A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma, Medulloblastoma/Primitive Neuroectodermal Tumor and Diffuse Intrinsic Pontine Glioma
I. To test the ability of imetelstat (GRN163L) (imetelstat sodium) to inhibit telomerase
activity by telomere repeat amplification protocol (TRAP) in tumor and peripheral blood
mononuclear cells (PBMNCs) of children with recurrent or refractory
medulloblastoma/primitive neuroectodermal tumor (PNET), high grade glioma (HGG) or
ependymoma. (Molecular Biology) II. To characterize the pharmacokinetics of imetelstat in
plasma, cerebrospinal fluid (CSF), and tumor tissue of children with recurrent or refractory
HGG, medulloblastoma/PNET or ependymoma. (Molecular Biology) III. To estimate the sustained
objective response rates (complete response (CR) plus partial response (PR), sustained for
at least 6 weeks) to imetelstat administered intravenously on days 1 and 8 of a 21-day
course at the recommended Phase II pediatric dose, 285 mg/m^2, in children with recurrent or
refractory medulloblastoma/PNET, HGG, ependymoma or diffuse intrinsic brainstem glioma
(DIPG). Independent estimates of the objective response rates will be made for each of the
four strata, three of which are histologically defined. (Phase II)
I. To assess evidence of telomerase expression by detection of human telomerase reverse
transcriptase (hTERT) messenger ribonucleic acid (mRNA) and telomerase RNA component (TERC)
RNA levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and
telomerase activity by TRAP in archival tumor tissue (for medulloblastoma/PNET, HGG, and
ependymoma strata) and to explore association of telomerase positivity with objective
response and progression-free survival (PFS). (Phase II) II. To estimate the
stratum-specific PFS distributions of children with recurrent or refractory
medulloblastoma/PNET, HGG, ependymoma or DIPG treated with imetelstat. (Phase II) III. To
characterize the plasma and CSF pharmacokinetics of imetelstat in children with recurrent or
refractory medulloblastoma/PNET, HGG, ependymoma or DIPG.
IV. To assess evidence of telomerase expression by detection of hTERT mRNA and TERC RNA
levels by qRT-PCR, telomerase activity by TRAP, and telomere length by telomere terminal
restriction fragment (TRF) analysis in PBMNCs prior to treatment with imetelstat and to
assess evidence of telomerase inhibition by TRAP and telomere shortening by TRF analysis
serially on treatment with imetelstat.
V. To compare incidence of alternative lengthening of telomeres (ALT) mechanism in pediatric
medulloblastoma/PNET, HGG, or ependymoma as determined by three different assays 1)
alpha-thalassemia (ATRX)/death-associated protein (DAXX) nuclear localization by
immunofluorescence (IF) assay; 2) telomere-specific signal by fluorescence in situ
hybridization (FISH); and 3) telomeric terminal restriction fragment (TRF) analysis by
Southern blot and to assess correlation of these methods for ALT detection.
VI. To assess whether ALT status is associated with objective response rates for children
with recurrent or refractory medulloblastoma/PNET, HGG, or ependymoma treated with
VII. To describe magnetic resonance imaging (MRI) characteristics and diffusion changes of
recurrent or refractory medulloblastoma/PNET, HGG, ependymoma and DIPG tumors prior to and
after treatment with imetelstat to assess for an early diffusion indicator of response.
VIII. To measure telomere length of tumors in children with recurrent or refractory
medulloblastoma/PNET, HGG, or ependymoma and to assess association of tumor length with
tumor response to imetelstat treatment.
Patients receive imetelstat sodium intravenously (IV) over 2 hours on days 1 and 8.
Treatment repeats every 21 days for up to 2 years in the absence of disease progression or
After completion of study treatment, patients are followed up for 30 days.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Percentage of subjects with telomerase-positive archival tumors who demonstrate at least 50% reduction in telomerase activity (Molecular biology study)
Summarized and described via summary statistics and plots.
Up to 30 days
Pediatric Brain Tumor Consortium
United States: Food and Drug Administration
|Memorial Sloan-Kettering Cancer Center||New York, New York 10021|
|Duke Comprehensive Cancer Center||Durham, North Carolina 27710|
|Children's National Medical Center||Washington, District of Columbia 20010-2970|
|Children's Hospital of Pittsburgh||Pittsburgh, Pennsylvania 15213|
|Saint Jude Children's Research Hospital||Memphis, Tennessee 38105-2794|
|Cincinnati Children's Hospital Medical Center||Cincinnati, Ohio 45229-3039|
|Childrens Hospital Los Angeles||Los Angeles, California 90027|
|Lucile Packard Children's Hospital at Stanford University Medical Center||Palo Alto, California 95798|
|Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital||Houston, Texas 77030-2399|
|NCI - Pediatric Oncology Branch||Bethesda, Maryland|
|Lurie Children's Hospital- Chicago||Chicago, Illinois 60614|