Phase II Lung Metcore - Preoperative Metformin for Lung Cancer (Metcore)

August 18, 2020 updated by: University Health Network, Toronto

Phase II Study of Single Agent Pre-operative Metformin in Patients With Clinical Stage I - IIIA NSCLC Proceeding to Surgical Resection. 'Lung Metcore Study'

This is a phase II single centre open label single arm pre-operative window of metformin treatment in stage I-IIIa Non small cell lung cancer.

In which patients will be invited to participate by receiving Metformin treatment during 14 to 21 days at 850 mg BID until the day before surgery.

They will be followed closely for any Adverse Events during treatment and 30 days after surgery. During treatment there will be no follow up tests except 1 fasting blood glucose at week 2 of treatment.

Survival data will be prospectively gathered after study treatment has ended until death.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Title of study: Phase II study of single agent pre-operative metformin in patients with clinical stage I - IIIA NSCLC proceeding to surgical resection. 'Lung Metcore Study'

Objectives:

To evaluate the effects of short-term pre-operative exposure to metformin in operable stages I to IIIA NSCLC.

Primary end-points:

  • The difference in the proportion of proliferating NSCLC cells (measured by comparing Ki67 levels) prior to and after metformin treatment.
  • The rate of apoptosis of NSCLC (measured by the TUNEL assay) prior to and after metformin treatment.

Secondary end-points:

  • The safety and tolerability of preoperative metformin administration in NSCLC, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE [version 4.0])
  • Pathologic changes in lung tissue after metformin administration. Study Design: This trial is designed as a single center, open label, single arm Phase II study of a pre-operative window of metformin treatment in stages I - IIIA NSCLC. The efficacy of metformin will be assessed by its effects on markers of cellular proliferation and apoptosis. Exploratory analysis of molecular markers of the hypothesized effects of metformin in NSCLC will also be carried out. Furthermore, changes in serum ligands to growth signaling pathways in lung cancer with metformin treatment will be measured.

Number of patients: Thus, the total expected sample size is approximately 50 patients, anticipating minimal loss of eligible participants through treatment intolerance or acceleration of surgery. Accrual is estimated at 1.5 to 2 patients per month for 25 to 33 months, based on accrual rates for a recent pre-operative window thoracic surgical study at UHN.

• Metformin will be started at a dose of 850mg daily then increased to 850mg b.i.d. (morning and evening) after 5 days as tolerated. Treatment will be given from the time of enrollment till the evening prior to surgery.

Correlatives:

The following molecular and serological correlative biomarkers will be considered covariates in the analysis of primary endpoints of the phase II study. Covariate pretreatment values and changes in covariate values (where applicable) will be used to estimate the relationship between covariates and patient's Ki67 or apoptotic response using logistic regression. It is noted that several covariates are being tested and the number of patients being analyzed is small, thus, some tests may be statistically significant due to chance even if no association exists.

  • Genetic Mutations in NSCLC (On pre-treatment biopsies by molecular techniques):

    • LKB1 mutational status (Sequencing)
    • EGFR, Ras, AKT, PI3K mutations (Oncocarta platform)
    • EGFR gene copy number (FISH)
    • ALK rearrangement status

  • Protein Marker of Resistance To Metformin (On pre-treatment biopsies by immunohistochemistry

    • OCT1 expression
    • PROTEIN MARKERS OF RECEPTORS AND ACTIVATED PATHWAYS TO mtor IN NSCLC (Comparison between pre-treatment biopsies and post-resection specimens by immunohistochemistry):
    • IR
    • IGF-1R
    • Phosphorylated-AMPK
    • EGFR and phospho-EGFR
    • PKB (AKT) and phospho-AKT
    • Phosphorylated (erbb2, erbb3, erbb4)
    • Phosphorylated-STAT3
    • Phospho-ribosomal protein S6

  • VASCULARITY IN NSCLC (Comparison between pre-treatment biopsies and post-resection specimens by immunohistochemistry):

    • VEGF
    • Microvessel density count (CD34, CD105)

  • SERUM LIGANDS TO SIGNALLING PATHWAYS IN NSCLC (Comparison between pre-treatment biopsies and post-resection specimens by ELISA):

    • Insulin
    • Glucose
    • IGF-1
    • TGF-α
    • TNF-α
    • Calculated HOMA
    • CRP
    • Adiponectin

Statistics:

Patients who completed metformin treatment will have the Ki67 and apoptosis scores compared between samples obtained pre and post-metformin treatment. Changes in Ki67 and apoptotic scores with metformin treatment will be correlated with the biomarkers of various pathways hypothesized to mediate an effect of metformin on NSCLC development.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
28

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

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

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 2C4
        • Toronto General Hospital
      • Toronto, Ontario, Canada, M5G 2M9
        • Princess Margaret Hospital

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Have biopsy-proven non-small cell lung carcinoma (NSCLC) of any histological variant except for neuroendocrine tumors. Patients must not have mixed NSCLC and small cell lung cancer (SCLC).
  • Be of clinical stage I to IIIA (according to the 7th lung cancer TNM classification and staging system) by radiologic and/or pathologic criteria where appropriate (e.g. mediastinoscopic staging). Baseline CT-chest scan must be within 4 weeks of study entry.
  • Be deemed appropriate candidates for surgical resection by the treating surgeon and assessing team.
  • Be aged - 18 years or more.
  • Have ECOG performance status - 2.

  • Have organ and marrow function as defined below for safe lung biopsy and administration of metformin:

    • Platelets -100 000
    • Total bilirubin -1.5 X institutional upper limit of normal
    • AST/ALT -2 X institutional upper limit of normal
    • Creatinine clearance -60 mL/min/1.73 m2
  • Have the ability to understand and the willingness to sign a written informed consent document.
  • Not require emergency surgery within 14 days of staging investigations.
  • Not have received anticancer treatment with chemotherapy, radiotherapy or Epidermal - - Growth Factor Receptor (EGFR) inhibitor therapy for the current lung cancer.
  • Not have a concomitant active malignancy or be receiving any other investigational or anticancer agents while on the study, to avoid the influence of alternative anti-cancer therapy. Otherwise, those with a past history of cancer are eligible.

Exclusion Criteria:

  • Not have a past history of an allergic reaction to metformin.
  • Not have a past history of diabetes mellitus or fasting glucose ≥ 7.0 mmol/L.
  • Not have a past history of lactic acidosis or metabolic acidosis.
  • Not have consumption of ≥ 3 alcoholic beverages per day (average).
  • Not have had regular use of agents that may influence insulin sensitivity/levels within 4 weeks of study entry.

  • Not have uncontrolled intercurrent illness (es) including but not limited to: ongoing or active:

    • Infection,
    • Symptomatic congestive
    • Cardiac failure or evidence of cardiac dysfunction,
    • Unstable angina pectoris,
    • Cardiac arrhythmia,
    • Active peptic ulcer disease or gastrointestinal conditions (e.g. Inflammatory bowel disease) or
    • Psychiatric illness/social situations that would limit compliance with study requirements.
  • Not be on a loop diuretic due to their potential to cause renal impairment and predispose to lactic acidosis.
  • Not have contrast-enhanced imaging (except when clinically indicated) while on the study. Iodinated contrast agents can cause renal failure, leading to metformin accumulation and lactic acidosis.
  • Women should not be pregnant or become pregnant during study.

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: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Metformin
14 to 21 days of pre-operative Metformin tablets First 5 days 850 mg OD v/o 850 mg BID thereafter until 21 days are completed.
Drug: Metformin
850 mg tablets v/o OD for first 5 days 850 mg tablets v/o BID until day 21
Other Names:
  • Glucophage

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Ki67
Time Frame: 45 days after surgery
• The difference in the proportion of proliferating NSCLC cells (measured by comparing Ki67 levels) prior to and after metformin treatment.
45 days after surgery
Apoptosis
Time Frame: 45 days after surgery
• The rate of apoptosis of NSCLC (measured by the TUNEL assay) prior to and after metformin treatment.
45 days after surgery

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: During a minimum of 14 days and maximum of 21 days patients will be assessed every 5 days during treatment and 30 days after surgery
• The safety and tolerability of preoperative metformin administration in NSCLC, as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE [version 4.0])
During a minimum of 14 days and maximum of 21 days patients will be assessed every 5 days during treatment and 30 days after surgery
Pathology
Time Frame: 45 days after surgery
• Pathologic changes in lung tissue after metformin administration
45 days after surgery

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Health Network, Toronto

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Tom Waddell, MD, Head of Thoracic Surgery Division

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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 5, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2020

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 24, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 15, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 22, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 19, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 18, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 15-9560.0 - Lung Metcore Study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

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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