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Metformin Pharmacology in Human Cancers: A Proof of Principle Study

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ClinicalTrials.gov Identifier: NCT03477162
Recruitment Status : Recruiting
First Posted : March 26, 2018
Last Update Posted : January 25, 2019
Sponsor:
Information provided by (Responsible Party):
Joseph D. Phillips, MD., Dartmouth-Hitchcock Medical Center

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.

Condition or disease Intervention/treatment Phase
Thoracic Neoplasm Drug: Metformin Early Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Metformin Pharmacology in Human Cancers
Actual Study Start Date : May 15, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2019

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Tumor 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.


Secondary Outcome Measures :
  1. Concentration of Metformin in adipose tissue [ Time Frame: Within 7 days from surgery ]
    To determine the concentration of metformin in adipose tissue.

  2. 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.

  3. Concentration of Metformin in plasma. [ Time Frame: Within 7 days from surgery ]
    To determine the concentration of metformin in plasma.

  4. Concentration of Metformin in whole blood. [ Time Frame: Within 7 days from surgery ]
    To determine the concentration of metformin in whole blood.

  5. AMPK activity alterations. [ Time Frame: Within 7 days from surgery. ]
    To determine whether metformin alters AMPK activity in tumor cells.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03477162


Contacts
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Contact: Kayla Fay 603-650-8537 Kayla.A.Fay@hitchcock.org
Contact: Research Nurse 800-639-6918 cancer.research.nurse@dartmouth.edu

Locations
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United States, New Hampshire
Dartmouth Hitchcock Medical Center Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Kayla Fay    603-650-8537    Kayla.A.Fay@hitchcock.org   
Contact: Research Nurse    800-639-6918    cancer.research.nurse@dartmouth.edu   
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
Investigators
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Principal Investigator: Joseph Phillips, MD Dartmouth-Hitchcock Medical Center

Publications:
Glucophage XR product insert. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0ahUKEwjcrMLO8cPXAhWGZiYKHVe1DoMQFggrMAA&url=https%3A%2F%2Fpackageinserts.bms.com%2Fpi%2Fpi_glucophage.pdf&usg=AOvVaw2zAbyMgwlF7wxaXv60vtv3.

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Responsible Party: Joseph D. Phillips, MD., Staff Physician, Thoracic Surgery, Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT03477162     History of Changes
Other Study ID Numbers: D17188
First Posted: March 26, 2018    Key Record Dates
Last Update Posted: January 25, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs