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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
- Source :
- Journal of Neuro-Oncology. 129:443-451
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
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/m(2), 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/m(2). 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.
- Subjects :
- Male
Niacinamide
0301 basic medicine
Ependymoma
Cancer Research
Telomerase
Indoles
Time Factors
Pediatric Brain Tumor Consortium
Adolescent
Neutrophils
Oligonucleotides
Phases of clinical research
Antineoplastic Agents
Neutropenia
Article
Central Nervous System Neoplasms
Young Adult
03 medical and health sciences
Imetelstat
0302 clinical medicine
Glioma
Humans
Medicine
Lymphocytes
Child
business.industry
Alanine Transaminase
Recurrent Medulloblastoma
medicine.disease
Molecular biology
Blood Cell Count
Treatment Outcome
030104 developmental biology
Neurology
Oncology
Child, Preschool
030220 oncology & carcinogenesis
Female
Neurology (clinical)
Neoplasm Recurrence, Local
business
Subjects
Details
- ISSN :
- 15737373 and 0167594X
- Volume :
- 129
- Database :
- OpenAIRE
- Journal :
- Journal of Neuro-Oncology
- Accession number :
- edsair.doi.dedup.....c2fd32dd112df1b6c72f92395dfe01f0