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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Pediatric Brain Tumor Consortium
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier:
NCT01836549
First received: April 17, 2013
Last updated: March 21, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
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 Oligodendroglioma
Recurrent Childhood Brain Stem Glioma
Drug: imetelstat sodium
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Pediatric Brain Tumor Consortium:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    Summarized and described via summary statistics and plots.

  • Stratum-specific objective response (CR+PR) rate (Phase II) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. Estimated by cumulative incidence functions.


Secondary Outcome Measures:
  • Quantitative assessments of hTERT mRNA and TERC RNA levels (Molecular biology study) [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Summarized and described via summary statistics and plots.


Estimated Enrollment: 90
Study Start Date: March 2013
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (imetelstat sodium)

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.

Drug: imetelstat sodium
Given IV
Other Names:
  • GRN163L
  • telomerase inhibitor GRN163L
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   12 Months to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  • MOLECULAR BIOLOGY STUDY

    • Tumor: Subjects must have a histologically confirmed diagnosis of 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.
  • PHASE II STUDY

    • 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 (B-D): (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 B-C. Tissue slides must be sent per Section 10.1. 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.
  • FOR BOTH MOLECULAR BIOLOGY AND PHASE II STUDIES

    • 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 4 week 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]) =< 3 x institutional ULN
    • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 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 ULN
    • 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 females
  • Age 2 to < 6 years: maximum serum creatinine (mg/mL) 0.8 for males and 0.8 for females
  • Age 6 to < 10 years: maximum serum creatinine (mg/mL) 1 for males and 1 for females
  • Age 10 to < 13 years: maximum serum creatinine (mg/mL) 1.2 for males and 1.2 for females
  • Age 13 to < 16 years: maximum serum creatinine (mg/mL) 1.5 for males and 1.4 for females
  • Age >= 16 years: maximum serum creatinine (mg/mL) 1.7 for males and 1.4 for females
  • 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 irradiation

    • 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 formulations
    • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01836549

Locations
United States, California
Childrens Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027-0700
Contact: Girish Dhall, MD    323-361-8589    gdhall@chla.usc.edu   
Lucile Packard Children's Hospital at Stanford University Medical Center Recruiting
Palo Alto, California, United States, 94304
Contact: Paul G. Fisher, MD, MHS    650-497-8953    pfisher@stanford.edu   
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010-2970
Contact: Roger J. Packer, MD    202-884-2120    rpacker@cnmc.org   
United States, Illinois
Lurie Children's Hospital- Chicago Recruiting
Chicago, Illinois, United States, 60614
Contact: Stewart Goldman, MD    773-880-4562      
United States, Maryland
NCI - Pediatric Oncology Branch Not yet recruiting
Bethesda, Maryland, United States, 20892
Contact: Katherine Warren, MD    301-435-4683      
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ira Dunkel, MD    212-639-2153    dunkeli@mskcc.org   
United States, North Carolina
Duke Comprehensive Cancer Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Sri Gururangan, MD    919-668-6288    gurur002@mc.duke.edu   
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229-3039
Contact: Clinical Trials Office - Cincinnati Children's Hospital Medica    513-636-2799      
United States, Pennsylvania
Children's Hospital of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Ian F. Pollack, MD    412-692-5881    pollaci@upmc.edu   
United States, Tennessee
Saint Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105-2794
Contact: Alberto Broniscer    901-595-4925    alberto.broniscer@stjude.org   
United States, Texas
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030-2399
Contact: Murali M. Chintagumpala, MD    832-822-4266      
Sponsors and Collaborators
Pediatric Brain Tumor Consortium
Investigators
Principal Investigator: Maryam Fouladi Pediatric Brain Tumor Consortium
  More Information

No publications provided

Responsible Party: Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier: NCT01836549     History of Changes
Other Study ID Numbers: PBTC-036, NCI-2013-00482, U01CA081457
Study First Received: April 17, 2013
Last Updated: March 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Glioma
Astrocytoma
Ependymoma
Gliosarcoma
Oligodendroglioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue

ClinicalTrials.gov processed this record on September 18, 2014