Ignite Creation Date:
2025-12-25 @ 2:54 AM
Ignite Modification Date:
2026-03-12 @ 10:44 AM
Study NCT ID:
NCT03086733
Status:
COMPLETED
Last Update Posted:
2020-08-19
First Post:
2017-02-24
Is Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Phase II Lung Metcore - Preoperative Metformin for Lung Cancer
Sponsor:
University Health Network, Toronto
Organization:
Study Overview
Official Title:
Phase II Study of Single Agent Pre-operative Metformin in Patients With Clinical Stage I - IIIA NSCLC Proceeding to Surgical Resection. 'Lung Metcore Study'
Status:
COMPLETED
Status Verified Date:
2020-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Metcore
Brief Summary:
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.
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.
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.
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 Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?: