Metformin for Oral Leukoplakia/Erythroplakia Prevention

Recruiting at 10 trial locations

Overseen By Amy Selegue

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Arizona

Must not be taking: Insulin, Anti-diabetics, Investigational agents, Carbonic anhydrase inhibitors

Disqualifiers: Diabetes, Oral carcinoma, Liver disease, others

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: 24

Duration: 24 weeks

86 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if metformin can prevent oral cancer in patients with pre-cancerous mouth patches. Metformin is a diabetes drug that controls blood sugar and may stop these patches from becoming cancerous. Metformin, widely used as a diabetes medication, has recently been reported to reduce cancer risk and improve outcomes in certain cancers.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using insulin, anti-diabetic medications, or certain other drugs like carbonic anhydrase inhibitors or ranolazine.

What data supports the effectiveness of the drug Metformin for preventing oral leukoplakia/erythroplakia?

Research suggests that Metformin, commonly used for type 2 diabetes, may help prevent the progression of oral lesions to cancer, as seen in lab and animal studies. However, clinical data on its effectiveness in reducing cancer risk in head and neck areas is mixed. ^{1 2 3 4 5}

Is Metformin generally safe for humans?

There is no specific safety data on Metformin for oral leukoplakia/erythroplakia prevention in the provided research articles, but Metformin is a well-known medication commonly used to treat type 2 diabetes and is generally considered safe for humans when used as prescribed. ^{6 7 8 9 10}

How is the drug metformin unique for preventing oral leukoplakia/erythroplakia?

Metformin, commonly used for type 2 diabetes, is unique in this context because it may prevent the progression of oral lesions to cancer by affecting cellular pathways, such as downregulating the epidermal growth factor receptor (EGFR), which is involved in cancer progression. This potential anticancer effect is separate from its role in controlling blood sugar levels. ^{1 3 4 11 12}

Research Team

Scott M Lippman

Principal Investigator

University of California, San Diego Moores Cancer Center

Eligibility Criteria

Adults over 21 with oral leukoplakia or erythroplakia, not caused by radiation, and certain health criteria met (e.g., kidney function). Smokers are eligible. Excludes those allergic to metformin, heavy alcohol users, recent cancer treatments other than skin/certain organ-confined cancers, uncontrolled diseases, pregnant/nursing women.

Inclusion Criteria

I have oral leukoplakia or erythroplakia with abnormal cell growth in high-risk areas, but not from radiation.

Platelets >= 100,000/microliter

I can take pills by mouth.

Exclusion Criteria

I have had allergic reactions to metformin or similar drugs, or I've used metformin in the last year.

I haven't had cancer treatments, except for hormone therapy, in the last 18 months.

I am currently taking medication like topiramate or ranolazine.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive extended release metformin or placebo orally once daily for 24 weeks

24 weeks

Biopsies and blood collections at baseline and week 24

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 weeks

Treatment Details

Interventions

• Extended Release Metformin Hydrochloride

Trial Overview This trial is testing if extended-release metformin can prevent oral cancer in patients with white or red patches in their mouth. Participants will either receive metformin or a placebo while undergoing biopsies and biospecimen collection to monitor changes.

Participant Groups

Group I: Arm I (extended release metformin) Experimental Treatment 3 Interventions

Patients receive extended release metformin hydrochloride PO QD for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients will also undergo biopsies and blood collections on study.

Group II: Arm II (placebo) Placebo Group 3 Interventions

Patients receive a placebo PO QD for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients will also undergo biopsies and blood collections on study.

Extended Release Metformin Hydrochloride is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Metformin for:

• Type 2 diabetes
• Polycystic ovary syndrome

Approved in United States as Metformin for:

• Type 2 diabetes
• Polycystic ovary syndrome
• Gestational diabetes

Approved in Canada as Metformin for:

• Type 2 diabetes
• Polycystic ovary syndrome

Approved in Japan as Metformin for:

• Type 2 diabetes

Approved in China as Metformin for:

• Type 2 diabetes

Approved in Switzerland as Metformin for:

• Type 2 diabetes
• Polycystic ovary syndrome

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a case series of 3 nondiabetic patients with recurrent dysplastic lesions from head and neck cancer, adjuvant therapy with metformin resulted in complete or partial regression of lesions without the need for additional surgeries, indicating its potential efficacy in this context.

The study suggests that using metformin in nondiabetic patients may provide a clearer understanding of its effects on malignancy risk reduction, as these patients are not influenced by the complications associated with diabetes, such as increased cancer risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Prevents the Progression of Dysplastic Mucosa of the Head and Neck to Carcinoma in Nondiabetic Patients. Lerner, MZ., Mor, N., Paek, H., et al.[2019]

Leukoplakia is the most common premalignant oral lesion, and its risk of becoming cancerous can be assessed based on its appearance, location in the mouth, and biopsy results.

Erythroplakia, while less common, poses a much higher risk of malignant transformation and should always be surgically removed and closely monitored afterward.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The diagnosis and treatment of precancerous lesions. van der Waal, I.[2005]

A study involving over 300,000 patients with type 2 diabetes found that those who used metformin had a significantly lower risk of developing oral cancer compared to those who did not use metformin, with a hazard ratio of 0.584.

The protective effect of metformin against oral cancer increased with longer use, showing a dramatic reduction in risk for those who used it for more than 21.5 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin may reduce oral cancer risk in patients with type 2 diabetes. Tseng, CH.[2018]

In patients with type 2 diabetes mellitus (T2DM) and oral squamous cell carcinoma (OSCC), those taking metformin showed significantly lower levels of epidermal growth factor receptor (EGFR) expression compared to those not taking the medication, suggesting a potential anticancer effect of metformin.

The study found that fluctuations in fasting blood glucose levels were positively correlated with EGFR expression in OSCC tissues of T2DM patients not on metformin, indicating that metformin may regulate EGFR independently of its blood glucose-lowering effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin Downregulates the Expression of Epidermal Growth Factor Receptor Independent of Lowering Blood Glucose in Oral Squamous Cell Carcinoma. Wang, WM., Yang, SS., Shao, SH., et al.[2022]

Pioglitazone effectively inhibits the proliferation of human leukoplakia cells and transformed bronchial epithelial cells in a dose-dependent manner, suggesting its potential as a chemopreventive therapy for oral and aerodigestive cancers.

The treatment with pioglitazone leads to the induction of the p21 protein, which is linked to decreased cell proliferation, indicating that p21 could serve as a biomarker for evaluating the effectiveness of pioglitazone in future cancer prevention studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PPARγ-Mediated p21 Induction in Aerodigestive Preneoplastic Cell Lines. Miller, WA., Wuertz, BR., Ondrey, FG.[2022]

Targeted anticancer therapies can cause various oral mucosal toxicities, including anti-EGFR-induced mucositis and BRAF-inhibitor-associated hyperkeratosis, which are important to recognize in clinical practice.

Specific lesions such as benign migratory glossitis and osteonecrosis of the jaw have been linked to angiogenesis inhibitors, highlighting the need for careful monitoring of oral health in patients undergoing these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Oral toxicity of targeted anticancer therapies]. Sibaud, V., Boralevi, F., Vigarios, E., et al.[2022]

Tacrolimus is an effective treatment for symptomatic oral lichen planus, showing similar clinical resolution rates compared to corticosteroids, based on a systematic review of 9 randomized controlled trials.

While tacrolimus may cause mild adverse effects more frequently than some corticosteroids, these effects are generally minor and transient, allowing for its continued use in patients who do not respond to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of topical administration of tacrolimus in oral lichen planus: An updated systematic review and meta-analysis of randomized controlled trials. Su, Z., Hu, J., Cheng, B., et al.[2022]

mTOR inhibitors, such as everolimus and sirolimus, are effective immunosuppressive agents for organ transplant recipients and cancer treatments, but they are associated with a range of adverse events (AEs) including stomatitis, wound-healing complications, and diabetes.

Most AEs related to mTOR inhibitors can be effectively managed or reversed through careful monitoring and appropriate interventions, highlighting the importance of patient selection and management strategies in optimizing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for the management of adverse events associated with mTOR inhibitors. Kaplan, B., Qazi, Y., Wellen, JR.[2022]

Pembrolizumab, an anti-PD-1 antibody used for treating various cancers, can cause immune-related adverse events (IRAEs) affecting multiple body systems, including rare oral mucosal issues like glossitis.

In a case study of a 71-year-old male with lung cancer, treatment with oral prednisone effectively improved tongue ulcerations caused by pembrolizumab, highlighting the need for awareness of such rare side effects and their management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-Induced Immune-Mediated Glossitis. Alias, A., Hall, JA., Kulkarni, P., et al.[2022]

New targeted cancer therapies and immune checkpoint inhibitors have introduced a range of specific oral toxicities that differ from traditional chemotherapy-related injuries, affecting over 20% of patients and potentially leading to significant morbidity or treatment discontinuation.

This review provides the first structured data on oral toxicities associated with recently approved monoclonal antibodies targeting PD-1, highlighting the need for better characterization and management of these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. Vigarios, E., Epstein, JB., Sibaud, V.[2022]

Metformin extended release (ER) provides effective glycaemic control with once-daily dosing, showing similar effectiveness to twice-daily dosing of immediate-release formulations over a 24-week period in clinical trials.

The metformin ER formulation was well tolerated at doses of 1500 and 2000 mg/day, with no increase in adverse events, indicating its safety for patients managing their blood sugar levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin extended release for the treatment of type 2 diabetes mellitus. Schwartz, SL., Wu, JF., Berner, B.[2019]

Glumetz (M-ER) is a newly approved extended-release formulation of metformin that provides effective and sustained glycemic control with once-daily dosing, showing similar bioavailability to immediate-release metformin taken twice daily.

In clinical trials lasting 24 weeks, M-ER demonstrated good efficacy and was well tolerated, with continued glycemic control maintained in an additional 24-week open-label extension study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. Schwartz, SL., Gordi, T., Hou, E., et al.[2013]

References

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

Metformin Prevents the Progression of Dysplastic Mucosa of the Head and Neck to Carcinoma in Nondiabetic Patients. [2019]

2. England pubmed.ncbi.nlm.nih.gov

The diagnosis and treatment of precancerous lesions. [2005]

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

Metformin may reduce oral cancer risk in patients with type 2 diabetes. [2018]

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

Metformin Downregulates the Expression of Epidermal Growth Factor Receptor Independent of Lowering Blood Glucose in Oral Squamous Cell Carcinoma. [2022]

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

PPARγ-Mediated p21 Induction in Aerodigestive Preneoplastic Cell Lines. [2022]

6. France pubmed.ncbi.nlm.nih.gov

[Oral toxicity of targeted anticancer therapies]. [2022]

7. Denmark pubmed.ncbi.nlm.nih.gov

Efficacy and safety of topical administration of tacrolimus in oral lichen planus: An updated systematic review and meta-analysis of randomized controlled trials. [2022]

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

Strategies for the management of adverse events associated with mTOR inhibitors. [2022]

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

Pembrolizumab-Induced Immune-Mediated Glossitis. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Oral mucosal changes induced by anticancer targeted therapies and immune checkpoint inhibitors. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Metformin extended release for the treatment of type 2 diabetes mellitus. [2019]

12. England pubmed.ncbi.nlm.nih.gov

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview. [2013]