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
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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.
KeywordsTelomerase Telomerase inhibition Imetelstat Pediatric brain tumors Phase 2 trial
We acknowledge the outstanding clinical research support of Christopher Smith and Emily Carps and the regulatory support of Dr. Renee Doughman. This work was supported in part by Cincinnati Children’s Basic Science Research and the Clinical Translational, Outcomes and Health Services Redesign grant (R.D.), National Institute of Health Grant U01 CA81457 for the Pediatric Brain Tumor Consortium (M.F. and J.B.) and American Lebanese Syrian Associated Charities.
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Conflict of interest
- 5.Barszczyk M, Buczkowicz P, Castelo-Branco P, Mack SC, Ramaswamy V, Mangerel J, Agnihotri S, Remke M, Golbourn B, Pajovic S, Elizabeth C, Yu M, Luu B, Morrison A, Adamski J, Nethery-Brokx K, Li XN, Van Meter T, Dirks PB, Rutka JT, Taylor MD, Tabori U, Hawkins C (2014) Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells. Acta Neuropathol (Berl) 128(6):863–877. doi: 10.1007/s00401-014-1327-6 CrossRefGoogle Scholar
- 6.Ridley L, Rahman R, Brundler MA, Ellison D, Lowe J, Robson K, Prebble E, Luckett I, Gilbertson RJ, Parkes S, Rand V, Coyle B, Grundy RG, Children’s C Leukaemia group biological studies C (2008) Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma. Neuro-Oncol 10(5):675–689. doi: 10.1215/15228517-2008-036 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Dorris K, Sobo M, Onar-Thomas A, Panditharatna E, Stevenson CB, Gardner SL, Dewire MD, Pierson CR, Olshefski R, Rempel SA, Goldman S, Miles L, Fouladi M, Drissi R (2014) Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas. J Neurooncol 117(1):67–76. doi: 10.1007/s11060-014-1374-9 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Marian CO, Cho SK, McEllin BM, Maher EA, Hatanpaa KJ, Madden CJ, Mickey BE, Wright WE, Shay JW, Bachoo RM (2010) The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. Clin Cancer Res 16(1):154–163. doi: 10.1158/1078-0432.CCR-09-2850 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Gryaznov SM, Jackson S, Dikmen G, Harley C, Herbert BS, Wright WE, Shay JW (2007) Oligonucleotide conjugate GRN163L targeting human telomerase as potential anticancer and antimetastatic agent. Nucleosides Nucleotides Nucleic Acids 26(10–12):1577–1579. doi: 10.1080/15257770701547271 CrossRefPubMedGoogle Scholar
- 13.Ferrandon S, Malleval C, El Hamdani B, Battiston-Montagne P, Bolbos R, Langlois JB, Manas P, Gryaznov SM, Alphonse G, Honnorat J, Rodriguez-Lafrasse C, Poncet D (2015) Telomerase inhibition improves tumor response to radiotherapy in a murine orthotopic model of human glioblastoma. Mol Cancer 14:134. doi: 10.1186/s12943-015-0376-3 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, Laborde RR, Wassie E, Schimek L, Hanson CA, Gangat N, Wang X, Pardanani A (2015) A pilot study of the telomerase inhibitor imetelstat for myelofibrosis. N Engl J Med 373(10):908–919. doi: 10.1056/NEJMoa1310523 CrossRefPubMedGoogle Scholar
- 15.Baerlocher GM, Oppliger Leibundgut E, Ottmann OG, Spitzer G, Odenike O, McDevitt MA, Roth A, Daskalakis M, Burington B, Stuart M, Snyder DS (2015) Telomerase inhibitor imetelstat in patients with essential thrombocythemia. N Engl J Med 373(10):920–928. doi: 10.1056/NEJMoa1503479 CrossRefPubMedGoogle Scholar
- 16.Thompson PA, Drissi R, Muscal JA, Panditharatna E, Fouladi M, Ingle AM, Ahern CH, Reid JM, Lin T, Weigel BJ, Blaney SM (2013) A phase I trial of imetelstat in children with refractory or recurrent solid tumors: a children’s oncology group phase I consortium study (ADVL1112). Clin Cancer Res 19(23):6578–6584. doi: 10.1158/1078-0432.CCR-13-1117 CrossRefPubMedPubMedCentralGoogle Scholar