Metformin, Neo-adjuvant Temozolomide and Hypo- Accelerated Radiotherapy Followed by Adjuvant TMZ in Patients With GBM

Inclusion Criteria:

* Age: 18 years or older
* Histological confirmation of supra-tentorial GBM
* KPS \> 60
* Neurological function 0 or 1
* Adequate bone marrow as defined below:

Absolute neutrophil count (ANC) ≥ 1500 cells/mm3. Platelets ≥ 100,000 cells/mm3 Hemoglobin ≥ 10 g/dl.

* Adequate renal function, as defined below:
* Creatinine clearance of \>60 ml/min/1.73m2 (using the Cockcroft Gault equation for eGFR) within 14 days prior to study registration
* Adequate hepatic function, as defined below:
* Bilirubin of 1.7 to 18.9 umol/L within 14 days prior to study registration
* ALT ≤ 3 x normal range within 14 days prior to study registration
* Neo-adjuvant TMZ and Metformin to start within 4 weeks of surgery
* Concomitant TMZ and Metformin and accelerated Hypofractionated EBRT to start at least 2 weeks after adjuvant TMZ starting date, and no later than five weeks from surgery.
* Surgical diagnosis/intervention may include: partial or near total resection
* Patients must have recovered from the effects of surgery, postoperative infection and other complications before study registration.
* A diagnostic contrast-enhanced MRI or CT scan of the brain must be performed preoperatively and postoperatively. The postoperative scan must be done within 28 days prior to the initiation of neo-adjuvant TMZ. Preoperative and postoperative scans must be the same type. Patients unable to undergo MR imaging can be enrolled provided pre- and post-operative contrast-enhanced CT scans are obtained and are of sufficient quality.
* History/physical examination, including neurologic exam within 14 days prior to study registration.
* Documentation of steroid doses within 14 days prior to study registration and stable or decreasing steroid dose within 5 days prior to registration.
* For females of child-bearing potential, negative serum pregnancy test within 72hours prior to starting TMZ and Metformin. Women of childbearing potential and male participants must practice adequate contraception.
* Adequate tissue specimen for MGMT status analysis.
* Able to sign an informed study-specific consent

Exclusion Criteria:

* Diabetic patients both type I and type II.
* No tissue provided for MGMT promoter methylation status determination.
* Margin of contrast-enhanced residual mass closer than 15 mm from the optic chiasm or optic nerves.
* Prior invasive malignancy (except for non-melanoma skin cancer) unless disease free for ≥ 3 years
* Recurrent or multifocal GBM.
* Prior chemotherapy or radio-sensitizers for cancers of the head and neck region; prior chemotherapy for a different cancer is allowable.
* Severe, active co-morbidity, defined as follows:

  * Acute or chronic renal failure.
  * Unstable angina and/or congestive heart failure requiring hospitalization
  * Transmural myocardial infarction within the last 6 months
  * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration.
  * Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
  * Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition.
  * Major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy.
  * Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
  * Pregnant or lactating women, due to possible adverse effects on the developing foetus or infant due to study drug.
  * Prior allergic reaction to Temozolomide or Metformin.
  * Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study