Metformin for Oral Leukoplakia/Erythroplakia Prevention

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether metformin, a drug commonly used to manage blood sugar levels, can help prevent oral cancer in people with oral leukoplakia (white patches) or erythroplakia (red patches) in the mouth. Participants will take either metformin or a placebo for 24 weeks to determine if metformin can halt changes in the mouth that could lead to cancer. This trial may suit current or former smokers with noticeable patches in their mouth. As a Phase 2 trial, it focuses on assessing metformin's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that extended-release metformin is generally well-tolerated. In one study, 97.4% of participants completed 12 weeks of treatment without major issues, while only about 3.3% experienced some stomach-related side effects. Another source reported that between 62% and 100% of people found this type of metformin easy to tolerate. It is also gentler on the stomach than the regular version, potentially causing fewer stomach issues. Overall, the evidence suggests that extended-release metformin is safe for most people, with only a few experiencing mild side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for oral leukoplakia and erythroplakia focus on surgical removal or laser therapy. Unlike these options, extended release metformin hydrochloride acts on cellular metabolism by improving insulin sensitivity and reducing inflammation. Researchers are excited about metformin because it targets the underlying metabolic pathways that may contribute to the development of these precancerous lesions, offering a non-invasive, oral treatment alternative. Its potential to prevent disease progression without surgery makes it a promising candidate for those at risk.

What evidence suggests that metformin might be an effective treatment for oral leukoplakia or erythroplakia?

This trial will compare extended-release metformin with a placebo for preventing oral leukoplakia and erythroplakia. Studies have shown that metformin can reduce the size of oral leukoplakia, which are white patches in the mouth that might become cancerous. Metformin controls blood sugar levels, potentially affecting cancer risk factors. Early research indicates that it influences certain indicators related to cancer risk. This suggests that metformin might help prevent oral cancer by affecting these early changes in the mouth. Although more research is needed, these findings provide a promising basis for its potential use in preventing oral cancer. ^{2 4 5 6 7}

Who Is on the Research Team?

Scott M Lippman

Principal Investigator

University of California, San Diego Moores Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05237960

Metformin for the Prevention of Oral Cancer in Patients ... This phase IIb trial tests whether metformin works in preventing oral cancer in patients with oral leukoplakia (white patches) or erythroplakia (red patches).

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs002437.v1.p1

Metformin for Oral Cancer Prevention ... metformin decreases the size of oral leukoplakia (clinical response). Additionally, effects on biomarkers of cancer risk and metformin effect were ascertained.

3. prevention.cancer.gov prevention.cancer.gov/clinical-trials/clinical-trials-search/nct05237960

Metformin for the Prevention of Oral Cancer in Patients With ... This phase IIb trial tests whether metformin works in preventing oral cancer in patients with oral leukoplakia (white patches) or erythroplakia (red patches).

4. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT02581137

Metformin Hydrochloride in Preventing Oral Cancer ... This phase IIa trial studies how well metformin hydrochloride works in preventing oral cancer in patients with an oral premalignant lesion (oral leukoplakia ...

5. withpower.com withpower.com/trial/phase-2-leukoplakia-6-2022-19b11

Metformin for Oral Leukoplakia/Erythroplakia Prevention This trial is testing if extended-release metformin can prevent oral cancer in patients with white or red patches in their mouth.

6. hcp.merckgroup.com hcp.merckgroup.com/en/cmc/diabetes/products/glucophage-xr/safety-and-tolerability-profile.html

Glucophage® XR | Safety and Tolerability Profile Between 62% and 100% of patients from the centres tolerated the prolonged-release formulation.8. Treatment with metformin is better tolerated than immediate ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3549486/

Safety, tolerability, and efficacy of metformin extended-release ... Treatment with MXR was well tolerated, with 97.4% of patients completing 12 weeks of treatment. Only 3.3% of patients experienced one or more gastrointestinal ( ...