Clinical Trial: Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

Brief Summary: 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.

Detailed Summary:

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.

Sponsor: Pediatric Brain Tumor Consortium

Current Primary Outcome:

  • Molecular biology study: Percentage of subjects with telomerase-positive archival tumors who demonstrate at least 50% reduction in telomerase activity [ Time Frame: Up to 30 days ]
    Summarized and described via summary statistics and plots.
  • Phase II: Stratum-specific objective response (CR+PR) rate [ Time Frame: 6 months ]
    For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. Estimated by cumulative incidence functions.


Original Primary Outcome:

  • Percentage of subjects with telomerase-positive archival tumors who demonstrate at least 50% reduction in telomerase activity (Molecular biology study) [ Time Frame: Up to 30 days ]
    Summarized and described via summary statistics and plots.
  • Stratum-specific objective response (CR+PR) rate (Phase II) [ Time Frame: 6 months ]
    For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. Estimated by cumulative incidence functions.


Current Secondary Outcome:

  • Quantitative assessments of hTERT mRNA and TERC RNA levels (Molecular biology study) [ Time Frame: Up to 30 days ]
    Summarized and described via summary statistics and plots. Descriptive statistics, plots and, if adequate data are available to make such models viable, mixed effects models and changes in telomerase activity in peripheral blood mononuclear cells (PBMNCs) longitudinally will be explored.
  • Stratum-specific progression-free survival (PFS) (Phase II) [ Time Frame: From the date of initial treatment to the earliest date of disease progression, second malignancy or death for subjects who fail; and to the date of last contact for subjects who remain at risk for failure, assessed up to 3 years ]
    Kaplan-Meier estimates of distributions of survival and PFS for all eligible subjects who received at least one dose of imetelstat will be provided separately. Similarly, Cox regression models may be used to look for associations between PK parameters and PFS separately in each stratum in the Phase II study.
  • Quantitative assessment of telomerase activity by TRAP and telomere length by Southern blot (Molecular biology and Phase II studies) [ Time Frame: Up to 30 days ]
    95% confidence intervals will be estimated. Summarized and described via summary statistics and plots.
  • ALT use by TRF analysis/Southern blot, telomere-specific FISH and localization of ATRX/DAXX (Molecular biology and Phase II studies) [ Time Frame: Up to 30 days ]
    Summarized and described via summary statistics and plots.
  • Quantitative MRI parameters of tumors prior to and after treatment with imetelstat (Molecular biology and Phase II studies) [ Time Frame: Up to 30 days ]
    Summarized and described via summary statistics and plots.


Original Secondary Outcome: Same as current

Information By: Pediatric Brain Tumor Consortium

Dates:
Date Received: April 17, 2013
Date Started: March 2013
Date Completion:
Last Updated: April 8, 2016
Last Verified: April 2016