Metformin for Medulloblastoma Recovery

(Met Med Can Trial)

Recruiting at 17 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

Trial Summary

What is the purpose of this trial?

The efficacy of treatment with metformin for promoting cognitive recovery and brain growth in children/adolescents treated for medulloblastoma will be investigated in a multi-site Phase III randomized double-blind placebo-controlled parallel arm superiority trial. Specifically, in children/adolescents aged 7 years to 17 years and 11 months who have completed treatment for medulloblastoma, is oral administration of metformin for 16 weeks associated with greater improvement of cognitive function and brain growth compared to placebo administered for 16 weeks?

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 Metformin safe for humans?

There is no specific safety data on Metformin for medulloblastoma recovery in the provided research articles, but Metformin is generally considered safe for humans and is widely used for managing diabetes. ^{1 2 3 4 5}

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

Metformin is unique in treating medulloblastoma because it targets the Sonic hedgehog (Shh) signaling pathway, which is involved in the cancer's progression. This approach is different from standard treatments, as metformin is primarily known as a diabetes medication but has shown potential in inhibiting cancer cell growth and metastasis. ^{6 7 8 9 10}

Research Team

Eric Bouffet, MD

Principal Investigator

The Hospital for Sick Children

Donald Mabbott, Ph.D.

Principal Investigator

The Hospital for Sick Children

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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 (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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Development of Randomized Trials in Adults with Medulloblastoma-The Example of EORTC 1634-BTG/NOA-23. [2021]

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

Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Carboplatin and ototoxicity: hearing loss rates among survivors of childhood medulloblastoma. [2021]

4. United States 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. [2022]

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

Preclinical Models of Craniospinal Irradiation for Medulloblastoma. [2022]

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

Effects of metformin on Sonic hedgehog subgroup medulloblastoma progression: In vitro and in vivo studies. [2022]

7. England 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. [2021]

8. Greece pubmed.ncbi.nlm.nih.gov

Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Rationale and protocol of MetNET-2 trial: Lanreotide Autogel plus metformin in advanced gastrointestinal or lung neuroendocrine tumors. [2018]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Inhibition of mTORC1/P70S6K pathway by Metformin synergistically sensitizes Acute Myeloid Leukemia to Ara-C. [2020]