This phase IIa trial studies how well metformin hydrochloride works in preventing oral cancer in patients with an oral premalignant lesion (oral leukoplakia or erythroplakia). Oral premalignant lesions look like red or whitish plaques or lesions in the mouth that do not rub off and can be associated with a higher risk of cancer. Metformin hydrochloride may help prevent oral cancer from forming in patients with an oral premalignant lesion.

PRIMARY OBJECTIVES:

I. To determine the clinical response of oral premalignant lesions to 12-14 weeks of metformin (metformin hydrochloride) intervention.

SECONDARY OBJECTIVES:

I. Histologic response to metformin intervention in the target lesion. II. Tissue-based biomarkers: metformin effect on cell proliferation and its molecular targets in the target lesion and in the normal tissue (marker of cell proliferation, Ki67, molecular targets of metformin, including, in order of priority, phosphorylated ribosomal protein S6 kinase [pS6], phosphorylated v-akt murine thymoma viral oncogene homolog 1 [pAKT]S473, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 [p4EBP], phosphorylated acetyl-CoA carboxylase alpha [pACC]).

III. Tissue-based biomarkers: expression of dysregulated molecular mechanisms and organic cation transporter 3 (OCT 3) in the target lesion and in the normal tissue, including, in order of priority, epidermal growth factor receptor (EGFR), phosphorylated (p)EGFR, tumor protein 53 (p53), phosphatase and tensin homolog (PTEN), phosphorylated mitogen-activated protein kinase 1 (pERK), cyclin-dependent kinase inhibitor 2A (p16), and OCT3.

IV. Tissue-based biomarkers: targeted analysis of cancer-associated genes in the target lesion and blood deoxyribonucleic acid (DNA).

V. Serum and saliva based biomarkers: metformin effect on serum metabolic markers (C-peptide, glycosylated hemoglobin [HbA1c]).

VI. Serum and saliva based biomarkers: metformin concentrations in serum and saliva.

VII Serum and saliva based biomarkers: metformin effect on serum and saliva inflammatory and angiogenic cytokines, including interleukin (IL)-6, IL-8, growth-related oncogene-1 (GRO-1), and vascular endothelial growth factor (VEGF).

EXPLORATORY OBJECTIVES:

I. To characterize changes in the saliva microbiome before and after metformin intervention, including both the absolute microbial load and taxonomic composition.

II. To evaluate the potential microbiome signatures that are correlated with treatment response.

OUTLINE:

Patients receive extended-release metformin hydrochloride orally (PO) once daily (QD) for 2 weeks and then twice daily (BID) for 10-12 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2-4 weeks.

Inclusion Criteria:

• Participants with oral leukoplakia or erythroplakia with mild, moderate, or severe histologic dysplasia, or hyperplasia not associated with mechanical factors such as ill-fitted dentures
• Measurable disease - minimum lesion size of 8 x 3 mm before initial biopsy
• Karnofsky performance status >= 70%
• Leukocytes >= 3,000/microliter
• Absolute neutrophil count >= 1,000/microliter
• Platelets >= 100,000/microliter
• Total bilirubin =< 1.5 × institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =<1.5 × institutional ULN
• eGFR > 40 mL/min using the Cockcroft-Gault equation
• Life expectancy > 3 months
• Willing to use adequate contraception (barrier method, abstinence, subject has had a vasectomy or partner is using effective birth control or is postmenopausal) for the duration of study participation
• Ability to take oral medication
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients with diabetes who are taking insulin or oral agents
• History of diabetic ketoacidosis
• Participants may not be receiving any other investigational agents within past 3 months
• History of allergic reactions attributed to compounds of similar chemical composition to metformin or prior use of metformin within the last year
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, human immunodeficiency virus (HIV)-positive, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Oral carcinoma in situ
• History of chronic alcohol use or abuse defined as any one of the following: a) average consumption of 3 or more alcohol containing beverages daily in the past 12 months; b) consumption of 7 or more alcoholic beverages within a 24 hour (hr) period in the past 12 months
• Glycated hemoglobin (HbA1c) > 8%
• Pregnancy or nursing women
• Acute or chronic liver disease, evidence of hepatitis (infectious or autoimmune), cirrhosis or portal hypertension
• History of renal disease
• History of prior head and neck squamous cell carcinoma (HNSCC) unless curatively treated for >= 1 year
• Have received chemotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) in the past 2 years; ongoing adjuvant hormonal therapy for breast cancer is allowed