<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02247453</url>
  </required_header>
  <id_info>
    <org_study_id>INT11-21</org_study_id>
    <nct_id>NCT02247453</nct_id>
  </id_info>
  <brief_title>Plasma microRNA Profiling as First Line Screening Test for Lung Cancer Detection: a Prospective Study</brief_title>
  <acronym>BIOMILD</acronym>
  <official_title>Plasma microRNA Profiling as First Line Screening Test for Lung Cancer Detection: a Prospective Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In the present project we propose a large prospective study in heavy smokers volunteers based&#xD;
      on plasma miRNA profiling to assess its efficacy as a first line screening test for lung&#xD;
      cancer detection.&#xD;
&#xD;
      The study will be articulated in different phases: i) analysis of 1000 plasma samples of&#xD;
      disease-free smokers already collected in our biological repository in the last two years ii)&#xD;
      de-novo enrollment of 4000 smoking volunteers, collection of their blood samples and&#xD;
      inclusion in a program of active surveillance on the basis of their miRNA risk profile iii)&#xD;
      assessment of miRNA expression profile using a custom made microfluidic card containing the&#xD;
      24 miRNA previously identified in the diagnostic signatures iii) bioinformatic analyses of&#xD;
      miRNA ratios in the cohort in order to determine which individuals are in presence or will&#xD;
      develop lung cancer and in particular the aggressive form of the disease iv) assessment of&#xD;
      the best diagnostic and treatment algorithm for subjects with suspicious miRNA profiles v)&#xD;
      functional validation of miRNAs as novel therapeutic targets using novel cellular genetically&#xD;
      engineered models of transformation and patients' tumorgrafts models.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Three decades of research have shown that radiological screening of heavy smokers can detect&#xD;
      resectable early lung cancers with higher frequency but benefit on mortality is still&#xD;
      debated. The preliminary results of the first two randomized spiral-CT screening trials&#xD;
      appear conflicting, with one study showing no benefit and the other a limited mortality&#xD;
      reduction (-7%). In the next 3-4 years the ongoing randomised trials in Europe will provide&#xD;
      conclusive data on the efficacy of CT-screening for lung cancer. Nonetheless, no major impact&#xD;
      on mortality is to be expected.&#xD;
&#xD;
      A possible explanation of these finding is that not all aggressive lung tumors arise from&#xD;
      identifiable slow-growing precursors, thus suggesting a possible paradigm shift in our&#xD;
      understanding of the natural history of lung cancer. In this respect the identification of&#xD;
      biologic and molecular features of indolent and aggressive disease could be useful to define&#xD;
      clinical predictors of high risk lesions and select suitable cohorts of patients who might&#xD;
      benefit of current treatments as well as to identify genetic signatures that might represent&#xD;
      novel therapeutic targets.&#xD;
&#xD;
      The investigators recently reported that microRNA (miRNA) expression expression profiles in&#xD;
      tumors and, for the first time, also in normal lung tissue are indicative of aggressive lung&#xD;
      cancer development and, of remarkable interest, that specific miRNA signatures can be&#xD;
      identified in plasma samples of patients up to two years before spiral-CT detection of the&#xD;
      disease, and able to identify the occurrence of early metastatic but spiral-CT invisible lung&#xD;
      tumors or small spiral-CT detected lesions with aggressive potential.&#xD;
&#xD;
      In the present project we propose a large prospective study in heavy smokers volunteers based&#xD;
      on plasma miRNA profiling to assess its efficacy as a first line screening test for lung&#xD;
      cancer detection.&#xD;
&#xD;
      The study will be articulated in different phases: i) analysis of 1000 plasma samples of&#xD;
      disease-free smokers already collected in our biological repository in the last two years ii)&#xD;
      de-novo enrollment of 4000 smoking volunteers, collection of their blood samples and&#xD;
      inclusion in a program of active surveillance on the basis of their miRNA risk profile iii)&#xD;
      assessment of miRNA expression profile using a custom made microfluidic card containing the&#xD;
      24 miRNA previously identified in the diagnostic signatures iii) bioinformatic analyses of&#xD;
      miRNA ratios in the cohort in order to determine which individuals are in presence or will&#xD;
      develop lung cancer and in particular the aggressive form of the disease iv) assessment of&#xD;
      the best diagnostic and treatment algorithm for subjects with suspicious miRNA profiles v)&#xD;
      functional validation of miRNAs as novel therapeutic targets using novel cellular genetically&#xD;
      engineered models of transformation and patients' tumorgrafts models.&#xD;
&#xD;
      Overall, the results of this large prospective study will permit to establish the potential&#xD;
      of our plasma microRNA assay as a first-line screening test for lung cancer detection in a&#xD;
      routine clinical practice for high-risk population screening with a low cost, non toxic and&#xD;
      non invasive procedure. Moreover, the related functional studies foreseen in the project&#xD;
      could lead to the identification of novel, miRNA targeted, therapeutic approaches for this&#xD;
      malignancy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>January 2013</start_date>
  <completion_date type="Anticipated">October 2026</completion_date>
  <primary_completion_date type="Actual">November 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Screening</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction of false positive cases in lung cancer detection in heavy smokers volunteers through plasma miRNA profiling as a first line screening test</measure>
    <time_frame>3 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>overall survival</measure>
    <time_frame>5 years</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">4119</enrollment>
  <condition>Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Screening</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Healthy heavy smokers aged 50-75 years</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>screening</intervention_name>
    <description>All subjects undergo baseline LDCT examination, spirometry and miRNA profiling. Individuals with negative miRNA profile repeat the plasma assay at 3 years. Individuals with low-risk miRNA profile repeat the plasma assay and LDCT at 2 years, without additional diagnostic examinations if not required by the screening protocol.&#xD;
Individuals with high-risk miRNA profile undergo additional diagnostic examinations consisting in PET in case of concurrent suspicious or positive CT, or WB MRI +- needle aspiration biopsy in case of negative CT.</description>
    <arm_group_label>Screening</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  current heavy smokers of ≥ 30 pack/years, aged 50-75, or former smokers with the same&#xD;
             smoking habits having stopped from 10 years or less;&#xD;
&#xD;
          -  current or former smokers of &lt; 30 pack/years, aged ≥ 50, with additional risk factors&#xD;
             such as family history of lung cancer, prior diagnosis of chronic obstructive&#xD;
             pulmonary disease (COPD) or pneumonia, professional exposure to known carcinogens&#xD;
             (i.e. asbestos).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  subjects with neoplasms within previous five years-&#xD;
&#xD;
          -  subjects with suspected lung nodules under investigation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ugo Pastorino, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Fondazione IRCCS Istituto Nazionale dei Tumori</name>
      <address>
        <city>Milan</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <link>
    <url>http://www.biomild.org</url>
    <description>clinical trial website</description>
  </link>
  <reference>
    <citation>Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabro E, Croce CM, Pastorino U, Sozzi G. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3713-8. doi: 10.1073/pnas.1100048108. Epub 2011 Feb 7.</citation>
    <PMID>21300873</PMID>
  </reference>
  <reference>
    <citation>Sozzi G, Pastorino U, Croce CM. MicroRNAs and lung cancer: from markers to targets. Cell Cycle. 2011 Jul 1;10(13):2045-6. doi: 10.4161/cc.10.13.15712. No abstract available.</citation>
    <PMID>21623159</PMID>
  </reference>
  <reference>
    <citation>Pastorino U, Rossi M, Rosato V, Marchiano A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, Pelosi G, La Vecchia C. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev. 2012 May;21(3):308-15. doi: 10.1097/CEJ.0b013e328351e1b6.</citation>
    <PMID>22465911</PMID>
  </reference>
  <reference>
    <citation>Boeri M, Pastorino U, Sozzi G. Role of microRNAs in lung cancer: microRNA signatures in cancer prognosis. Cancer J. 2012 May-Jun;18(3):268-74. doi: 10.1097/PPO.0b013e318258b743.</citation>
    <PMID>22647364</PMID>
  </reference>
  <reference>
    <citation>Pastorino U. Current status of lung cancer screening. Thorac Surg Clin. 2013 May;23(2):129-40. doi: 10.1016/j.thorsurg.2013.01.018.</citation>
    <PMID>23566965</PMID>
  </reference>
  <reference>
    <citation>Pastorino U, Sverzellati N. Lung cancer: CT screening for lung cancer--do we have an answer? Nat Rev Clin Oncol. 2013 Dec;10(12):672-3. doi: 10.1038/nrclinonc.2013.198. Epub 2013 Nov 5. No abstract available.</citation>
    <PMID>24189470</PMID>
  </reference>
  <reference>
    <citation>Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, Roz L, Conte D, Grassi M, Sverzellati N, Marchiano A, Negri E, La Vecchia C, Pastorino U. Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. J Clin Oncol. 2014 Mar 10;32(8):768-73. doi: 10.1200/JCO.2013.50.4357. Epub 2014 Jan 13. Erratum In: J Clin Oncol. 2014 May 10;32(14):1520.</citation>
    <PMID>24419137</PMID>
  </reference>
  <reference>
    <citation>Fortunato O, Boeri M, Verri C, Conte D, Mensah M, Suatoni P, Pastorino U, Sozzi G. Assessment of circulating microRNAs in plasma of lung cancer patients. Molecules. 2014 Mar 10;19(3):3038-54. doi: 10.3390/molecules19033038.</citation>
    <PMID>24619302</PMID>
  </reference>
  <reference>
    <citation>Sestini S, Boeri M, Marchiano A, Pelosi G, Galeone C, Verri C, Suatoni P, Sverzellati N, La Vecchia C, Sozzi G, Pastorino U. Circulating microRNA signature as liquid-biopsy to monitor lung cancer in low-dose computed tomography screening. Oncotarget. 2015 Oct 20;6(32):32868-77. doi: 10.18632/oncotarget.5210. Erratum In: Oncotarget. 2019 Oct 15;10(57):6043.</citation>
    <PMID>26451608</PMID>
  </reference>
  <reference>
    <citation>Boeri M, Sestini S, Fortunato O, Verri C, Suatoni P, Pastorino U, Sozzi G. Recent advances of microRNA-based molecular diagnostics to reduce false-positive lung cancer imaging. Expert Rev Mol Diagn. 2015 Jun;15(6):801-13. doi: 10.1586/14737159.2015.1041377. Epub 2015 Apr 30.</citation>
    <PMID>25924864</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>April 24, 2014</study_first_submitted>
  <study_first_submitted_qc>September 19, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 25, 2014</study_first_posted>
  <last_update_submitted>February 24, 2023</last_update_submitted>
  <last_update_submitted_qc>February 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</investigator_affiliation>
    <investigator_full_name>Ugo Pastorino</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>lung cancer</keyword>
  <keyword>clinical trial</keyword>
  <keyword>screening</keyword>
  <keyword>microRNA</keyword>
  <keyword>biomarkers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02247453
org study id: INT11-21
nct id: NCT02247453
lead sponsor: 
has dmc: Yes
In the present project we propose a large prospective study in heavy smokers volunteers based
      on plasma miRNA profiling to assess its efficacy as a first line screening test for lung
      cancer detection.

      The study will be articulated in different phases: i) analysis of 1000 plasma samples of
      disease-free smokers already collected in our biological repository in the last two years ii)
      de-novo enrollment of 4000 smoking volunteers, collection of their blood samples and
      inclusion in a program of active surveillance on the basis of their miRNA risk profile iii)
      assessment of miRNA expression profile using a custom made microfluidic card containing the
      24 miRNA previously identified in the diagnostic signatures iii) bioinformatic analyses of
      miRNA ratios in the cohort in order to determine which individuals are in presence or will
      develop lung cancer and in particular the aggressive form of the disease iv) assessment of
      the best diagnostic and treatment algorithm for subjects with suspicious miRNA profiles v)
      functional validation of miRNAs as novel therapeutic targets using novel cellular genetically
      engineered models of transformation and patients' tumorgrafts models.
Three decades of research have shown that radiological screening of heavy smokers can detect
      resectable early lung cancers with higher frequency but benefit on mortality is still
      debated. The preliminary results of the first two randomized spiral-CT screening trials
      appear conflicting, with one study showing no benefit and the other a limited mortality
      reduction (-7%). In the next 3-4 years the ongoing randomised trials in Europe will provide
      conclusive data on the efficacy of CT-screening for lung cancer. Nonetheless, no major impact
      on mortality is to be expected.

      A possible explanation of these finding is that not all aggressive lung tumors arise from
      identifiable slow-growing precursors, thus suggesting a possible paradigm shift in our
      understanding of the natural history of lung cancer. In this respect the identification of
      biologic and molecular features of indolent and aggressive disease could be useful to define
      clinical predictors of high risk lesions and select suitable cohorts of patients who might
      benefit of current treatments as well as to identify genetic signatures that might represent
      novel therapeutic targets.

      The investigators recently reported that microRNA (miRNA) expression expression profiles in
      tumors and, for the first time, also in normal lung tissue are indicative of aggressive lung
      cancer development and, of remarkable interest, that specific miRNA signatures can be
      identified in plasma samples of patients up to two years before spiral-CT detection of the
      disease, and able to identify the occurrence of early metastatic but spiral-CT invisible lung
      tumors or small spiral-CT detected lesions with aggressive potential.

      In the present project we propose a large prospective study in heavy smokers volunteers based
      on plasma miRNA profiling to assess its efficacy as a first line screening test for lung
      cancer detection.

      The study will be articulated in different phases: i) analysis of 1000 plasma samples of
      disease-free smokers already collected in our biological repository in the last two years ii)
      de-novo enrollment of 4000 smoking volunteers, collection of their blood samples and
      inclusion in a program of active surveillance on the basis of their miRNA risk profile iii)
      assessment of miRNA expression profile using a custom made microfluidic card containing the
      24 miRNA previously identified in the diagnostic signatures iii) bioinformatic analyses of
      miRNA ratios in the cohort in order to determine which individuals are in presence or will
      develop lung cancer and in particular the aggressive form of the disease iv) assessment of
      the best diagnostic and treatment algorithm for subjects with suspicious miRNA profiles v)
      functional validation of miRNAs as novel therapeutic targets using novel cellular genetically
      engineered models of transformation and patients' tumorgrafts models.

      Overall, the results of this large prospective study will permit to establish the potential
      of our plasma microRNA assay as a first-line screening test for lung cancer detection in a
      routine clinical practice for high-risk population screening with a low cost, non toxic and
      non invasive procedure. Moreover, the related functional studies foreseen in the project
      could lead to the identification of novel, miRNA targeted, therapeutic approaches for this
      malignancy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Screening
masking: None (Open Label)
measure: Reduction of false positive cases in lung cancer detection in heavy smokers volunteers through plasma miRNA profiling as a first line screening test
time frame: 3 years
measure: overall survival
time frame: 5 years
arm group label: Screening
arm group type: Experimental
description: Healthy heavy smokers aged 50-75 years
intervention type: Other
intervention name: screening
description: All subjects undergo baseline LDCT examination, spirometry and miRNA profiling. Individuals with negative miRNA profile repeat the plasma assay at 3 years. Individuals with low-risk miRNA profile repeat the plasma assay and LDCT at 2 years, without additional diagnostic examinations if not required by the screening protocol.
Individuals with high-risk miRNA profile undergo additional diagnostic examinations consisting in PET in case of concurrent suspicious or positive CT, or WB MRI +- needle aspiration biopsy in case of negative CT.
arm group label: Screening
criteria: 
gender: All
minimum age: 50 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ugo Pastorino, MD
role: Principal Investigator
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
facility: 
country: Italy
url: http://www.biomild.org
description: clinical trial website
citation: Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabro E, Croce CM, Pastorino U, Sozzi G. MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3713-8. doi: 10.1073/pnas.1100048108. Epub 2011 Feb 7.
PMID: 21300873
citation: Sozzi G, Pastorino U, Croce CM. MicroRNAs and lung cancer: from markers to targets. Cell Cycle. 2011 Jul 1;10(13):2045-6. doi: 10.4161/cc.10.13.15712. No abstract available.
PMID: 21623159
citation: Pastorino U, Rossi M, Rosato V, Marchiano A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, Pelosi G, La Vecchia C. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev. 2012 May;21(3):308-15. doi: 10.1097/CEJ.0b013e328351e1b6.
PMID: 22465911
citation: Boeri M, Pastorino U, Sozzi G. Role of microRNAs in lung cancer: microRNA signatures in cancer prognosis. Cancer J. 2012 May-Jun;18(3):268-74. doi: 10.1097/PPO.0b013e318258b743.
PMID: 22647364
citation: Pastorino U. Current status of lung cancer screening. Thorac Surg Clin. 2013 May;23(2):129-40. doi: 10.1016/j.thorsurg.2013.01.018.
PMID: 23566965
citation: Pastorino U, Sverzellati N. Lung cancer: CT screening for lung cancer--do we have an answer? Nat Rev Clin Oncol. 2013 Dec;10(12):672-3. doi: 10.1038/nrclinonc.2013.198. Epub 2013 Nov 5. No abstract available.
PMID: 24189470
citation: Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, Roz L, Conte D, Grassi M, Sverzellati N, Marchiano A, Negri E, La Vecchia C, Pastorino U. Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. J Clin Oncol. 2014 Mar 10;32(8):768-73. doi: 10.1200/JCO.2013.50.4357. Epub 2014 Jan 13. Erratum In: J Clin Oncol. 2014 May 10;32(14):1520.
PMID: 24419137
citation: Fortunato O, Boeri M, Verri C, Conte D, Mensah M, Suatoni P, Pastorino U, Sozzi G. Assessment of circulating microRNAs in plasma of lung cancer patients. Molecules. 2014 Mar 10;19(3):3038-54. doi: 10.3390/molecules19033038.
PMID: 24619302
citation: Sestini S, Boeri M, Marchiano A, Pelosi G, Galeone C, Verri C, Suatoni P, Sverzellati N, La Vecchia C, Sozzi G, Pastorino U. Circulating microRNA signature as liquid-biopsy to monitor lung cancer in low-dose computed tomography screening. Oncotarget. 2015 Oct 20;6(32):32868-77. doi: 10.18632/oncotarget.5210. Erratum In: Oncotarget. 2019 Oct 15;10(57):6043.
PMID: 26451608
citation: Boeri M, Sestini S, Fortunato O, Verri C, Suatoni P, Pastorino U, Sozzi G. Recent advances of microRNA-based molecular diagnostics to reduce false-positive lung cancer imaging. Expert Rev Mol Diagn. 2015 Jun;15(6):801-13. doi: 10.1586/14737159.2015.1041377. Epub 2015 Apr 30.
PMID: 25924864
responsible party type: Principal Investigator
investigator affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
investigator full name: Ugo Pastorino
investigator title: MD
mesh term: Lung Neoplasms
sharing ipd: Undecided