Metformin and Standard Therapy for Glioblastoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

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

Must be taking: Temozolomide, Metformin

Disqualifiers: Diabetes, Prior malignancy, Severe comorbidity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests if Metformin, a diabetes drug, can improve treatment for patients with newly diagnosed aggressive brain cancer (GBM). Metformin, a commonly used drug for the treatment of diabetes, has recently emerged as a promising anticancer molecule. It may help by slowing cancer cell growth and enhancing current treatments.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are diabetic, you cannot participate in this trial, which suggests that certain medications might not be compatible. It's best to discuss your current medications with the trial team.

Is metformin safe for use in humans, particularly in combination with standard glioblastoma therapy?

Metformin, commonly used for diabetes, has been tested in combination with glioblastoma treatments and was generally well tolerated, with common side effects like appetite loss, nausea, and diarrhea being manageable. In a study, doses up to 2250 mg/day did not show serious safety concerns, and no dose-limiting toxicities were observed. ^{1 2 3 4 5}

How does the drug metformin differ from other treatments for glioblastoma?

Metformin, commonly used for diabetes, is being explored for glioblastoma due to its potential to suppress tumor cells and improve survival, especially when combined with the chemotherapy drug temozolomide. This combination may offer enhanced anti-tumor effects compared to standard treatments alone. ^{2 4 5 6 7}

What data supports the effectiveness of the drug Metformin for treating glioblastoma?

Some studies suggest that Metformin, a drug commonly used for diabetes, might have anti-tumor effects on glioblastoma cells, especially when combined with other treatments like temozolomide. However, a large analysis found that Metformin alone did not significantly improve survival in glioblastoma patients, indicating more research is needed to understand its potential benefits. ^{2 3 4 5 8}

Who Is on the Research Team?

George Shenouda, M.D.

Principal Investigator

Radiation Oncologist

Are You a Good Fit for This Trial?

This trial is for adults with a confirmed diagnosis of GBM in the brain, who have had surgery and are recovering well. They must not have other serious health issues or prior treatments that could interfere, be able to undergo MRI or CT scans, and agree to use contraception if they can have children.

Inclusion Criteria

My blood counts meet the required levels for treatment.

For females of child-bearing potential, negative serum pregnancy test within 72 hours prior to starting TMZ and Metformin

I can care for myself but may need occasional help.

Exclusion Criteria

I have diabetes, either type 1 or type 2.

My tumor is near my optic nerves or chiasm.

I do not have severe health issues that would stop me from completing the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neo-adjuvant Treatment

Two weeks of neo-adjuvant Metformin and Temozolomide

2 weeks

Radiotherapy and Concomitant Treatment

Accelerated hypofractionated radiotherapy with IMRT technique, combined with Temozolomide and Metformin

4 weeks

Adjuvant Treatment

Adjuvant Temozolomide and Metformin for 6 to 12 cycles

6 to 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

11 months

What Are the Treatments Tested in This Trial?

Interventions

• Metformin

Trial Overview The study tests Metformin combined with Temozolomide chemotherapy before and after a shortened course of radiotherapy for GBM treatment. The goal is to see if this approach extends survival while maintaining acceptable levels of side effects.

How Is the Trial Designed?

Group I: Registered one arm study Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

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

Lead Sponsor

Trials

476

Recruited

170,000+

Published Research Related to This Trial

In a pooled analysis of 1,731 glioblastoma patients from three clinical trials, metformin use was not significantly associated with improved overall survival (OS) or progression-free survival (PFS) during or after treatment with radiochemotherapy.

While there was a nonsignificant trend suggesting potential benefits of metformin monotherapy at baseline, this effect was not observed during concurrent treatment with temozolomide and radiotherapy, indicating that metformin does not prolong survival in newly diagnosed glioblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis. Seliger, C., Genbrugge, E., Gorlia, T., et al.[2020]

In a phase II clinical trial involving 81 patients with recurrent or refractory glioblastoma, the combination of metformin and low-dose temozolomide was well tolerated but did not show a significant clinical benefit in terms of progression-free survival or overall survival compared to the control group receiving placebo and temozolomide.

The median overall survival was 17.22 months for the metformin group versus 7.69 months for the control group, but this difference was not statistically significant, indicating that metformin may not improve outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study). Yoon, WS., Chang, JH., Kim, JH., et al.[2023]

The combination of temozolomide (TMZ) and metformin significantly increased cell death in glioblastoma (GBM) cell lines compared to using either drug alone, indicating a synergistic effect in fighting this aggressive cancer.

In an orthotopic mouse model, the combination treatment improved median survival rates, with the highest survival observed in the group receiving high-dose metformin and TMZ, suggesting that targeting fatty acid synthase (FASN) may be a promising therapeutic strategy for GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In Vivo Compared with Monotherapy. Lee, JE., Lim, JH., Hong, YK., et al.[2022]

Metformin, traditionally used to treat type 2 diabetes, has shown potential effectiveness against various types of tumors, including high-grade gliomas like glioblastoma, which have limited treatment options.

Understanding how metformin works could lead to the development of new cancer therapies, expanding its role beyond diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin as Potential Therapy for High-Grade Glioma. Mazurek, M., Litak, J., Kamieniak, P., et al.[2020]

Metformin (MET) significantly reduces the viability and proliferation of glioblastoma endothelial cells, promoting apoptosis through increased activity of caspases 3/7, indicating its potential as a therapeutic agent against this aggressive brain cancer.

MET also decreases angiogenesis and invasiveness in glioblastoma cells by altering sphingolipid metabolism, suggesting it could be safely repurposed as an add-on therapy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics. Guarnaccia, L., Navone, SE., Masseroli, MM., et al.[2022]

In a phase I/II study involving patients with newly diagnosed glioblastoma, metformin (MF) was well tolerated at doses up to 2250 mg/day when combined with maintenance temozolomide (TMZ), with no dose-limiting toxicities observed.

The study showed that while some patients experienced tumor progression, five out of eight patients remained stable, suggesting potential benefits of MF in managing glioblastoma after standard therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies. Ohno, M., Kitanaka, C., Miyakita, Y., et al.[2022]

Metformin, an anti-diabetic drug, was found to decrease cell survival in glioblastoma multiforme (GBM) cells and reduce the expression of certain microRNAs associated with tumor aggressiveness, suggesting its potential as a therapeutic agent against GBM.

The study showed that metformin increased the expression of proteins involved in exosome biogenesis and secretion, indicating that it may enhance the release of exosomes from GBM cells, which could influence tumor behavior and treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Increases Exosome Biogenesis and Secretion in U87 MG Human Glioblastoma Cells: A Possible Mechanism of Therapeutic Resistance. Soraya, H., Sani, NA., Jabbari, N., et al.[2021]

In a study of 241 glioblastoma patients, metformin use was linked to longer overall survival, particularly in those with tumors that had a methylated MGMT promoter, showing a survival time of 484 days compared to 394 days for non-users.

Cox regression analysis indicated that metformin significantly reduced the risk of death at 2 years for patients with methylated MGMT promoters, suggesting it may be an effective adjunct treatment for this specific group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin use is associated with longer survival in glioblastoma patients with MGMT gene silencing. Mohammad, AH., Jatana, S., Ruiz-Barerra, MA., et al.[2023]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of metformin plus low-dose temozolomide in patients with recurrent or refractory glioblastoma: a randomized, prospective, multicenter, double-blind, controlled, phase 2 trial (KNOG-1501 study). [2023]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In Vivo Compared with Monotherapy. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Metformin as Potential Therapy for High-Grade Glioma. [2020]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Metformin with Temozolomide for Newly Diagnosed Glioblastoma: Results of Phase I Study and a Brief Review of Relevant Studies. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Metformin Increases Exosome Biogenesis and Secretion in U87 MG Human Glioblastoma Cells: A Possible Mechanism of Therapeutic Resistance. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Metformin use is associated with longer survival in glioblastoma patients with MGMT gene silencing. [2023]