Phase II Lung Metcore - Preoperative Metformin for Lung Cancer

Titre officiel

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

Sommaire:

Cette étude monocentrique ouverte de phase II à groupe unique porte sur une fenêtre préopératoire de traitement par la metformine chez des patients atteints d’un cancer du poumon non à petites cellules de stade I à IIIa. Les patients seront invités à y participer en recevant un traitement par la metformine pendant 14 à 21 jours à une dose de 850 mg deux fois par jour jusqu’à la veille de l’intervention chirurgicale. Ils feront l’objet d’une surveillance étroite pour détecter tout effet indésirable pendant le traitement et 30 jours après l’intervention chirurgicale. Aucune analyse de suivi ne sera effectuée pendant le traitement, sauf une analyse de la glycémie à jeun à la deuxième semaine du traitement. Des données sur la survie seront recueillies de façon prospective après la fin du traitement à l’étude jusqu’au décès des patients.

Description de l'essai

Primary Outcome:

  • Ki67
  • Apoptosis
Secondary Outcome:
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
  • Pathology
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 centre, 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.

Voir cet essai sur ClinicalTrials.gov

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