Metformin Pharmacology in Human Cancers: A Proof of Principle Study

Metformin Pharmacology in Human Cancers

Status

Terminated

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03477162

Enrollment

Registered

2018-03-26

Start date

2018-05-15

Completion date

2021-11-30

Last updated

2023-10-03

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Thoracic Neoplasm

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.

Interventions

DRUGMetformin

Metformin will be given to patients prior to surgery.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Lung Tumor Tissue Concentration of Metformin	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.

Secondary

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

Other

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Metformin Patients given Metformin prior to surgery	14
Control Patient not given metformin prior to surgery	1
Total	15

Baseline characteristics

Characteristic	Metformin	Total	Control
Age, Continuous	70.9 years STANDARD_DEVIATION 6	70.9 years STANDARD_DEVIATION 7.2	75 years
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	14 Participants	15 Participants	1 Participants
Region of Enrollment United States	14 participants	15 participants	1 participants
Sex: Female, Male Female	9 Participants	9 Participants	0 Participants
Sex: Female, Male Male	5 Participants	6 Participants	1 Participants
Subject already taking metformin at time of study entry	13 Participants	13 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 14	0 / 1
other Total, other adverse events	1 / 14	0 / 1
serious Total, serious adverse events	0 / 14	0 / 1

Outcome results

Primary

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.