Glioblastoma Clinical Trial
Official title:
A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma and Diffuse Intrinsic Pontine Glioma
This molecular biology and phase II trial studies how well imetelstat sodium works in treating younger patients with recurrent or refractory brain tumors. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:
* Molecular Biology:
I. To test the ability of imetelstat (GRN163L) to inhibit telomerase activity by Telomere
Repeat Amplification Protocol (TRAP) in tumor and peripheral blood mononuclear cells (PBMNCs)
of children with recurrent or refractory HGG or ependymoma.
II. To characterize the pharmacokinetics of imetelstat in plasma, cerebrospinal fluid (CSF),
and tumor tissue of children with recurrent or refractory HGG or ependymoma.
* Phase II:
I. 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, 285mg/m2, in
children with recurrent or refractory HGG, ependymoma or DIPG. Independent estimates of the
objective response rates will be made for each of the three strata, two of which are
histologically defined.
SECONDARY OBJECTIVES:
* Phase II only:
I. To assess evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels
by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and telomerase
activity by TRAP in archival tumor tissue (for HGG, and ependymoma strata) and to explore
association of telomerase positivity with objective response and progression-free survival
(PFS).
II. To estimate the stratum-specific PFS distributions of children with recurrent or
refractory HGG, ependymoma or DIPG treated with imetelstat.
* Molecular Biology and Phase II:
I. To characterize the plasma and CSF pharmacokinetics of imetelstat in children with
recurrent or refractory HGG, ependymoma or DIPG.
II. 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.
III. To compare incidence of Alternative Lengthening of Telomeres (ALT) mechanism in
pediatric HGG, or ependymoma as determined by four different assays 1) ATRX/DAXX nuclear
localization by immunofluorescence (IF) assay; 2) telomere-specific signal by fluorescence in
situ hybridization (FISH); 3) telomeric terminal restriction fragment (TRF) analysis by
Southern blot; and 4) by C circle assay and to assess correlation of these methods for ALT
detection.
IV. To assess whether ALT status is associated with objective response rates for children
with recurrent or refractory HGG, or ependymoma treated with imetelstat.
V. To describe MRI characteristics and diffusion changes of recurrent or refractory HGG,
ependymoma and DIPG tumors prior to and after treatment with imetelstat to assess for an
early diffusion indicator of response.
VI. To measure telomere length of tumors in children with recurrent or refractory HGG, or
ependymoma and to assess association of tumor length with tumor response to imetelstat
treatment.
VII. To assess hTERT promoter mutations and methylation, H3F3A, ATRX, and DAXX mutations, and
examine the effects of these modifications in children with recurrent brain tumors using
targeted gene, exome, RNA sequencing and methylation arrays of targeted genomic regions.
OUTLINE:
Molecular Biology Phase: Patients will receive one infusion of imetelstat prior to surgery.
Surgery will take place 12-24 hours after the infusion of imetelstat. Patients will continue
to receive therapy on the same schedule as the Phase II patients starting 14-21 days after
surgery.
Phase II: Patients receive imetelstat sodium 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.
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