- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01836549
Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
A Molecular Biology and Phase II Study of Imetelstat (GRN163L) in Children With Recurrent High-Grade Glioma, Ependymoma and Diffuse Intrinsic Pontine Glioma
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
California
-
Los Angeles, California, United States, 90027-0700
- Childrens Hospital Los Angeles
-
Palo Alto, California, United States, 94304
- Lucile Packard Children's Hospital at Stanford University Medical Center
-
-
District of Columbia
-
Washington, District of Columbia, United States, 20010-2970
- Children's National Medical Center
-
-
Illinois
-
Chicago, Illinois, United States, 60614
- Lurie Children's Hospital- Chicago
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- NCI - Pediatric Oncology Branch
-
-
New York
-
New York, New York, United States, 10065
- Memorial Sloan-Kettering Cancer Center
-
-
North Carolina
-
Durham, North Carolina, United States, 27710
- Duke Comprehensive Cancer Center
-
-
Ohio
-
Cincinnati, Ohio, United States, 45229-3039
- Cincinnati Children's Hospital Medical Center
-
-
Pennsylvania
-
Pittsburgh, Pennsylvania, United States, 15213
- Children's Hospital of Pittsburgh
-
-
Tennessee
-
Memphis, Tennessee, United States, 38105-2794
- Saint Jude Children's Research Hospital
-
-
Texas
-
Houston, Texas, United States, 77030-2399
- Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
INCLUSION CRITERIA:
MOLECULAR BIOLOGY STUDY
- Tumor: Histologically confirmed Dx 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 Dx 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 Dx 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 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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. |
Given IV
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Numver of Patients With Telomerase-positive Archival Tumors Who Demonstrate at Least 50% Reduction
Time Frame: Up to 30 days
|
This outcome measure is for the Molecular biology study only.
The assessment was done to identify cases with at least 50% reduction in telomerase activity.
|
Up to 30 days
|
Phase II: Stratum-specific Objective Response (CR+PR) Rate
Time Frame: 6 months
|
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=50% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR sustained for at least 6 weeks. For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. Estimated by cumulative incidence functions. |
6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Telomerase Inhibition
Time Frame: Up to 30 days
|
This outcome measure is applicable only for the Molecular biology study arm.
Telomerase inhibition was assessed in PBMCs and summarised as 'yes-inhibited' vs. 'no inhibition'
|
Up to 30 days
|
Stratum-specific Progression-free Survival (PFS) (Phase II)
Time Frame: Up to 2 years, 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.
|
Up to 2 years, 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
|
Number of Patients With Telomerase Expression Data by Detection of hTERT mRNA and TERC RNA Levels by qRT-PCR and Telomerase Activity by TRAP in Archival Tumor Tissue and to Explore Association of Telomerase Positivity With Objective Response and PFS
Time Frame: Up to 30 days. Due to small number of patients evaluable for this objective, we can only provide number of patients with the targetted markers as no analysis with PFS is possible.
|
This secondary objective is for Stratum-B and C only, which enroll HGG and ependymoma patients.
We will describe the evidence of telomerase expression by detection of hTERT mRNA and TERC RNA levels by qRT-PCR and telomerase activity by TRAP in archival tumor tissue; Association of telomerase positivity with objective response and PFS will not be able to be conducted as the study was terminated early and there was no objective response.
|
Up to 30 days. Due to small number of patients evaluable for this objective, we can only provide number of patients with the targetted markers as no analysis with PFS is possible.
|
Quantitative MRI Parameters of Tumors Prior to and After Treatment With Imetelstat (Molecular Biology and Phase II Studies)
Time Frame: Up to 30 days
|
This outcome measure was for both Molecular biology and Phase II studies.
We will not be able to present the results of this objective as the study was terminated early.
|
Up to 30 days
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Maryam Fouladi, Pediatric Brain Tumor Consortium
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Neoplasms, Glandular and Epithelial
- Glioma
- Neoplasms, Neuroepithelial
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Brain Neoplasms
- Central Nervous System Neoplasms
- Nervous System Neoplasms
- Infratentorial Neoplasms
- Glioblastoma
- Ependymoma
- Astrocytoma
- Gliosarcoma
- Oligodendroglioma
- Brain Stem Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Protein Kinase Inhibitors
- Imetelstat
- Motesanib diphosphate
Other Study ID Numbers
- PBTC-036
- U01CA081457 (U.S. NIH Grant/Contract)
- NCI-2013-00482 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Glioblastoma
-
Celldex TherapeuticsCompletedGlioblastoma | Gliosarcoma | Recurrent Glioblastoma | Small Cell Glioblastoma | Giant Cell Glioblastoma | Glioblastoma With Oligodendroglial Component | Relapsed GlioblastomaUnited States
-
Juan M Garcia-GomezHospital Universitario 12 de Octubre; Hospital Clínico Universitario de ValenciaRecruitingGlioblastoma | Glioblastoma Multiforme | High Grade Glioma | Astrocytoma, Grade IV | Glioblastoma, IDH-mutant | Glioblastoma, IDH-wildtype | Glioblastoma IDH (Isocitrate Dehydrogenase) Wildtype | Glioblastoma IDH (Isocitrate Dehydrogenase) MutantSpain
-
Jasper GerritsenMassachusetts General Hospital; Universitaire Ziekenhuizen KU Leuven; University... and other collaboratorsRecruitingGlioblastoma | Glioblastoma Multiforme | Glioblastoma, IDH-wildtype | Glioblastoma Multiforme, Adult | Glioblastoma Multiforme of BrainUnited States, Belgium, Switzerland, Germany, Netherlands
-
Jasper GerritsenMassachusetts General Hospital; Universitaire Ziekenhuizen KU Leuven; University... and other collaboratorsRecruitingGlioblastoma | Glioblastoma Multiforme | Recurrent Glioblastoma | Glioblastoma, IDH-wildtype | Glioblastoma Multiforme, Adult | Glioblastoma Multiforme of Brain | Astrocytoma of Brain | Astrocytoma, MalignantUnited States, Germany, Netherlands, Switzerland, Belgium
-
Leland MethenyNational Cancer Institute (NCI)RecruitingGlioblastoma Multiforme | Supratentorial Gliosarcoma | Glioblastoma Multiforme, Adult | Supratentorial GlioblastomaUnited States
-
Northwestern UniversityAgenus Inc.; CarTheraRecruitingGlioblastoma Multiforme | Gliosarcoma | Newly Diagnosed Glioblastoma | Glioblastoma, Isocitric Dehydrogenase (IDH)-WildtypeUnited States
-
University Hospital, GenevaActive, not recruitingGlioblastoma Multiforme | Glioblastoma Multiforme of Brain | Glioma of Brain | Glioblastoma, AdultSwitzerland
-
Milton S. Hershey Medical CenterRecruitingGlioblastoma | Glioblastoma Multiforme | Glioblastoma Multiforme, Adult | Glioblastoma Multiforme of BrainUnited States
-
Northwestern UniversityNational Cancer Institute (NCI)RecruitingGlioblastoma | Astrocytoma | Recurrent Glioblastoma | MGMT-Unmethylated Glioblastoma | Glioblastoma, IDH-WildtypeUnited States
-
Milton S. Hershey Medical CenterNational Cancer Institute (NCI)RecruitingGlioblastoma | Glioblastoma Multiforme | Glioblastoma Multiforme, Adult | Glioblastoma Multiforme of BrainUnited States
Clinical Trials on imetelstat sodium
-
Geron CorporationCompletedMultiple MyelomaUnited States
-
Geron CorporationCompletedSolid Tumor MalignanciesUnited States
-
Children's Oncology GroupNational Cancer Institute (NCI)WithdrawnRhabdomyosarcoma | Recurrent Neuroblastoma | Recurrent Osteosarcoma | Hepatoblastoma | Recurrent Childhood Rhabdomyosarcoma | Previously Treated Childhood Rhabdomyosarcoma | Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Recurrent Childhood Liver Cancer
-
Geron CorporationCompleted
-
Children's Oncology GroupNational Cancer Institute (NCI)CompletedLymphoma | Unspecified Childhood Solid Tumor, Protocol Specific | Small Intestine Cancer | Brain and Central Nervous System Tumors | Lymphoproliferative DisorderUnited States, Canada
-
Indiana UniversityBreast Cancer Research Foundation; Geron CorporationCompletedBreast NeoplasmsUnited States
-
Geron CorporationCompletedMultiple MyelomaUnited States
-
Geron CorporationCompletedMyelofibrosisUnited States, France, Italy, United Kingdom, Belgium, Germany, Taiwan, Spain, Israel, Korea, Republic of, Canada
-
Geron CorporationCompletedLocally Recurrent or Metastatic Breast CancerUnited States, Canada
-
Geron CorporationCompletedNon-small Cell Lung CancerUnited States, Canada, Germany