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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

Phase 2
12 Months
21 Years
Open (Enrolling)
Recurrent Childhood Anaplastic Astrocytoma, Recurrent Childhood Anaplastic Ependymoma, Recurrent Childhood Diffuse Astrocytoma, Recurrent Childhood Ependymoma, Recurrent Childhood Giant Cell Glioblastoma, Recurrent Childhood Glioblastoma, Recurrent Childhood Gliosarcoma, Recurrent Childhood Medulloblastoma, Recurrent Childhood Oligodendroglioma, Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor (PNET), Recurrent Childhood Brain Stem Glioma

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Trial Information

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
unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:


- Tumor: Subjects must have a histologically confirmed diagnosis of
medulloblastoma/PNET, ependymoma or HGG (such as anaplastic astrocytoma,
glioblastoma, gliosarcoma, or anaplastic oligodendroglioma) that is recurrent or
refractory to conventional therapy

- Subjects must have clinical indications for surgical resection and be amenable to
receiving imetelstat prior to tumor resection; subjects who require emergent surgery
are not eligible for the Molecular Biology study

- Subjects must provide, fresh flash frozen tumor samples (target 50 mg tissue; as low
as 20 mg is adequate) from the time of diagnosis or previous recurrence for the
assessment of tumor telomerase activity by the TRAP assay


- Tumor: Subjects must have recurrent or refractory disease with a histological
diagnosis from either the initial presentation or at the time of recurrence; the
requirement for histologic verification is waived for subjects with DIPG (stratum D);
the following diagnoses are eligible and will be treated in separate strata (A-D): A)
Recurrent or refractory medulloblastoma/PNET; B) Recurrent or refractory high-grade
glioma, (such as anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma,
anaplastic oligodendroglioma); C) Recurrent or refractory ependymoma; D) Recurrent or
refractory DIPG (diagnosis by imaging characteristics acceptable; no histologic
confirmation required)

- Slides from either initial diagnosis or relapse must be available for central
pathology review for Strata A-C; tissue slides must be sent; if tissue slides are
unavailable, the study chair must be notified prior to study enrollment

- All subjects must have bi-dimensionally measurable disease in the brain and/or spine,
defined as at least one lesion that can be accurately measured in at least two planes
in order to be eligible for this study.; subjects who are enrolled on the Molecular
Biology trial and who have measurable disease after the surgical resection and meet
all other eligibility criteria for the Phase II study will be counted towards the
accrual of the Phase II study


- Subjects with neurological deficits should have deficits that are stable for a
minimum of one (1) week prior to registration; a baseline detailed neurological exam
should clearly document the neurological status of the subject at the time of
registration on the study

- Karnofsky >= 50% for > 16 years of age; Lansky >= 50% for children < 16 years of age
documented within 14 days of study registration and within 7 days of the start of
study drug administration

- Hemoglobin >= 8 g/dL (may receive blood transfusions)

- Absolute neutrophil count > 1,000/ul

- Platelet count >= 100,000/ul (transfusion independent defined as no platelet
transfusions with a 7-day period prior to enrollment)

- Serum bilirubin < 2.0 mg/dL (patients with Gilbert syndrome, serum bilirubin < 3.0 x
upper limit of normal [ULN])

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 x institutional ULN

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5
x institutional ULN

- Alkaline phosphatase < 2.5 x institutional ULN

- Albumin >= 2 g/dL

- Adequate coagulation defined as activated partial thromboplastin time (aPTT) < 1.2 x

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

- Age 1 to < 2 years: maximum serum creatinine (mg/mL) 0.6 for males and 0.6 for

- Age 2 to < 6 years: maximum serum creatinine (mg/mL) 0.8 for males and 0.8 for

- Age 6 to < 10 years: maximum serum creatinine (mg/mL) 1 for males and 1 for

- Age 10 to < 13 years: maximum serum creatinine (mg/mL) 1.2 for males and 1.2 for

- Age 13 to < 16 years: maximum serum creatinine (mg/mL) 1.5 for males and 1.4 for

- Age >= 16 years: maximum serum creatinine (mg/mL) 1.7 for males and 1.4 for

- The threshold creatinine values were derived from the Schwartz formula for
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length
and stature data published by the Centers for Disease and Control (CDC)

- Subjects on systemic anticoagulants are excluded from this study as the drug can
cause minor, transient changes in aPTT

- Female subjects of childbearing potential must not be pregnant or breast-feeding;
female subjects of childbearing potential must have a negative serum or urine
pregnancy test; (pregnancy test must be repeated within 48 hours prior to the start
of therapy)

- Subjects of childbearing or child fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while being
treated on this study

- Subjects must have recovered from the acute toxicities of all prior therapy before
entering this study; for those acute baseline adverse events attributable to prior
therapy, recovery is defined as a toxicity grade =< 2, using Common Terminology
Criteria for Adverse Events (CTCAE) v.4.0, unless otherwise specified in the
Inclusion and Exclusion Criteria

- Subjects must have received their last dose of known myelosuppressive anticancer
chemotherapy at least three (3) weeks prior to study registration or at least six (6)
weeks if nitrosourea

- Subjects must have received their last dose of investigational or biologic agent >= 7
days prior to study registration; in the event that a subject has received an
investigational or biologic agent and has experienced >= grade 2 myelosuppression,
then at least three (3) weeks must have elapsed prior to registration; if the
investigational or biologic agent has a prolonged half-life (>= 7 days) then at least
three (3) weeks must have elapsed prior to registration

- Subjects must have completed at least 3 half-life periods from the last dose of
monoclonal antibody prior to registration; Note: A list of half-lives of commonly
used monoclonal antibodies is available on the Pediatric Brain Tumor Consortium
(PBTC) website under Generic Forms and Templates

- Subjects must have received their last dose of radiation (XRT):

- 2 weeks prior to study registration for local palliative XRT (small volume)

- 3 months prior to study registration for craniospinal XRT

- 6 weeks (wks) prior to study registration for other substantial bone marrow

- Subject must be >= 3 months since autologous bone marrow/stem cell transplantation
prior to registration

- Subjects who are receiving a corticosteroid, such as dexamethasone, must be on a
stable or decreasing dosage for at least 1 week prior to registration

- At least 7 days since the completion of therapy with a hematopoietic growth agent
(filgrastim, sargramostim, and erythropoietin) and 14 days for long-acting

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Subjects must not be receiving any other investigational agents

- Subjects with inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to imetelstat

- Known coagulopathy or bleeding diathesis

- Subjects with imaging evidence of CNS hemorrhage on baseline MRI obtained within 14
days prior to study enrollment are not eligible; Note: The presence of small punctate
areas consistent with hemorrhage will not exclude subjects from participation

- Use of systemic anticoagulant medications

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
serious infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, cirrhosis or psychiatric illness/social situations that would
limit compliance with study requirements

- Pregnant women are excluded from this study because imetelstat is an investigational
agent with unknown potential for teratogenic or abortifacient effects; because there
is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with imetelstat, breastfeeding should be discontinued if the
mother is treated with imetelstat; these potential risks may also apply to other
agents used in this study

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Percentage of subjects with telomerase-positive archival tumors who demonstrate at least 50% reduction in telomerase activity (Molecular biology study)

Outcome Description:

Summarized and described via summary statistics and plots.

Outcome Time Frame:

Up to 30 days

Safety Issue:


Principal Investigator

Maryam Fouladi

Investigator Role:

Principal Investigator

Investigator Affiliation:

Pediatric Brain Tumor Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

March 2013

Completion Date:

Related Keywords:

  • Recurrent Childhood Anaplastic Astrocytoma
  • Recurrent Childhood Anaplastic Ependymoma
  • Recurrent Childhood Diffuse Astrocytoma
  • Recurrent Childhood Ependymoma
  • Recurrent Childhood Giant Cell Glioblastoma
  • Recurrent Childhood Glioblastoma
  • Recurrent Childhood Gliosarcoma
  • Recurrent Childhood Medulloblastoma
  • Recurrent Childhood Oligodendroglioma
  • Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor (PNET)
  • Recurrent Childhood Brain Stem Glioma
  • Astrocytoma
  • Ependymoma
  • Glioblastoma
  • Glioma
  • Medulloblastoma
  • Oligodendroglioma
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Gliosarcoma



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