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

• ClinicalTrials.gov Identifier: NCT02997423
• Recruitment Status: Active, not recruiting
• First Posted: December 20, 2016
• Last Update Posted: March 20, 2019
• Sponsor: Corinne Griguer
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); NeuroNEXT Network
• Information provided by (Responsible Party): Corinne Griguer, University of Iowa

Tracking Information

• First Submitted Date: December 9, 2016
• First Posted Date: December 20, 2016
• Last Update Posted Date: March 20, 2019
• Actual Study Start Date: November 30, 2016
• Estimated Primary Completion Date: November 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 18, 2019)

Overall Survival (OS) [ Time Frame: Date of diagnosis through 24 months after enrollment ]

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.

Original Primary Outcome Measures (submitted: December 15, 2016)

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.

• Change History: Complete list of historical versions of study NCT02997423 on ClinicalTrials.gov Archive Site
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: March 18, 2019)

• Progression Free Survival (PFS) [ Time Frame: Date of diagnosis through 48 months after enrollment ]
  This biomarker trial is 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 surgery to first documented progression according to the RANO criteria, irrespective of post-SOC therapies.
• MGMT methylation status on OS and PFS [ Time Frame: Date of diagnosis through 24 months after enrollment ]
  Compare the prognostic abilities of CcO activity to another frequently used biomarker, the methylation status of O6-methylguanine-DNA methyltransferase (MGMT) on OS and PFS times.

Original Other Pre-specified Outcome Measures (submitted: December 15, 2016)

• 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).
• 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.

Descriptive Information

• Brief Title: Cytochrome C Oxidase Activity in Newly Diagnosed Glioblastoma Multiforme (GBM)
• Official Title: Prospective Phase II Study of Cytochrome C Oxidase Activity as a Novel Biomarker In Subjects With Newly Diagnosed Primary Glioblastoma Multiforme
• 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.

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
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Tumor tissue and DNA

• Sampling Method: Non-Probability Sample
• Study Population: Newly diagnosed primary Glioblastoma multiforme (GBM) patients who will receive standard of care treatment.
• Condition: Glioblastoma
• Intervention: Not Provided
• Study Groups/Cohorts: Not Provided

Publications *

• Vogelbaum MA, Jost S, Aghi MK, Heimberger AB, Sampson JH, Wen PY, Macdonald DR, Van den Bent MJ, Chang SM. Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. Neurosurgery. 2012 Jan;70(1):234-43; discussion 243-4. doi: 10.1227/NEU.0b013e318223f5a7. Review.
• Galanis E, Wu W, Cloughesy T, Lamborn K, Mann B, Wen PY, Reardon DA, Wick W, Macdonald D, Armstrong TS, Weller M, Vogelbaum M, Colman H, Sargent DJ, van den Bent MJ, Gilbert M, Chang S. Phase 2 trial design in neuro-oncology revisited: a report from the RANO group. Lancet Oncol. 2012 May;13(5):e196-204. doi: 10.1016/S1470-2045(11)70406-5. Review.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 15, 2018): 153
• Original Estimated Enrollment (submitted: December 15, 2016): 200
• Estimated Study Completion Date: November 30, 2022
• Estimated Primary Completion Date: November 30, 2020 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02997423
• Other Study ID Numbers: NN106; U01NS093663 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

The requestor must submit a formal written request for data sharing, and the request must be approved by the NeuroNEXT Steering Committee and the Publication Committee before any data are shared. Prior to data sharing, the DCC and the external source must also execute a data sharing agreement that includes a description of the data that are requested and how the data will be shared. A contract / usage agreement may be required.

The DCC will submit de-identified datasets and associated documentation to NINDS for archiving and public access, consistent with the current NINDS Data Sharing policy. The DCC will provide documentation with each final dataset to ensure that other users can efficiently and accurately use the dataset, and to prevent misinterpretation or misuse. This documentation may include information about how the data were collected, provide details about the code used to generate the dataset, and define variables and variable field locations.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Analytic Code
• Time Frame: Upon request.
• Access Criteria: Written request to principal investigator.

• Responsible Party: Corinne Griguer, University of Iowa
• Study Sponsor: Corinne Griguer

Collaborators

• National Institute of Neurological Disorders and Stroke (NINDS)
• NeuroNEXT Network

Investigators

• Principal Investigator: Corinne E Griguer, PhD; University of Iowa

• PRS Account: University of Iowa
• Verification Date: March 2019