title: 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.
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.
authors.affiliation: Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Salloum
authors.affiliation: Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
authors.forename: Trent R
authors.initials: TR
authors.lastname: Hummel
authors.affiliation: Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
authors.forename: Shiva Senthil
authors.initials: SS
authors.lastname: Kumar
authors.affiliation: Children's Hospital Colorado, Aurora, CO, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Dorris
authors.affiliation: University of North Carolina, Charlotte, NC, USA.
authors.forename: Shaoyu
authors.initials: S
authors.lastname: Li
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Lin
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Vinay M
authors.initials: VM
authors.lastname: Daryani
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.affiliation: Nemours Children's Hospital, Orlando, FL, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Miles
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Tina Young
authors.initials: TY
authors.lastname: Poussaint
authors.affiliation: Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Stevenson
authors.affiliation: Anne and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.affiliation: Children's Hospital of Los Angeles, Los Angeles, CA, USA.
authors.forename: Girish
authors.initials: G
authors.lastname: Dhall
authors.affiliation: Children's National Medical Center, Washington, DC, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Packer
authors.affiliation: Lucile Packard Children's Hospital Stanford, Palo Alto, CA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Fisher
authors.affiliation: Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.affiliation: Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: James
authors.initials: J
authors.lastname: Boyett
authors.affiliation: Brain Tumor Center, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Ave, Cincinnati, OH, 45229, USA. rachid.drissi@cchmc.org.
authors.forename: Rachid
authors.identifier: 0000-0003-0564-0181
authors.initials: R
authors.lastname: Drissi
mesh_terms: D000293:Adolescent; D000410:Alanine Transaminase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001772:Blood Cell Count; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000601:surgery; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009841:Oligonucleotides; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D000410:Alanine Transaminase; D019098:Telomerase; C519562:imetelstat
keywords: Imetelstat; Pediatric brain tumors; Phase 2 trial; Telomerase; Telomerase inhibition