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Metformin for Chemoprevention of Lung Cancer in Overweight or Obese Individuals at High Risk for Lung Cancer

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ClinicalTrials.gov Identifier: NCT04931017
Recruitment Status : Recruiting
First Posted : June 18, 2021
Last Update Posted : June 30, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial determines the effect of metformin extended release on the risk for developing lung cancer in overweight/obese patients that are at high-risk for developing lung cancer. Metformin is widely used to treat type II diabetes and has a long history of safety and minimal side effects. At similar dosage, the drug may have potential anti-cancer activity. Metformin use has been associated with improved survival in patients with non-small cell lung carcinoma, a specific type of lung cancer, and it has also been shown to enhance immune mobilization against tumors. This trial aims to see whether metformin extended release as a preventative treatment may lower the chance of developing lung cancer, and whether it may help patients' immune system learn ("reprogram") to lower a certain type of immune cell (called regulatory T cells) that are linked to tumor development.

Condition or disease Intervention/treatment Phase
Lung Carcinoma Drug: Extended Release Metformin Hydrochloride Phase 2

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate the effect of metformin treatment on the expression of programmed cell death protein 1 (PD-1) on airway regulatory T cells (Tregs) in overweight and obese individuals at high risk for lung cancer.

SECONDARY OBJECTIVES:

I. To examine the impact of metformin on histologic progression of abnormal airway lesions (key secondary endpoint).

II. Estimated PD-1 expression of pulmonary Tregs change in Cohort B (arm II) during the wait period (26 weeks with no treatment).

III. To examine the impact of metformin on circulating immune cell subsets of blood.

EXPLORATORY OBJECTIVES:

I. To examine the impact of metformin on cancer-related transcriptome features of airway lesions.

II. To examine the impact of metformin on immune profile of pulmonary parenchyma represented by bronchoalveolar lavage (BAL).

III. To examine the impact of metformin on serum adipokines and inflammatory cytokines.

OUTLINE: Participants are randomized to 1 of 2 arms.

COHORT A: Participants receive metformin extended release (ER) orally (PO) once daily (QD) for 26 weeks in the absence of unacceptable toxicity.

COHORT B: Participants receive no intervention for 26 weeks, then cross-over to Arm I.

After completion of study treatment, participants are followed up at weeks 30-32 (Cohort A) and weeks 56-58 (Cohort B).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: This is a partial crossover model whereby the no-treatment subjects will receive the drug after being controls.
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Metformin for Chemoprevention of Lung Cancer in High Risk Obese Individuals
Actual Study Start Date : March 18, 2022
Estimated Primary Completion Date : April 30, 2025
Estimated Study Completion Date : April 30, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Cohort A (metformin ER)
Participants receive metformin ER PO QD for 26 weeks in the absence of unacceptable toxicity.
Drug: Extended Release Metformin Hydrochloride
Given PO
Other Names:
  • ER Metformin Hydrochloride
  • Extended-release Metformin Hydrochloride
  • Glucophage XR
  • Glumetza
  • Metformin Hydrochloride Extended Release

Active Comparator: Cohort B (metformin ER with waiting period))
Participants receive no intervention for 26 weeks, then cross-over to Cohort A.
Drug: Extended Release Metformin Hydrochloride
Given PO
Other Names:
  • ER Metformin Hydrochloride
  • Extended-release Metformin Hydrochloride
  • Glucophage XR
  • Glumetza
  • Metformin Hydrochloride Extended Release




Primary Outcome Measures :
  1. PD-1 expression of pulmonary regulatory T cells (Tregs) before and after metformin extended release (ER) treatment [ Time Frame: Pre- to post-treatment ]
    Change from pre- to post-metformin ER treatment in cell surface PD-1 expression levels of pulmonary (BAL) Tregs, measured as mean fluorescent intensity (MFI). Changes in MFI due to metformin ER treatment among all n = 40 subjects will be used for the primary analysis.


Secondary Outcome Measures :
  1. Histologic progression [ Time Frame: Up to study completion ]
    Bronchoscopic biopsies of at least 6 standard sites will be graded on the World Health Organization (WHO) scale of dysplasia and assigned numerical scores from 1 (normal) to 8 (invasive cancer). Each lesion will be classified as complete response (CR), partial response (PR), stable disesae (SD) or progressive disease (PD) and each response rate will be calculated on a per-site and a per-participant basis. Additional measures of dysplasia will include the average dysplastic score and the dysplasia index (% of sites with dysplasia score >= 3 (mild dysplasia)). Changes in maximum dysplasia will be analyzed using a paired t test to determine whether a reduction occurs.

  2. Estimated PD-1 expression of pulmonary Tregs change in cohort B during the wait period (6 months with no treatment) [ Time Frame: Randomization to week 26 ]
    This is the estimate of change in MFI following the 6-month wait period among n = 20 subjects randomized to arm II. This will confirm the stability of the PD-1 expression of pulmonary Tregs over time.

  3. Circulating immune cells [ Time Frame: Pre- to post-treatment ]
    Circulating immune cell composition between blood samples collected pre- and post-metformin ER treatment to assess the effect of metformin ER on circulating immune cells and to identify potential biomarkers of metformin ER response.

  4. Airway gene expression [ Time Frame: Up to study completion ]
    RNA sequencing of endobronchial biopsies will be performed at visually normal mainstem airway for each participant. The analysis of the RNA seq data will be an unsupervised comparison of differentially expressed genes with and without metformin ER exposure.


Other Outcome Measures:
  1. Examination of the immune profile of pulmonary parenchyma represented by bronchoalveolar lavage [ Time Frame: Pre- to post-treatment ]
    This will compare the immune composition of bronchoalveolar lavage samples of participants before and after metformin exposure. Specifically, the prevalence and composition of myeloid derived suppressor cells (MDSCs) as well as monocyte, macrophage and dendritic cells will be assessed.

  2. Examination of the effect of metformin on systemic adipokines and inflammatory cytokines [ Time Frame: Pre- to post-treatment ]
    Frozen sera will be analyzed by commercial enzyme-linked immunosorbent assay kits for levels of leptin, adiponectin, resistin, IL6 and TNFalpha. Pre- and post-treatment serum levels will be compared in parametric paired testing.



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Former smokers (male and female) with a >= 20 pack year smoking history
  • Quit smoking >= 12 months prior to enrollment
  • Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCOm2012) Lung Cancer Risk Prediction Score > 1.34
  • Overweight

    • Body mass index (BMI) > 25 and
    • Waist circumference

      • Female > 88 cm (35")
      • Male > 102 cm (40")
  • Age greater than 30 years. Participants younger than 30 years are unlikely to accrue enough smoking exposure followed by enough time after quitting (>12 months) to qualify.
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Leukocytes >= 3,000/microliter
  • Absolute neutrophil count (ANC) >= 1,500/microliter
  • Platelets >= 100,000/microliter
  • Total bilirubin < 1.5 x institutional upper limit of normal (IULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x IULN
  • Estimated glomerular filtration rate (eGFR) > 45 ml/min (eGFR will be calculated using the equation Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine)
  • Abnormal histology of at least one biopsy site on the baseline bronchoscopy defined as either metaplasia or dysplasia (mild, moderate, or severe). These correspond to a dysplasia score of 3-6
  • The effects of metformin ER on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Current or previous diagnosis of diabetes mellitus (type I or type II diabetes)
  • Use of metformin within the past 2 years
  • Glycosylated hemoglobin A1C (HbA1c) > 8%
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin ER.
  • Participants currently using immunosuppressive medication, including systemic steroids (not inhalational) and episodic use of inhaled steroids are excluded from this trial due to the potential impact of these treatments on the primary trial endpoint.
  • Participants receiving any other investigational agents.
  • History of chronic alcohol use or abuse defined by any one of the following:

    • Average consumption of 3 or more alcohol containing beverages daily in the past 12 months
    • Consumption of 7 or more alcoholic beverages within a 24 hour period in the past 12 months
  • Acute or chronic liver disease, evidence of hepatitis (infectious or autoimmune), cirrhosis or portal hypertension.
  • History of or current condition predisposing to increased risk for lactic acidosis such as: severe congestive heart failure (New York Heart Association [NYHA] class III or IV), metabolic acidosis, severe liver disease, or renal failure.
  • Uncontrolled intercurrent illness that would raise concerns of safety or limit compliance with study requirements.
  • Pregnant women are excluded from this study. Metformin ER is a class B agent that was not teratogenic in rats and rabbits at doses representing 3 and 6 times the maximum recommended human daily dose of 2000 mg; however, animal reproduction studies are not always predictive of human response. Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with metformin ER, breastfeeding should be discontinued if the mother is treated with metformin ER.

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): NCT04931017


Locations
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United States, Colorado
Rocky Mountain Regional VA Medical Center Recruiting
Aurora, Colorado, United States, 80045
Contact: Robert L. Keith    720-857-5120    Robert.keith@cuanschutz.edu   
Principal Investigator: Robert L. Keith         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Contact: Saikrishna S. Yendamuri    716-364-4852    sai.yendamuri@roswellpark.org   
Principal Investigator: Saikrishna S. Yendamuri         
Canada, British Columbia
University of British Columbia Hospital Not yet recruiting
Vancouver, British Columbia, Canada, V6T 2B5
Contact: Stephen Lam    604-675-8090    slam2@bccancer.bc.ca   
Principal Investigator: Stephen Lam         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Saikrishna S Yendamuri Roswell Park University
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04931017    
Other Study ID Numbers: NCI-2021-06112
NCI-2021-06112 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NCI20-04-01 ( Other Identifier: Northwestern University )
NWU20-04-01 ( Other Identifier: DCP )
P30CA060553 ( U.S. NIH Grant/Contract )
UG1CA242643 ( U.S. NIH Grant/Contract )
First Posted: June 18, 2021    Key Record Dates
Last Update Posted: June 30, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs