Metformin Pharmacology in Human Cancers: A Proof of Principle Study

November 30, 2022 updated by: Joseph D. Phillips, MD., Dartmouth-Hitchcock Medical Center

Metformin Pharmacology in Human Cancers

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New Hampshire
      • Lebanon, New Hampshire, United States, 03756
        • Dartmouth Hitchcock Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin
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
Metformin will be given to patients prior to surgery.

What is the study measuring?

Primary Outcome Measures

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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
AMPK Activity Alterations.
Time Frame: Within 7 days from surgery.
To determine whether metformin alters AMPK activity in tumor cells.
Within 7 days from surgery.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Dartmouth-Hitchcock Medical Center

Investigators

  • Principal Investigator: Joseph Phillips, MD, Dartmouth-Hitchcock Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 15, 2018

Primary Completion (Actual)

November 30, 2021

Study Completion (Actual)

November 30, 2021

Study Registration Dates

First Submitted

March 14, 2018

First Submitted That Met QC Criteria

March 23, 2018

First Posted (Actual)

March 26, 2018

Study Record Updates

Last Update Posted (Actual)

October 3, 2023

Last Update Submitted That Met QC Criteria

November 30, 2022

Last Verified

November 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • D17188

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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