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.
Brief Title
Cytochrome C Oxidase Activity in Newly Diagnosed Glioblastoma Multiforme (GBM)
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Glioblastoma
Eligibility Criteria
Inclusion Criteria
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). If patient lacks capacity to consent, a legally authorized representative is allowed to provide written informed consent.
2. Age ≥ 21 years
3. Karnofsky Performance Status (KPS) ≥ 60.
4. Subjects' planned upfront treatment to be standard of care treatment 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
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. Viability 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:
Exclusion criteria are proposed that will exclude subjects with pre-existing co-morbidities that could contribute to pre-mature death (e.g., significant cardiovascular history), with non-included pretreated tumors occupying either intracranial and extra-axial space, significantly impaired neurological performance status (e.g., KPS\>60), with glial tumors that are genomically distinct from primary GBM tumors (e.g., gliomas arising from a previously diagnosed lower grade than GBM) or those unable to complete the fundamental requirements of the study.
1. Inability to fulfill the requirements of the protocol
2. Secondary GBM or other gliomas.
3. History of sensitivity to Temozolomide.
4. 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.
5. 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.
Note: Use of Gliadel wafers, in combination with surgical resection, is allowed if the patient is to follow standard-of-care treatment post-operatively (i.e., radiation therapy with temozolomide). Use of Gliadel wafers during surgery with only radiation therapy post-operatively is excluded (i.e., omitting temozolomide).
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). If patient lacks capacity to consent, a legally authorized representative is allowed to provide written informed consent.
2. Age ≥ 21 years
3. Karnofsky Performance Status (KPS) ≥ 60.
4. Subjects' planned upfront treatment to be standard of care treatment 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
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. Viability 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:
Exclusion criteria are proposed that will exclude subjects with pre-existing co-morbidities that could contribute to pre-mature death (e.g., significant cardiovascular history), with non-included pretreated tumors occupying either intracranial and extra-axial space, significantly impaired neurological performance status (e.g., KPS\>60), with glial tumors that are genomically distinct from primary GBM tumors (e.g., gliomas arising from a previously diagnosed lower grade than GBM) or those unable to complete the fundamental requirements of the study.
1. Inability to fulfill the requirements of the protocol
2. Secondary GBM or other gliomas.
3. History of sensitivity to Temozolomide.
4. 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.
5. 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.
Note: Use of Gliadel wafers, in combination with surgical resection, is allowed if the patient is to follow standard-of-care treatment post-operatively (i.e., radiation therapy with temozolomide). Use of Gliadel wafers during surgery with only radiation therapy post-operatively is excluded (i.e., omitting temozolomide).
Inclusion Criteria
Inclusion Criteria
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). If patient lacks capacity to consent, a legally authorized representative is allowed to provide written informed consent.
2. Age ≥ 21 years
3. Karnofsky Performance Status (KPS) ≥ 60.
4. Subjects' planned upfront treatment to be standard of care treatment 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
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. Viability 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.
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). If patient lacks capacity to consent, a legally authorized representative is allowed to provide written informed consent.
2. Age ≥ 21 years
3. Karnofsky Performance Status (KPS) ≥ 60.
4. Subjects' planned upfront treatment to be standard of care treatment 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
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. Viability 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.
Gender
All
Gender Based
false
Keywords
Glioblastoma Multiforme
Biomarker
Cytochrome C Oxidase
Newly diagnosed
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
21 Years
NCT Id
NCT02997423
Org Class
Other
Org Full Name
University of Iowa
Org Study Id
NN106
Overall Status
Completed
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Prospective Phase II Study of Cytochrome C Oxidase Activity as a Novel Biomarker In Subjects With Newly Diagnosed Primary Glioblastoma Multiforme
Primary Outcomes
Outcome 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 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.
Outcome Measure
Overall Survival (OS)
Outcome Time Frame
Date of diagnosis through 24 months after enrollment
Secondary Ids
Secondary Id
U01NS093663
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Study Population
Newly diagnosed primary Glioblastoma multiforme (GBM) patients who will receive standard of care treatment.
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
21
Investigators
Investigator Type
Principal Investigator
Investigator Name
Katharine Mcneill
Investigator Email
kmcneill@montefiore.org
Investigator Phone