Summary

This phase IIb trial tests whether metformin works in preventing oral cancer in patients with oral leukoplakia (white patches) or erythroplakia (red patches). Metformin is in a class of drugs called biguanides. Metformin helps to control the amount of glucose (sugar) in the blood. It decreases the amount of glucose patients absorb from food and the amount of glucose made by the liver. Metformin also increases the body's response to insulin, a natural substance that controls the amount of glucose in the blood. This trial may help researchers determine if metformin can stop changes in the mouth that are related to pre-cancer growths in the mouth.

Objectives

PRIMARY OBJECTIVE:
I. To determine the histological response to metformin hydrochloride (metformin) intervention in the target lesion.

SECONDARY OBJECTIVES:
I. Clinical response to metformin intervention in the target lesion.
II. Effect of metformin on cell proliferation (Ki67) and its molecular targets (pS6 and nuclear YAP) in the target lesion.
III. Metformin effect on serum metabolic markers (C-peptide, glucose and HbA1c).
IV. Trough plasma metformin concentrations.

EXPLORATORY OBJECTIVES:
I. Expression of dysregulated molecular mechanisms in the target lesion, including, in order of priority, p53, PTEN, p16, EGFR, and pEGFR.
II. Immune cell infiltration and markers of inflammation in the target lesion.
III. Analysis of genomic alterations in the target lesion and blood deoxyribonucleic acid (DNA).
IV. Microbiome in oral rinses.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive extended release metformin hydrochloride orally (PO) once daily (QD) for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and biopsy at baseline and week 24.

ARM II: Patients receive a placebo PO QD for 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and biopsy at baseline and week 24.

After completion of study treatment, patients are followed for up to 3 weeks.

Eligibility

1. Participants with oral leukoplakia or erythroplakia with mild, moderate, or severe histologic dysplasia or hyperplasia at the high risk sites (e.g., floor of mouth, tongue). Oral proliferative verrucous leukoplakia (PVL) or proliferative verrucous hyperplasia are allowed. Lesions arising from the radiation field are excluded as study lesions.
2. Measurable disease – minimum lesion size of 8x3 mm before initial biopsy
3. Age >= 21 years. Adults 18-20 are not included as Canadian law prohibits purchase of cigarettes under the age of 21; investigators wish to keep criteria consistent among all trial sites. Also, smokers aged < 20 years would most likely not have oral leukoplakia
4. Karnofsky performance scale >= 70%
5. Current and former use of tobacco products, with a minimum use of smokeless tobacco (such as snuff or chewing tobacco) at least 20 times OR combustible tobacco (such as cigarettes, cigars, or pipe smoking) equivalent to at least 100 cigarettes over one’s lifetime. For cigarette equivalence, 1 cigar is considered equivalent to 4 cigarettes, and 1 pipe fill is considered equivalent to 3.5 cigarettes.
6. Leukocytes >= 3,000/microliter
7. Absolute neutrophil count >= 1,000/microliter
8. Platelets >= 100,000/microliter
9. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
10. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional ULN
11. Estimation glomerular filtration rate (eGFR) > 45 mL/min (eGFR calculated using the equation Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine)
12. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
13. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
14. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
15. Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
16. Ability to take oral medication
17. Willing to use adequate contraception (barrier method, abstinence, subject or partner has had a vasectomy or partner is using effective birth control or is postmenopausal) for the duration of study participation because the effects of metformin on the developing human fetus are unknown even though it is not teratogenic in rats and rabbits at 2-6 times the maximum recommended human daily dose. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
18. Ability to understand and the willingness to sign a written informed consent document in English or Spanish
19. Willing to avoid excessive alcohol consumption during the course of the study, defined as: * For males: avoiding consumption of more than 14 drinks per week OR more than 4 drinks on a single occasion (defined as a 2-hour period) * For females: avoiding consumption of more than 7 drinks per week OR more than 3 drinks on a single occasion (defined as a 2-hour period)

Treatment Sites in Georgia