloum
Trent R. Hummel
Shiva Senthil Kumar
Kathleen Dorris
Shaoyu Li
Tong Lin
Vinay M. Daryani
Clinton F. Stewart
Lili Miles
Tina Young Poussaint
Charles Stevenson
Stewart Goldman
Girish Dhall
Roger Packer
Paul Fisher
Ian F. Pollack
Maryam Fouladi
James Boyett
Rachid Drissi
Publikationsdatum
27.06.2016
Verlag
Springer US
Erschienen in
Journal of Neuro-Oncology / Ausgabe 3/2016
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-016-2189-7

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