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

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

Study Description

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).

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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.

Contacts and Locations

Locations

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

• Principal Investigator: Saikrishna S Yendamuri; Roswell Park University

More Information

• 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
• 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Metformin; Hypoglycemic Agents; Physiological Effects of Drugs