Metformin for the Prevention of Oral Cancer in Patients With Oral Premalignant Lesions

Study Overview
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Brief Summary
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This phase I trial tests whether metformin works in reducing the annual transformation (development of invasive cancer) of oral precancerous lesions into cancerous lesions. Metformin is a drug approved for the treatment of diabetes, but studies have shown that it may have some anticancer properties. Giving metformin may help prevent or slow the development of oral cancer from precancerous lesions.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the transformation-free-survival in lesion types erythroplakia (EP) and verrucous hyperplasia (VH). 'Transformation' is defined as the development of invasive cancer. SECONDARY OBJECTIVE: I. To evaluate the current spontaneous regression rates, i.e., percentages of patients having lesion disappear within 1-year post treatment, in all four lesion types and compare them with historical documented regression rate in literature. EXPLORATORY OBJECTIVE: I. To evaluate the transformation-free-survival in lesion types homogenous leukoplakia (HL) and non-homogenous leukoplakia (NHL). OUTLINE: Patients receive metformin orally (PO) once daily (QD) on days 1-3 and then PO twice daily (BID) for up to 12 months in the absence of unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 24 months.

Official Title
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Metformin Chemoprevention of Oral Premalignant Lesions

Conditions
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Erythroplakia, Leukoplakia, Oral Cavity Carcinoma, Proliferative Verrucous Leukoplakia

Intervention / Treatment
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* Drug: Metformin
* Procedure: Biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-85 Clinical appearance of lesion Homogenous leukoplakia Non- homogenous leukoplakia Erythroplakia Proliferative verrucous leukoplakia Histologic appearance No dysplasia Mild dysplasia Moderate dysplasia Severe dysplasia Diabetics: if on metformin, will get them to 2000 mg per day, if not, will add metformin in consultation with endocrinologist All subjects must be able to comprehend and sign a written informed consent document Willing and able to be available for the duration of the study In general good health with no contraindication to biopsy or metformin therapy Laboratory results Exclusion Criteria: Carcinoma in-situ, verrucous carcinoma, invasive squamous cell carcinoma (SCCa) Exclude systemic causes of the lesion: pemphigus, pemphigoid, systemic lupus erythematosus (SLE), lichenoid drug reaction, human immunodeficiency virus (HIV), syphilis Exclude local inciting factors: rule out (r/o) but allowing 2 weeks to pass and see if there is resolution, if not and doesn't resolve with local measures, medical treatment, enroll Frictional: sharp tooth Trauma Immunosuppression by natural illness or medically induced Hypersensitivity or allergic reaction to metformin or some other contraindication

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (metformin)<br>Patients receive metformin PO QD on days 1-3 and then PO BID for up to 12 months in the absence of unacceptable toxicity. | Drug: Metformin<br>* Given PO<br>* Other names: N-Dimethylimidodicarbonimidic Diamide;Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transformation-free-survival, in lesion types erythroplakia and verrucous hyperplasia | Will be summarized using Kaplan-Meier curves as well as 95% confidence ands. Kaplan-Meier estimates of the 3-year transformation-free-survival rates will be reported with 95% confidence interval. One-sample two-sided log-rank test will be applied to all four lesions as well. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lesion status | Evaluated on a Likert-scale with three levels: 'worsen', 'same' and 'disappear', compared to each patient's baseline lesion status (as measured at pre-treatment and one year post initiation of treatment). The lesion size and status evaluated at 1-year post-treatment will be summarized using percentages as well as 95% Clopper-Pearson exact confidence intervals. The current spontaneous regression rates (i.e., percentage of 'disappear') will be compared against the historically documented regression rate of 35% using two-sided exact binomial test. | Baseline to 1 year after treatment |