TR-11: A 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

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