Journal of Neuro-Oncology

, Volume 129, Issue 3, pp 443–451

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

  • 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
Clinical Study

DOI: 10.1007/s11060-016-2189-7

Cite this article as:
Salloum, R., Hummel, T.R., Kumar, S.S. et al. J Neurooncol (2016) 129: 443. doi:10.1007/s11060-016-2189-7

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.

Keywords

Telomerase Telomerase inhibition Imetelstat Pediatric brain tumors Phase 2 trial 

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ralph Salloum
    • 1
  • Trent R. Hummel
    • 1
  • Shiva Senthil Kumar
    • 1
  • Kathleen Dorris
    • 2
  • Shaoyu Li
    • 3
  • Tong Lin
    • 4
  • Vinay M. Daryani
    • 4
  • Clinton F. Stewart
    • 4
  • Lili Miles
    • 5
  • Tina Young Poussaint
    • 6
  • Charles Stevenson
    • 1
  • Stewart Goldman
    • 7
  • Girish Dhall
    • 8
  • Roger Packer
    • 9
  • Paul Fisher
    • 10
  • Ian F. Pollack
    • 11
  • Maryam Fouladi
    • 1
  • James Boyett
    • 4
  • Rachid Drissi
    • 1
  1. 1.Brain Tumor Center, Cancer and Blood Diseases InstituteCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  2. 2.Children’s Hospital ColoradoAuroraUSA
  3. 3.University of North CarolinaCharlotteUSA
  4. 4.St Jude Children’s Research HospitalMemphisUSA
  5. 5.Nemours Children’s HospitalOrlandoUSA
  6. 6.Boston Children’s HospitalBostonUSA
  7. 7.Anne and Robert H. Lurie Children’s Hospital of ChicagoChicagoUSA
  8. 8.Children’s Hospital of Los AngelesLos AngelesUSA
  9. 9.Children’s National Medical CenterWashingtonUSA
  10. 10.Lucile Packard Children’s Hospital StanfordPalo AltoUSA
  11. 11.Children’s Hospital of PittsburghPittsburghUSA