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

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ClinicalTrials.gov Identifier: NCT02780024

Recruitment Status : Recruiting

First Posted : May 23, 2016

Last Update Posted : August 16, 2019

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Sponsor:

Information provided by (Responsible Party):

George Shenouda, McGill University Health Centre/Research Institute of the McGill University Health Centre

Tracking Information

First Submitted Date ^ICMJE

May 20, 2015

First Posted Date ^ICMJE

May 23, 2016

Last Update Posted Date

August 16, 2019

Study Start Date ^ICMJE

March 2015

Estimated Primary Completion Date

December 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Number of patients completing the study treatment [ Time Frame: At one year ]

To determine overall survival

Original Primary Outcome Measures ^ICMJE

Percent of patients completing the study treatment [ Time Frame: At one year ]

To determine overall survival

Change History

Complete list of historical versions of study NCT02780024 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures ^ICMJE

To assess toxicity of the regimen [ Time Frame: One year ]

Toxicity will be assessed and graded according to CTCAE-V4

Original Secondary Outcome Measures ^ICMJE

Same as current

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

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

Official Title ^ICMJE

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

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.

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 2

Study Design ^ICMJE

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

Condition ^ICMJE

Glioblastoma Multiforme

Intervention ^ICMJE

Drug: Metformin

Metformin,

Other Name: Glucophage

Study Arms ^ICMJE

Experimental: Registered one arm study

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.

Intervention: Drug: Metformin

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Recruiting

Estimated Enrollment ^ICMJE

Original Estimated Enrollment ^ICMJE

Same as current

Estimated Study Completion Date ^ICMJE

December 2022

Estimated Primary Completion Date

December 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

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

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact: George Shenouda, M.D.	514-934-4400	george.shenouda@muhc.mcgill.ca
Contact: Marianna Perna, CCRP, CCRC	514-934-1934 ext 43191	marianna.perna@muhc.mcgill.ca

Listed Location Countries ^ICMJE

Canada

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT02780024

Other Study ID Numbers ^ICMJE

MUHC ID: 4315

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

Not Provided

IPD Sharing Statement ^ICMJE

Plan to Share IPD:

Responsible Party

George Shenouda, McGill University Health Centre/Research Institute of the McGill University Health Centre

Study Sponsor ^ICMJE

McGill University Health Centre/Research Institute of the McGill University Health Centre

Collaborators ^ICMJE

Not Provided

Investigators ^ICMJE

Principal Investigator:

George Shenouda, M.D.

Radiation Oncologist

PRS Account

McGill University Health Centre/Research Institute of the McGill University Health Centre

Verification Date

August 2019

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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