This phase II trial determines the effect of metformin extended release on the risk for developing lung cancer in overweight/obese patients that are at high-risk for developing lung cancer. Metformin is widely used to treat type II diabetes and has a long history of safety and minimal side effects. At similar dosage, the drug may have potential anti-cancer activity. Metformin use has been associated with improved survival in patients with non-small cell lung carcinoma, a specific type of lung cancer, and it has also been shown to enhance immune mobilization against tumors. This trial aims to see whether metformin extended release as a preventative treatment may lower the chance of developing lung cancer, and whether it may help patients' immune system learn ("reprogram") to lower a certain type of immune cell (called regulatory T cells) that are linked to tumor development.

PRIMARY OBJECTIVE:

I. To evaluate the effect of metformin treatment on the expression of programmed cell death protein 1 (PD-1) on airway regulatory T cells (Tregs) in overweight and obese individuals at high risk for lung cancer.

SECONDARY OBJECTIVES:

I. Estimated PD-1 expression of pulmonary Tregs change in Cohort B during the wait period (26 weeks with no treatment).

II. To examine the impact of metformin on circulating immune cell subsets of blood.

III. To evaluate the effect of metformin treatment on the expression of PD-1 on airway regulatory T cells (Tregs) in overweight and obese current smokers at high risk for lung cancer

EXPLORATORY OBJECTIVES:

I. To examine the impact of metformin on cancer-related transcriptome features of airway lesions.

II. To examine the impact of metformin on immune profile of pulmonary parenchyma represented by bronchoalveolar lavage (BAL).

III To examine the impact of metformin on histologic progression of abnormal airway lesions.

IV. To examine the impact of metformin on serum adipokines and inflammatory cytokines.

OUTLINE: Participants are randomized to 1 of 2 cohorts.

COHORT A: Former Smokers - Participants receive metformin extended release (ER) orally (PO) once daily (QD) for 26 weeks in the absence of unacceptable toxicity. Participants undergo bronchoscopy biopsy and blood sample collection at screening, and week 13.

COHORT B: Former Smokers - Participants receive no intervention for 26 weeks, then cross-over to cohort A. Participants undergo bronchoscopy biopsy and blood sample collection at screening, at week 26, and at 13 weeks after cross-over to Cohort A.

COHORT C: Current Smokers - Participants receive metformin extended release (ER) orally (PO) once daily (QD) for 26 weeks in the absence of unacceptable toxicity. Participants undergo bronchoscopy biopsy and blood sample collection at screening, and week 13.

After completion of study treatment, participants are followed up at weeks 30-32 (Cohorts A and C) and weeks 56-58 (Cohort B).

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) Lung Cancer 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 accrue enough smoking exposure followed by enough time after quitting (>12 months) to qualify

• 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 be calculated using the equation Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine)

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

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

• The effects of metformin ER on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, 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

• Ability to understand and the willingness to sign a written informed consent document

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 or biologic composition to metformin ER

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

• 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 the past 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 acidosis such as: severe congestive heart failure (New York Heart Association [NYHA] class III or IV), metabolic acidosis, severe liver disease, or renal failure

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

• Pregnant women are excluded from this study. Metformin ER is a class B agent that was not teratogenic in rats and rabbits at doses representing 3 and 6 times the maximum recommended human daily dose of 2000 mg; however, animal reproduction studies are not always predictive of human response. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with metformin ER, breastfeeding should be discontinued if the mother is treated 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) diagnosis are allowed to participate, as long as there has been 12 months since the completion of cancer treatment prior to enrollment with no evidence of recurrence or second primary cancer

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