Metformin for Medulloblastoma Recovery

(Met Med Can Trial)

Recruiting at 20 trial locations

Overseen By Cynthia de Medeiros, M.Sc.

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Donald Mabbott

Must not be taking: Diuretics, Cationic drugs, Metformin

Disqualifiers: Type 1 diabetes, Renal disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 3

Duration: 16 weeks

140 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether metformin (metformin hydrochloride) can improve brain function and growth in children and young adults who have completed brain tumor treatment. It compares the effects of metformin to a placebo (a pill with no active medication) over 16 weeks. The trial seeks participants aged 7 to 21 who have recently finished brain tumor treatment and can swallow pills. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that might interact with metformin, such as diuretics, cationic drugs, and some other specific medications. It's important to discuss your current medications with the study team to determine if any changes are needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that metformin is generally safe for patients and that adherence to the prescribed regimen is common. Previous studies found that patients tolerated the treatment well. Although specific safety information about using metformin for medulloblastoma recovery is lacking, the FDA has approved it for treating type 2 diabetes. This approval suggests it is likely safe for other uses in humans. The current study aims to gather more information about its long-term safety in aiding brain tumor recovery. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for medulloblastoma recovery?

Unlike the standard treatments for medulloblastoma, which primarily involve surgery, radiation, and chemotherapy, Metformin is a diabetes medication being repurposed for cancer recovery. Researchers are excited about Metformin because it has the potential to target cancer cell metabolism, which is different from traditional therapies that mainly focus on killing rapidly dividing cells. This unique mechanism may help reduce the risk of cancer recurrence and improve recovery outcomes. Additionally, Metformin is already widely used and has a well-known safety profile, making it an attractive option for enhancing treatment with fewer side effects.

What evidence suggests that metformin might be an effective treatment for cognitive recovery in children and adolescents treated for a brain tumor?

Research shows that metformin might aid brain recovery and enhance thinking skills in children treated for medulloblastoma, a type of brain tumor. Studies have found that metformin affects a specific pathway involved in the cancer's growth. In this trial, some participants will receive metformin, while others will receive a placebo. Children who took metformin in past studies showed possible improvements in brain repair after treatment. Early results suggest that taking metformin for 16 weeks could lead to better thinking skills compared to a placebo. This evidence supports the idea that metformin might improve brain function after medulloblastoma treatment. ^{1 2 3 4 6}

Who Is on the Research Team?

Eric Bouffet, MD

Principal Investigator

The Hospital for Sick Children

Donald Mabbott, Ph.D.

Principal Investigator

The Hospital for Sick Children

Are You a Good Fit for This Trial?

Children aged 7 to 17 years and 11 months who have finished treatment for medulloblastoma, a type of brain tumor. They must be able to swallow tablets, have normal kidney and liver function, speak English or French fluently or have been schooled in these languages for at least two years. Participants should not have severe low blood sugar history, metabolic acidosis, heart failure requiring medication within the past two years, unstable diabetes, or known allergies to metformin.

Inclusion Criteria

My kidney function is normal, with an eGFR over 75.

Informed consent (and assent, where applicable) will be obtained from the participants and/or their legal guardian(s) by study team members delegated to consent for this study

My bilirubin levels are within the normal range for my age and gender.

Exclusion Criteria

I have Type 1 diabetes that is not well-controlled.

You are allergic to metformin hydrochloride.

I am currently taking metformin.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either metformin or placebo for 16 weeks to assess cognitive recovery and brain growth

16 weeks

Weekly monitoring (virtual or in-person)

Post-Intervention Assessment

Outcome assessments conducted to evaluate cognitive function and brain growth

1 week

1 visit (in-person)

Follow-up

Participants are monitored for long-term effects and continued cognitive and brain growth improvements

24 weeks

1 visit (in-person) at 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Metformin hydrochloride
• Placebo

Trial Overview The trial is testing if metformin can help improve cognitive function and brain growth after treatment for medulloblastoma compared to a placebo. It's a Phase III study where participants are randomly assigned either metformin or placebo for 16 weeks in a double-blind setup (neither doctors nor patients know who gets what).

How Is the Trial Designed?

Group I: Metformin Experimental Treatment 1 Intervention

Oral metformin will be administered approximately 500mg/m2/day for 1 week and increased to 1000mg/m2/day for 15 weeks. Doses will be rounded to increments of half tablets (250mg, 500mg, 750mg and 1000mg).

Group II: Placebo Placebo Group 1 Intervention

Oral placebo will be administered approximately 500mg/m2/day for 1 week and increased to 1000mg/m2/day for 15 weeks. Doses will be rounded to increments of half tablets (250mg, 500mg, 750mg and 1000mg).

Who Is Running the Clinical Trial?

Donald Mabbott

Lead Sponsor

Trials

1

Recruited

140+

Published Research Related to This Trial

Metformin effectively inhibits the growth and spread of medulloblastoma (MB) cells by inducing apoptosis and blocking the cell cycle at the G0/G1 phase, as demonstrated through various in vitro assays and a xenograft murine model.

The anticancer effects of metformin are linked to its ability to decrease the activity of the Sonic hedgehog (Shh) signaling pathway, with this inhibition being mediated by the activation of AMP-activated protein kinase (AMPK).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of metformin on Sonic hedgehog subgroup medulloblastoma progression: In vitro and in vivo studies. Fang, H., Wang, L., Yu, L., et al.[2022]

Metformin enhances the effectiveness of Ara-C (cytarabine) in treating acute myeloid leukemia (AML) by inhibiting the mTORC1/P70S6K signaling pathway, which is crucial for cell growth and survival.

In vivo studies using mouse models confirmed that the combination of metformin and Ara-C resulted in a significantly stronger anti-leukemia effect compared to Ara-C alone, suggesting a promising new treatment strategy for AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of mTORC1/P70S6K pathway by Metformin synergistically sensitizes Acute Myeloid Leukemia to Ara-C. Yuan, F., Cheng, C., Xiao, F., et al.[2020]

In a study of 24 medulloblastoma patients treated with carboplatin instead of cisplatin, 23 patients were alive at the time of assessment, indicating a favorable overall survival rate.

Only 10.5% of patients experienced significant hearing loss, suggesting that carboplatin has a lower risk of ototoxicity compared to traditional cisplatin treatments, especially in younger patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and ototoxicity: hearing loss rates among survivors of childhood medulloblastoma. Musial-Bright, L., Fengler, R., Henze, G., et al.[2021]

MIBG, a mitochondrial inhibitor, effectively suppresses neuroblastoma (NB) cell growth by reducing MYCN and MYC expression, demonstrating its potential as a targeted therapy for this pediatric cancer.

The combination of MIBG with metformin or phenformin enhances anticancer effects, with both drugs promoting favorable gene expression and histone modifications that contribute to their growth-inhibitory mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin. Wang, SS., Hsiao, R., Limpar, MM., et al.[2021]

Metformin significantly inhibits the proliferation of neuroblastoma cells, with its effects linked to the inhibition of the Akt signaling pathway, suggesting its potential as an anti-cancer agent.

The antiproliferative effects of metformin vary depending on the differentiation status of the neuroblastoma cells, being diminished by retinoic acid treatment but enhanced by the overexpression of NDM29 non-coding RNA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin inhibition of neuroblastoma cell proliferation is differently modulated by cell differentiation induced by retinoic acid or overexpression of NDM29 non-coding RNA. Costa, D., Gigoni, A., Würth, R., et al.[2021]

The EORTC 1634-BTG/NOA-23 trial aims to improve treatment for post-pubertal medulloblastoma patients by comparing standard-dose versus reduced-dose craniospinal radiotherapy and adding the SMO inhibitor sonidegib to standard therapy, potentially reducing toxicity and enhancing efficacy.

This study will provide valuable long-term data on treatment side effects and quality of life, which is crucial for developing better treatment strategies for this rare brain cancer in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Randomized Trials in Adults with Medulloblastoma-The Example of EORTC 1634-BTG/NOA-23. Hau, P., Frappaz, D., Hovey, E., et al.[2021]

In a study of 76 children with medulloblastoma, those with desmoplastic tumors had significantly better event-free survival (EFS) at 77% and overall survival (OS) at 85%, compared to only 17% EFS and 29% OS for nondesmoplastic tumors, indicating a clear difference in prognosis based on tumor type.

Children under 3 years old with desmoplastic medulloblastoma may be classified as lower-risk, allowing for a potential reduction in treatment intensity, including the possibility of avoiding radiation therapy altogether, which can help minimize neurocognitive side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. Leary, SE., Zhou, T., Holmes, E., et al.[2021]

Metformin (MET) shows promise as a potential treatment for cancer, particularly in neuroendocrine tumors (NETs), by modifying metabolism and activating pathways that inhibit tumor growth.

The MetNET-2 trial is a pilot study designed to assess the safety of combining MET with lanreotide in patients with well-differentiated gastrointestinal and lung NETs, highlighting the need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and protocol of MetNET-2 trial: Lanreotide Autogel plus metformin in advanced gastrointestinal or lung neuroendocrine tumors. Pusceddu, S., Prinzi, N., Lo Russo, G., et al.[2018]

A modified chemotherapy regimen for young children with medulloblastoma, which reduced the number of intrathecal methotrexate doses and eliminated the need for Ommaya reservoir implantation, showed promising results with four out of five patients remaining in remission for 3 to 10 years post-treatment.

The approach demonstrated safety, as no learning difficulties were observed in the children who remained in remission, suggesting that this modified treatment could be a viable option for reducing neurocognitive deficits associated with traditional radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An intrathecal limited postoperative chemotherapy regimen for the treatment of young children with nodular/desmoplastic medulloblastoma and medulloblastoma with extensive nodularity. Naung, H., Cohen, KJ.[2022]

Medulloblastoma, a type of brain tumor, requires a combination of maximum safe surgical removal, craniospinal irradiation (CSI), and chemotherapy for optimal treatment, especially considering its four distinct molecular subgroups (WNT, SHH, G3, and G4) that have different characteristics and outcomes.

Recent advancements in preclinical models allow for precise delivery of CSI, enabling researchers to study the effects of radiation on tumor control and toxicity, which could lead to more tailored and effective treatments for each medulloblastoma subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Models of Craniospinal Irradiation for Medulloblastoma. Stripay, JL., Merchant, TE., Roussel, MF., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05230758

NCT05230758 | Effect of Metformin on Behaviour and the ... In this multi-site clinical trial, we will test the efficacy of treatment with metformin for brain repair and cognitive recovery in paediatric medulloblastoma ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8176964/

Assessment of cognitive and neural recovery in survivors of ... We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric ...

3. trialx.com trialx.com/clinical-trials/listings/263617/effect-of-metformin-on-behaviour-and-the-brain-in-children-treated-for-a-brain-tumour/

Effect of Metformin on Behaviour and the Brain in Children ... We hypothesize that 16 weeks of treatment with metformin will be associated with better cognitive outcomes than 16 weeks of treatment with placebo.

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT02040376/metformin-for-brain-repair-in-children-with-cranial-spinal-radiation-for-medulloblastoma

Metformin for Brain Repair in Children With Cranial-Spinal ... A placebo controlled double blind crossover trial of metformin in 30 children treated with radiation for medulloblastoma - the most common malignant brain ...

5. withpower.com withpower.com/trial/phase-3-cognitive-impairment-ci-1-2022-1de16

Metformin for Medulloblastoma Recovery Metformin is unique in treating medulloblastoma because it targets the Sonic hedgehog (Shh) signaling pathway, which is involved in the cancer's progression.

6. mcri.edu.au mcri.edu.au/research/projects/met-med-study

MET-MED Study MET-MED is a Phase 3 Randomised Double-Blind, Placebo-Controlled Trial of Metformin for Cognitive Recovery and White Matter Growth in Paediatric Medulloblastoma ...