Phase II Lung Metcore - Preoperative Metformin for Lung Cancer
Condition: Non Small Cell Lung Cancer; Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): Metformin
Intervention type(s): Drug
Intervention description(s): 850 mg tablets v/o OD for first 5 days 850 mg tablets v/o BID until day 21
Other intervention name(s): Glucophage
Intervention MeSH terms: Metformin
Intervention model: Single Group Assignment
Intervention model description: single center, open label, single arm Phase II study of a pre-operative window of metformin treatment in stages I - IIIA NSCLC
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lung Cancer; Non small cell lung cancer; Metformin; Pre-operative treatment; Neoadjuvant treatments; Cancer; Phase II