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

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.

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).