Metformin Pharmacology in Human Cancers: A Proof of Principle Study

To understand the variability in clinical results testing metformin as an anti-cancer agent,
it is important to determine the concentrations of metformin that are achievable in tissue.
Clinical effects of metformin develop gradually over several days of treatment. Steady-state
plasma metformin concentrations are correlated with anti-hyperglycemic response. Thus,
achieving steady-state concentrations in this study will allow accurate determination of the
most representative concentrations of metformin in normal and cancerous tissues, as well as
determine AMP-activated protein kinase (AMPK) signaling differences in these tissues. As tha
Primary Objective is to determine the concentration of metformin in tumors, patients will be
treated with metformin extended release (ER) (Glucophage® XR), starting at 750 milligrams
(mg) oral (PO) once daily (QD) for 4 days, then escalating to 750 mg PO twice daily (BID) for
3-6 days prior to surgery. FDA prescribing information indicates that metformin reaches
steady-state plasma concentrations within 24-48 hours after the start of dosing in humans;
thus, the 7-to-10-day time frame of this study will allow sufficient time for metformin to
reach steady-state plasma concentrations, in addition to time allotted for potential
accumulation in tissues. Metformin concentrations will be measured using a validated liquid
chromatography-mass spectrometry (LC-MS/MS) assay.

Inclusion Criteria:

- Invasive malignant solid tumor of thoracic origin (e.g., lung, esophageal, thymus,
mesothelioma, chest wall, mediastinum, trachea, pleura) with the intent to treat or
biopsy by surgery as standard of care. Tumor must be ≥2 centimeters (cm).

- Patients with multicentric disease are eligible. Samples from all available tumors are
requested for research purposes.

- Patients with Type 2 diabetes mellitus being treated with metformin (any dose) for a
clinical indication at the time of study enrollment are eligible, and will continue
metformin treatment as clinically indicated during the presurgical study period. Their
dose of metformin will NOT be changed.

- Patients not on metformin at the time of study entry must be willing to take metformin
extended release (Glucophage® XR, 750 mg QD for 4 days, then 750 mg BID for 3-6 days)
for a total of 7-10 days prior to surgery.

- Patients do not require a diagnosis of diabetes to be enrolled in the study.

- All patients must be willing to keep a drug diary indicating the dates and times of
metformin administration.

Patients must meet the following clinical laboratory criteria:

- Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 and platelet count
greater than or equal to 75,000/mm3.

- Total bilirubin less than or equal to 1.5x the upper limit of the normal range (ULN).

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal
to 3x ULN.

- Estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73m2 or estimated creatinine
clearance (eCrCL) > 60 mL/min

- Ability to give informed consent.

- Patients must be willing to provide 20 milliliters (mL) of blood for research use.

- Patient must be willing to provide consent for use of archived tissue for research.

Exclusion Criteria:

- History of diabetes that is currently being treated without metformin.

- Patients who, at the time of study entry, are not taking metformin for a clinical
indication, and who will need a radiographic analysis with an iodinated contrast agent
during the metformin study treatment period.

- This criterion does not apply to patients taking clinically indicated metformin at the
time of study entry.

- History of liver disease as defined with liver function tests (LFTs) above those in
the inclusion

- Known hypersensitivity to metformin.

- History of reactive hypoglycemia.

- Active or history of lactic acidosis, metabolic acidosis, or diabetic ketoacidosis.