TR-11A MOLECULAR BIOLOGY AND PHASE II STUDY OF IMETELSTAT (GRN163L) IN CHILDREN WITH RECURRENT OR REFRACTORY CENTRAL NERVOUS SYSTEM (CNS) MALIGNANCIES: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY

摘要: INTRODUCTION: Telomerase activation is critical in many cancers including CNS tumors making telomerase inhibition a potential therapeutic target. Imetelstat an oligonucleotide that binds to the template region of RNA component human and inhibits its enzymatic activity. METHODS: We conducted molecular biology (MB) phase II study estimate tumor activity sustained responses by imetelstat children with recurrent malignancies. In MB study, patients medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose as 2-hour intravenous infusion at 285 mg/m2, 12-24 hours before surgery. was evaluated TRAP assay fresh from Post-surgery IV (days 1 8 q 21-days) 285mg/m2. pharmacokinetic pharmacodynamics studies were performed during cycle 1. RESULTS: Of 2 evaluable on trial, intratumoral inhibited 95% compared baseline archival tissue patient inevaluable (medulloblastoma) due hemorrhage. Forty-two (40 for toxicity) enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, diffuse intrinsic pontine gliomas. The most common grade 3/4 toxicities included thrombocytopenia (32.5%), lymphopenia (17.5%), neutropenia (12.5%), ALT (7.5%) AST (5%) elevation. Two died hemorrhage secondary leading premature closure. median number courses trial (range 1-3). No objective observed. observed peripheral blood mononuclear cells (PBMCs) least days. CONCLUSION: demonstrated PBMC target inhibition; however, regimen proved too toxic tumors.