Metformin Pharmacology in Human Cancers: A Proof of Principle Study

Study Overview
=================
Brief Summary
-----------------
This is a presurgical (proof of principle, window of opportunity) study in patients with surgically resectable thoracic tumors to determine steady-state tissue and plasma concentrations of metformin.

Detailed Description
-----------------
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.

Official Title
-----------------
Metformin Pharmacology in Human Cancers

Conditions
-----------------
Thoracic Neoplasm

Intervention / Treatment
-----------------
* Drug: Metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Patients enrolled will be treated with metformin (administered orally; 750 mg QD for 4 days, then 750 mg BID for 3-6 days; or clinically indicated metformin) for a total of 7-10 days prior to surgery, up until the night before surgery. | Drug: Metformin<br>* Metformin will be given to patients prior to surgery.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lung Tumor Tissue Concentration of Metformin | To determine the intra-tumor concentrations of metformin, with a standard deviation ≤25% of the mean, in patients with solid tumors of thoracic origin administered metformin extended release. | Within 7 days from surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Metformin in Adipose Tissue | To determine the concentration of metformin in adipose tissue. | Within 7 days from surgery | 
| Concentration of Metformin in Tumor-adjacent Normal Tissue | To determine the concentration of metformin in tumor-adjacent normal tissue. | Within 7 days from surgery | 
| Concentration of Metformin in Plasma. | To determine the concentration of metformin in plasma. | Within 7 days from surgery | 
| Concentration of Metformin in Whole Blood. | To determine the concentration of metformin in whole blood. | Within 7 days from surgery |