Metformin Pharmacology in Human Cancers: A Proof of Principle Study

  • STATUS
    Recruiting
  • End date
    Dec 1, 2021
  • participants needed
    20
  • sponsor
    Dartmouth-Hitchcock Medical Center
Updated on 28 January 2021

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.

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.

Details
Condition Thoracic Neoplasms
Treatment Metformin
Clinical Study IdentifierNCT03477162
SponsorDartmouth-Hitchcock Medical Center
Last Modified on28 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Thoracic Neoplasms?
Do you have any of these conditions: Do you have Thoracic Neoplasms??
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
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