Metformin for Chemoprevention of Lung Cancer in Overweight or Obese Individuals at High Risk for Lung Cancer

Inclusion Criteria:

• Former smokers (male and female) with a >= 20 pack year smoking history

• Quit smoking >= 12 months prior to enrollment

• Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCOm2012) LungCancer Risk Prediction Score > 1.34%

• Overweight

• Body mass index (BMI) > 25 and

• Waist circumference

• Female > 88 cm (35")

• Male > 102 cm (40")

• Age greater than 30 years. Participants younger than 30 years are unlikely to accrueenough smoking exposure followed by enough time after quitting (>12 months) toqualify

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Leukocytes >= 3,000/microliter

• Absolute neutrophil count (ANC) >= 1,000/microliter

• Platelets >= 100,000/microliter

• Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x IULN

• Estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73 m^2 (eGFR will becalculated using the equation Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine)

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured

• Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) areeligible

• The effects of metformin ER on the developing human fetus at the recommendedtherapeutic dose are unknown. For this reason, women of child-bearing potential andmen must agree to use adequate contraception (hormonal or barrier method of birthcontrol; abstinence) prior to study entry and for the duration of studyparticipation. Should a woman become pregnant or suspect she is pregnant whileparticipating in this study, she should inform her study physician immediately

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Current or previous diagnosis of diabetes mellitus (type I or type II diabetes)

• Use of metformin within the past 2 years

• Use of GLP-1 agonists within 6 weeks prior to enrollment

• Glycosylated hemoglobin A1C (HbA1c) > 8%

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to metformin ER

• Participants currently using immunosuppressive medication, including systemicsteroids (not inhalational) and episodic use of inhaled steroids are excluded fromthis trial due to the potential impact of these treatments on the primary trialendpoint

• Participants receiving any other investigational agents

• History of chronic alcohol use or abuse defined by any one of the following:

• Average consumption of 3 or more alcohol containing beverages daily in the past 12 months

• Consumption of 7 or more alcoholic beverages within a 24 hour period in thepast 12 months

• Acute or chronic liver disease, evidence of hepatitis (infectious or autoimmune),cirrhosis or portal hypertension

• History of or current condition predisposing to increased risk for lactic acidosissuch as: severe congestive heart failure (New York Heart Association [NYHA] classIII or IV), metabolic acidosis, severe liver disease, or renal failure

• Uncontrolled intercurrent illness or psychiatric illness/social situations thatwould or limit compliance with study requirements

• Pregnant women are excluded from this study. Metformin ER is a class B agent thatwas not teratogenic in rats and rabbits at doses representing 3 and 6 times themaximum recommended human daily dose of 2000 mg; however, animal reproductionstudies are not always predictive of human response. Because there is an unknown butpotential risk for adverse events (AEs) in nursing infants secondary to treatment ofthe mother with metformin ER, breastfeeding should be discontinued if the mother istreated with metformin ER

• Biopsy with invasive carcinoma of the lung or carcinoma in situ

• Participants with prior stage 1 non-small cell lung cancer (NSCLC) diagnosisare allowed to participate, as long as there has been 12 months since thecompletion of cancer treatment prior to enrollment with no evidence ofrecurrence or second primary cancer