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Cytochrome C Oxidase Activity in Newly Diagnosed Glioblastoma Multiforme (GBM)

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ClinicalTrials.gov Identifier: NCT02997423
Recruitment Status : Active, not recruiting
First Posted : December 20, 2016
Last Update Posted : September 27, 2018
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Corinne Griguer, University of Iowa

Brief Summary:
This is a multi-institutional, consortium-based, non-interventional prospective blinded endpoints clinical study to determine whether high activity of Cytochrome C Oxidase (CcO) in tumor specimens from subjects with newly diagnosed primary GBM is associated with shortened OS (primary outcome) and PFS (secondary outcome) times.

Condition or disease
Primary Glioblastoma Multiforme

Detailed Description:

This Biomarker trial is designed to prospectively evaluate the hypothesis that the overall survival (OS) time of a subject with newly diagnosed primary GBM tumors, treated by standard of care (SOC), is a function of the CcO enzymatic activity in the tumor (OS; time interval from date of first diagnosis to death from any cause, irrespective of post-SOC therapies, assessed up to 24 months from accrual). In particular, tumors with high CcO activity are associated with shorter OS time as compared to tumors with low CcO activity. SOC consists of post-surgical radiation therapy with concurrent Temozolomide followed by up to 12 cycles of adjuvant Temozolomide.

Additional outcomes are to study the relation between CcO activity in the GBM tumors and progression free survival times (PFS; time intervals from dates of diagnosis to documented disease progression by MRI or tumor-related death) and, to compare the prognostic abilities of CcO activity to other frequently used biomarkers, namely the methylation status of O6-methylguanine-DNA methyltransferase (MGMT), on OS and PFS.

Tumor tissue will be submitted by participating centers for measurements of the CcO/Citrate Synthase (CS), MGMT promoter methylation. The subjects will agree to receive the SOC treatment. The therapeutic option at the time of first recurrence is at the discretion of the treating physician. PFS and OS times will be compared with high vs. low CcO activity and with the MGMT methylation status of the tumor. At the time of death or at 24 months s/p enrollment (whichever comes first), the site PI will complete an exit form documenting the details of enrollees' treatment history and date(s) of any tumor progression.


Study Type : Observational
Actual Enrollment : 153 participants
Observational Model: Other
Time Perspective: Prospective
Official Title: Prospective Phase II Study of Cytochrome C Oxidase Activity as a Novel Biomarker In Subjects With Newly Diagnosed Primary Glioblastoma Multiforme
Study Start Date : November 2016
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine





Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Date of diagnosis until death from any cause, assessed up to 24 months from accrual ]

    This Biomarker trial is designed to prospectively evaluate the hypothesis that the overall survival (OS) time of a subject with newly diagnosed primary GBM tumors, treated by standard of care (SOC), is a function of the CcO enzymatic activity in the tumor. OS is defined as the time interval from date of first diagnosis to death from any cause, irrespective of post-SOC therapies, assessed up to 24 months from accrual. In particular, tumors with high CcO activity, defined as CcO/citrate synthase (CcO/CS) ratio > 4, are associated with shorter OS time as compared to tumors with low CcO activity (CcO/CS < 4). SOC consists of post-surgical radiation therapy with concurrent Temozolomide followed by up to 12 cycles of adjuvant Temozolomide.

    While on therapy, the subjects will be evaluated either in clinic or via telephone interviews at 6 months s/p enrollment and then at 3 month intervals up to 24 months or death, whichever comes first.



Other Outcome Measures:
  1. Progression Free Survival (PFS) [ Time Frame: Time from the date of diagnosis until either death from any cause or determination of disease progression, up to 24 months from accrual ]
    This Biomarker trial is also designed to prospectively evaluate the hypothesis that Progression Free survival time (PFS) is a function of the CcO enzymatic activity in the tumor. PFS is defined as time interval from date of first diagnosis to first documented progression by MRI (RANO criteria) or tumor-related death of subjects, irrespective of post-SOC therapies, assessed up to 24 months from accrual. In particular, tumors with high CcO activity, defined as CcO/citrate synthase (CcO/CS) ratio > 4, are associated with shorter PFS time as compared to tumors with low CcO activity (CcO/CS < 4).

  2. MGMT methylation status on OS and PFS [ Time Frame: Time from the date of diagnosis until either death from any cause or determination of disease progression, up to 24 months from accrual ]
    Methylation status of O6-methylguanine-DNA methyltransferase (MGMT) from tumor tissues will be assayed. Using DNA methylation patterns of the MGMT gene will be determined by chemical modification of unmethylated cytosines to uracil and subsequent PCR (polymerase chain reaction) using primers specific for either methylated or modified unmethylated DNA.


Biospecimen Retention:   Samples With DNA
Brain tissue and DNA


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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Newly diagnosed primary Glioblastoma multiforme (GBM) patients who will receive standard of care treatment.
Criteria

Inclusion Criteria

Pre-Surgery:

  1. Willingness and ability to provide written informed consent and to comply with the study protocol as judged by Physician interview (NOTE: This could be patient's Neurosurgeon, Neuro-Oncologist or Study Investigator).
  2. Age ≥ 21years
  3. Karnofsky Performance Status (KPS) ≥ 60.
  4. Subjects' planned upfront treatment to be SOC with Radiotherapy and Temozolomide (i.e. TEMODAR) for histologically confirmed GBM at initial diagnosis
  5. No history of other malignancies except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for at least 5 years.
  6. No serious active infection (e.g., wound infection requiring parenteral antibiotics) or other serious underlying medical conditions that in the opinion of the investigator would compromise standard of care treatment.
  7. No other condition (e.g., psychological or geographical) that would preclude study compliance.
  8. An MRI that is consistent with a primary malignant glioma

    Post-Surgery:

  9. Histologically confirmed newly diagnosed Primary GBM before treatment using World Health Organization (WHO) classification criteria (A local pathology report constitutes adequate documentation of histology for initial study enrollment, however central pathology review will be required to confirm the diagnosis of GBM for final data analysis).
  10. Availability of tumor tissue representative of GBM > 70 mg, snap-frozen within 30 minutes of resection, 10 minutes or less at room temperature.
  11. All subjects must have received maximal safe resection followed by standard radiation therapy with concomitant Temozolomide taken during the course of radiation therapy.

Exclusion Criteria:

  1. Inability to fulfill the requirements of the protocol
  2. Any severe post-operative infection or other complications that may significantly delay the initiation of brain tumor therapy, or other conditions that, in the opinion of the investigator, would compromise the subject's ability to participate in the study.
  3. Secondary GBM or other gliomas.
  4. History of sensitivity to Temozolomide.
  5. Planned upfront treatment with any anti-angiogenic agent targeting the (vascular endothelial growth factor (VEGF) pathway including but not limited to bevacizumab, cediranib, vandetanib, sunitinib, pazopanib, aflibercept, or sorafenib or any immunotherapy regimen.
  6. GLIADEL wafers in combination with surgical resection.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02997423


Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, California
UC Davis
Sacramento, California, United States
United States, Florida
University of Miami
Miami, Florida, United States
United States, Illinois
Northwestern University
Chicago, Illinois, United States
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 64154
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States
United States, Missouri
Washington University Medical School
Saint Louis, Missouri, United States, 63110
United States, New York
Montefiore Medical Center
Bronx, New York, United States
Columbia University Medical Center
New York, New York, United States
University of Rodchester Medical Center
Rochester, New York, United States
SUNY Stony Brook
Stony Brook, New York, United States
United States, Ohio
University of Cincinnati
Cincinnati, Ohio, United States
Ohio State University
Columbus, Ohio, United States
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States
United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States
United States, Texas
University of Texas Southwestern
Dallas, Texas, United States
United States, Utah
University of Utah
Salt Lake City, Utah, United States
United States, Washington
Swedish Neuroscience Institute
Seattle, Washington, United States, 98122
Sponsors and Collaborators
University of Iowa
National Institute of Neurological Disorders and Stroke (NINDS)

Publications:
Responsible Party: Corinne Griguer, Associate Professor, University of Iowa
ClinicalTrials.gov Identifier: NCT02997423     History of Changes
Other Study ID Numbers: NN106
U01NS093663 ( U.S. NIH Grant/Contract )
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: September 27, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Corinne Griguer, University of Iowa:
Glioblastoma Multiforme
Biomarker
Cytochrome C Oxidase
Newly diagnosed

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