Clinical trial NCT02997423: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Glioblastoma
Keywords: Glioblastoma Multiforme
Biomarker
Cytochrome C Oxidase
Newly diagnosed
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: NeuroNEXT Network
First posted: 2016-12-20
Enrollment: 153
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Newly diagnosed primary Glioblastoma multiforme (GBM) patients who will receive standard of care treatment.

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.

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).

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Date of diagnosis through 24 months after enrollment
Secondary outcomes:
Other outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Date of diagnosis through 48 months after enrollment
measure: MGMT methylation status on OS and PFS
timeFrame: Date of diagnosis through 24 months after enrollment
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Sacramento
country: United States
facility: UC Davis
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University Medical School
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Swedish Neuroscience Institute
state: Washington
Study officials:
affiliation: University of Iowa
name: Corinne E Griguer, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: Griguer CE, Oliva CR, Coffey CS, Cudkowicz ME, Conwit RA, Gudjonsdottir AL, Ecklund DJ, Fedler JK, Neill-Hudson TM, Nabors LB, Benge M, Hackney JR, Chase M, Leonard TP, Patel T, Colman H, de la Fuente M, Chaudhary R, Marder K, Kreisl T, Mohile N, Chheda MG, McNeill K, Kumthekar P, Dogan A, Drappatz J, Puduvalli V, Kowalska A, Graber J, Gerstner E, Clark S, Salacz M, Markert J. Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial. Neurooncol Adv. 2021 Dec 24;4(1):vdab186. doi: 10.1093/noajnl/vdab186. eCollection 2022 Jan-Dec.