<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/NCT03252717</url>
  </required_header>
  <id_info>
    <org_study_id>ICM-URC-2014/22</org_study_id>
    <nct_id>NCT03252717</nct_id>
  </id_info>
  <brief_title>Predictive Role of New Biomarkers for Hypersensitive Patients to Radiation in Breast Cancer (BIORISE)</brief_title>
  <acronym>BIORISE</acronym>
  <official_title>Radiation-induced Late Side-effects: Predictive Role of New Biomarkers for Selecting Hypersensitive Patients to Ionizing Radiation in Breast Cancer (BIORISE)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut du Cancer de Montpellier - Val d'Aurelle</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut du Cancer de Montpellier - Val d'Aurelle</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To confirm the protein expression level in radiation-induced late effects patients and to&#xD;
      determine the performance value, in particular the positive predictive value, of a blood test&#xD;
      based on the dosage of a panel of five proteins, it is necessary to validate these&#xD;
      preliminary results by a prospective study on a large cohort of patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Molecular mechanisms involved in radiation-induced responses are complex, and proteomic&#xD;
      approaches can be used to better understand the overall reaction process of ionizing&#xD;
      radiation and to identify potential radio-sensitive predictive markers. Until now, few&#xD;
      publications have addressed the determination of radiosensitive patients.&#xD;
&#xD;
      Based on our previous results and in order to improve the positive predictive value of the&#xD;
      radiation induced late effect assay, we developed a quantitative proteomic approach to&#xD;
      identify predictive radiobiological markers in patients with severe toxicity. First, four&#xD;
      patients were selected with a low RILA value from the prospective studies mentioned above.&#xD;
      Two patients had no toxicity at least four years after the end of treatment whereas two&#xD;
      others patients developed a severe toxicity greater than grade 2. T-lymphocytes have been&#xD;
      isolated from whole blood and half of them have been irradiated in vitro. It will then&#xD;
      performed a quantitative proteomics workflow using an 8-plex iTRAQ labeling and after several&#xD;
      fractionations to optimize resolution of analysis (off gel fractionation followed by&#xD;
      nanoliquid chromatography), proteins were identified by tandem mass spectrometry (4800 plus&#xD;
      MALDI TOF/TOF). More than 1300 total proteins were identified with high confidence (95%, one&#xD;
      unique peptide). At 0 Gy, 135 proteins were differentially expressed between patients with or&#xD;
      without severe radio-induced toxicity. In irradiated T-lymphocytes (8 Gy), 107 proteins were&#xD;
      differentially expressed between patients with or without severe radio-induced toxicity.&#xD;
      Among them, five proteins (AK2, adenylate kinase 2; IDH2, isocitrate dehydrogenase 2 (NADP+);&#xD;
      ANX1, annexin 1; APEX1, DNA-(apurinic or apyrimidinic site) lyase, and HSC70, Heat shock&#xD;
      cognate 71 kDa) with the highest protein expression ratio (&gt;1.5) and that showed no&#xD;
      difference expression ratio in 0 Gy controls, were selected for consecutive validation. These&#xD;
      proteins are involved in several mechanisms including metabolism and energy production,&#xD;
      apoptosis, calcium binding protein, and DNA damages repair. These five proteins are currently&#xD;
      the subject of patent application.&#xD;
&#xD;
      Then,10 other patients will be recruited (5 patients with grade ≥ 2 breast fibrosis and 5&#xD;
      patients without toxicity) who presented a low RILA value to validate proteins expression by&#xD;
      western-blotting. Results showed that all proteins were overexpressed in irradiated&#xD;
      T-lymphocytes patients with severe toxicity comparatively to patients without toxicity.&#xD;
&#xD;
      However, to confirm the protein expression level in radiation-induced late effects patients&#xD;
      and to determine the performance value, in particular the positive predictive value, of a&#xD;
      blood test based on the dosage of a panel of five proteins, it is necessary to validate these&#xD;
      preliminary results by a prospective study on a large cohort of patients&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>August 2014</start_date>
  <completion_date type="Anticipated">August 2022</completion_date>
  <primary_completion_date type="Actual">August 31, 2017</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>blood sample to assess dosage of 5 proteins</measure>
    <time_frame>through study completion, an average of 5 years</time_frame>
    <description>Confirm the predictive value, of a blood test based on the dosage of a panel of five (5) proteins: AK2 - IDH2 - ANX1- APEX1 - HSC70 in radiation-induced late side effects after breast-conserving surgery and curative intent adjuvant radiotherapy.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">500</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>blood sample</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pre-treatment blood samples will be collected: 8 samples</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Blood sample</intervention_name>
    <description>Pre-treatment blood samples will be collected for downstream analyses:&#xD;
Three 6 ml EDTA samples for proteomic and genomic work package&#xD;
One 6 ml dry sample for auto-antibodies analysis in the immunology work package&#xD;
Two 4 ml EDTA samples for DNA extraction in the immunology work package&#xD;
Two 2.5 ml PAX Gene sample for RNA extraction in the immunology work package and the non-irradiated control in the genomic work package</description>
    <arm_group_label>blood sample</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients suitable for adjuvant radiotherapy for cancer of the breast (invasive or in&#xD;
             situ) including breast patients receiving neo-adjuvant chemotherapy. Patients&#xD;
             receiving chemotherapy should have completed their course of chemotherapy&#xD;
             (anthracyclines) at least one month prior to radiotherapy commencing.&#xD;
&#xD;
          -  No other malignancy prior to treatment for the specified tumour types except basal&#xD;
             cell or squamous cell carcinoma of the skin&#xD;
&#xD;
          -  No evidence of distant metastases&#xD;
&#xD;
          -  Patients able to provide a venous blood sample&#xD;
&#xD;
          -  Willingness and ability to comply with scheduled visits, treatment plans and available&#xD;
             for follow up&#xD;
&#xD;
          -  Greater than 18 years of age; no upper age limit&#xD;
&#xD;
          -  The capacity to understand the patient information sheet and the ability to provide&#xD;
             written informed consent&#xD;
&#xD;
          -  Patients must be affiliated to a Social Security System&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with metastatic disease&#xD;
&#xD;
          -  Prior irradiation at the same site&#xD;
&#xD;
          -  Planned use of protons&#xD;
&#xD;
          -  Breast patients receiving concomitant chemo-radiation&#xD;
&#xD;
          -  Male breast cancer patients&#xD;
&#xD;
          -  Mastectomy patients&#xD;
&#xD;
          -  Bilateral breast cancer&#xD;
&#xD;
          -  Mental disability or patient otherwise unable to give informed consent&#xD;
&#xD;
          -  Limited life expectancy due to co-morbidity&#xD;
&#xD;
          -  Pregnant patients&#xD;
&#xD;
          -  Partial breast irradiation&#xD;
&#xD;
          -  Patients with breast implants if not removed during surgery&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>david azria</last_name>
    <role>Study Chair</role>
    <affiliation>Institut régional du Cancer de Montpellier</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut régional du Cancer de Montpellier</name>
      <address>
        <city>Montpellier</city>
        <zip>34298</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>August 29, 2016</study_first_submitted>
  <study_first_submitted_qc>August 16, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 17, 2017</study_first_posted>
  <last_update_submitted>October 16, 2020</last_update_submitted>
  <last_update_submitted_qc>October 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 20, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Hypersensitivity</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03252717
org study id: ICM-URC-2014/22
nct id: NCT03252717
lead sponsor: 
has dmc: No
To confirm the protein expression level in radiation-induced late effects patients and to
      determine the performance value, in particular the positive predictive value, of a blood test
      based on the dosage of a panel of five proteins, it is necessary to validate these
      preliminary results by a prospective study on a large cohort of patients.
Molecular mechanisms involved in radiation-induced responses are complex, and proteomic
      approaches can be used to better understand the overall reaction process of ionizing
      radiation and to identify potential radio-sensitive predictive markers. Until now, few
      publications have addressed the determination of radiosensitive patients.

      Based on our previous results and in order to improve the positive predictive value of the
      radiation induced late effect assay, we developed a quantitative proteomic approach to
      identify predictive radiobiological markers in patients with severe toxicity. First, four
      patients were selected with a low RILA value from the prospective studies mentioned above.
      Two patients had no toxicity at least four years after the end of treatment whereas two
      others patients developed a severe toxicity greater than grade 2. T-lymphocytes have been
      isolated from whole blood and half of them have been irradiated in vitro. It will then
      performed a quantitative proteomics workflow using an 8-plex iTRAQ labeling and after several
      fractionations to optimize resolution of analysis (off gel fractionation followed by
      nanoliquid chromatography), proteins were identified by tandem mass spectrometry (4800 plus
      MALDI TOF/TOF). More than 1300 total proteins were identified with high confidence (95%, one
      unique peptide). At 0 Gy, 135 proteins were differentially expressed between patients with or
      without severe radio-induced toxicity. In irradiated T-lymphocytes (8 Gy), 107 proteins were
      differentially expressed between patients with or without severe radio-induced toxicity.
      Among them, five proteins (AK2, adenylate kinase 2; IDH2, isocitrate dehydrogenase 2 (NADP+);
      ANX1, annexin 1; APEX1, DNA-(apurinic or apyrimidinic site) lyase, and HSC70, Heat shock
      cognate 71 kDa) with the highest protein expression ratio (>1.5) and that showed no
      difference expression ratio in 0 Gy controls, were selected for consecutive validation. These
      proteins are involved in several mechanisms including metabolism and energy production,
      apoptosis, calcium binding protein, and DNA damages repair. These five proteins are currently
      the subject of patent application.

      Then,10 other patients will be recruited (5 patients with grade ≥ 2 breast fibrosis and 5
      patients without toxicity) who presented a low RILA value to validate proteins expression by
      western-blotting. Results showed that all proteins were overexpressed in irradiated
      T-lymphocytes patients with severe toxicity comparatively to patients without toxicity.

      However, to confirm the protein expression level in radiation-induced late effects patients
      and to determine the performance value, in particular the positive predictive value, of a
      blood test based on the dosage of a panel of five proteins, it is necessary to validate these
      preliminary results by a prospective study on a large cohort of patients
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: blood sample to assess dosage of 5 proteins
time frame: through study completion, an average of 5 years
description: Confirm the predictive value, of a blood test based on the dosage of a panel of five (5) proteins: AK2 - IDH2 - ANX1- APEX1 - HSC70 in radiation-induced late side effects after breast-conserving surgery and curative intent adjuvant radiotherapy.
arm group label: blood sample
arm group type: Experimental
description: Pre-treatment blood samples will be collected: 8 samples
intervention type: Biological
intervention name: Blood sample
description: Pre-treatment blood samples will be collected for downstream analyses:
Three 6 ml EDTA samples for proteomic and genomic work package
One 6 ml dry sample for auto-antibodies analysis in the immunology work package
Two 4 ml EDTA samples for DNA extraction in the immunology work package
Two 2.5 ml PAX Gene sample for RNA extraction in the immunology work package and the non-irradiated control in the genomic work package
arm group label: blood sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: david azria
role: Study Chair
affiliation: Institut régional du Cancer de Montpellier
facility: 
country: France
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Hypersensitivity
sharing ipd: No