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

Study Overview
=================
Brief Summary
-----------------
Glioblastoma Multiforme is one of the most common, and unfortunately one of the most aggressive brain tumors in adults with most of the patients recurring and dying of the disease with a median survival of 16 months from diagnosis. Current treatment for patients with newly diagnosed Glioblastoma Multiforme (GBM) is safe maximal surgical resection followed by concomitant conventional Radiotherapy (RT) delivered in 6 weeks + Temozolomide (TMZ) followed by TMZ for 6 to 12 cycles. Recent scientific research has shown that Metformin, a common drug used to treat diabetes mellitus, may improve the results of the treatment in patients with a variety of cancers, such as breast, colon, and prostate cancer. Metformin is an attractive and safe medication to be used in this group of patients because of its very low toxicity. In our center the investigators have been using TMZ for 2 weeks prior to a short course (4 weeks) of RT which equivalent to the standard RT of 6 weeks. Temozolomide is used 2 weeks before RT + TMZ, and this is followed by the 6 to 12 cycles of TMZ. Our results are quiet encouraging with a median survival of 20 months, and acceptable toxicity.

Detailed Description
-----------------
Metformin, a drug with a very safe toxicity profile, is an attractive molecule to be tested in patients with newly diagnosed GBM in a phase I clinical trial. This is based on its potential to inhibit the proliferation of GBM CSCs through its mechanism of action which is similar to IR and TMZ. Metformin, IR, and TMZ stimulate AMPK leading to the subsequent inhibition of cellular proliferation. Therefore, it is hypothesized that the addition of Metformin to concomitant IR and TMZ may increase the efficiency of IR and TMZ, which are currently considered as the standard of care for patients with GBM. In addition, Metformin lowers blood glucose levels, and subsequently reduces the insulin and Insulin-Growth-factors which are growth-promoting factors with a direct impact on GBM cellular proliferation and invasion. Metformin may improve the outcomes of patients with GBM when added to current treatment consisting of maximal safe surgical resection followed by neo-adjuvant TMZ and concomitant accelerated hypofractionated limited-margin XRT followed by adjuvant TMZ. Our Neuro-Oncology group at McGill University reviewed the results of an ongoing Phase II study in patients with GBM. A group of 33 patients were treated according to protocol, and with a median follow-up of 11 months, the median survival was 17.5 months which compares favourably to current results from standard treatment with a beneficial 2-week shortening of the XRT treatment time. This is a phase II clinical trial to assess the feasibility and overall toxicity of adding Metformin to Neoadjuvant Temozolomide followed by concomitant Temozolomide and accelerated hypofractionated limited-margin radiotherapy and followed by adjuvant Temozolomide in patients with newly diagnosed GBM. It is expected that the proposed study treatment will improve the median survival from current values of 20 months (current MUHC Neo-adjuvant Phase 2 data) to 25 months. This means an improved outcome of 25%. Using one-tailed statistics, and with a power of 0.8 and an alpha of 0.05, the sample size for this Phase II trial will be 50 patients.

Official Title
-----------------
Metformin and Neo-adjuvant Temozolomide and Hypofractionated Accelerated Limited-margin Radiotherapy Followed by Adjuvant Temozolomide in Patients With Glioblastoma Multiforme (M-HARTT STUDY)

Conditions
-----------------
Glioblastoma Multiforme

Intervention / Treatment
-----------------
* Drug: Metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Registered one arm study<br>Two weeks of neo-adjuvant Metformin+Temozolomide followed by accelerated hypofractionation using an IMRT technique+TMZ & Metformin followed by TMZ, and Metformin as adjuvant component. | Drug: Metformin<br>* Metformin,<br>* Other names: Glucophage;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients completing the study treatment | To determine overall survival | At one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess toxicity of the regimen | Toxicity will be assessed and graded according to CTCAE-V4 | One year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neo-Adjuvant Metformin, Neo-Adjuvant Temozolomide, Temozolomide and accelerated hypofractionation, Metformin and accelerated hypofractionation, Adjuvant Temozolomide, Adjuvant Metformin