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 foreGFR) 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 atleast 2 weeks after adjuvant TMZ starting date, and no later than five weeks fromsurgery.

• Surgical diagnosis/intervention may include: partial or near total resection

• Patients must have recovered from the effects of surgery, postoperative infectionand other complications before study registration.

• A diagnostic contrast-enhanced MRI or CT scan of the brain must be performedpreoperatively and postoperatively. The postoperative scan must be done within 28days prior to the initiation of neo-adjuvant TMZ. Preoperative and postoperativescans must be the same type. Patients unable to undergo MR imaging can be enrolledprovided pre- and post-operative contrast-enhanced CT scans are obtained and are ofsufficient quality.

• History/physical examination, including neurologic exam within 14 days prior tostudy registration.

• Documentation of steroid doses within 14 days prior to study registration and stableor decreasing steroid dose within 5 days prior to registration.

• For females of child-bearing potential, negative serum pregnancy test within 72hoursprior to starting TMZ and Metformin. Women of childbearing potential and maleparticipants 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 oroptic nerves.

• Prior invasive malignancy (except for non-melanoma skin cancer) unless disease freefor ≥ 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 thetime of registration.

• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illnessrequiring hospitalization or precluding study therapy at the time ofregistration

• Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition.

• Major medical illnesses or psychiatric impairments that in the investigator'sopinion will prevent administration or completion of protocol therapy.

• Pregnancy or women of childbearing potential and men who are sexually activeand not willing/able to use medically acceptable forms of contraception; thisexclusion is necessary because the treatment involved in this study may besignificantly teratogenic.

• Pregnant or lactating women, due to possible adverse effects on the developingfoetus or infant due to study drug.

• Prior allergic reaction to Temozolomide or Metformin.

• Patients treated on any other therapeutic clinical protocols within 30 daysprior to study entry or during participation in the study