<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/NCT03255252</url>
  </required_header>
  <id_info>
    <org_study_id>ICM-URC 2015/27</org_study_id>
    <nct_id>NCT03255252</nct_id>
  </id_info>
  <brief_title>Assessment Study to Evaluate Specific Immune Response in Locally Advanced Cervix Cancer After Radio-chemotherapy</brief_title>
  <acronym>IMMUVIX</acronym>
  <official_title>Assessment Study to Evaluate Specific Immune Response in Locally Advanced Cervix Cancer After Radio-chemotherapy (IMMUVIX)</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>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Perspectives:&#xD;
&#xD;
        -  To set-up another clinical trial with this specific phenotype as the main stratification&#xD;
           factor. Therefore a more aggressive or a more specific systemic treatment (with or&#xD;
           without an immunomodulator) could be proposed to those selected patients in the field of&#xD;
           personalized medicine.&#xD;
&#xD;
        -  To evaluate the use of the smear as a surrogate non-invasive technique to biopsy for&#xD;
           immunomonitoring.&#xD;
&#xD;
        -  To use the CTC/PD-L1 assay as a liquid biopsy in future clinical trials for&#xD;
           stratification and monitoring of cancer patients undergoing immune checkpoint&#xD;
           treatments. This specific subset of CTCs might represent metastatic cells with a high&#xD;
           potential to escape T cell-mediated lysis and might therefore be the actual targets of&#xD;
           immunotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cervical cancer is a real worldwide health care issue. High-risk human papillomavirus&#xD;
      (HR-HPV) chronic infection is a co-factor in the development of the cervical cancer.&#xD;
&#xD;
      The HR-HPV genome encodes two oncoproteins (E6 and E7) which are required to sustain the&#xD;
      malignant phenotype of pre-neoplastic lesions and are considered as foreign antigens&#xD;
      recognized by the immune system, Many studies have suggested that local immunologic escape&#xD;
      can cause the emergence of HPV-induced cervical cancer Radio-chemotherapy is the gold&#xD;
      standard treatment for locally advanced cervical cancer, resulting in 2 year-control rates of&#xD;
      about 70 to 85 %. A better and earlier understanding of the reasons for tumor escape may&#xD;
      hopefully help to improve these outcomes.&#xD;
&#xD;
      Both radiation and chemotherapy are myelosuppressive treatments, but new treatment modalities&#xD;
      such as Intensity-Modulated Radiation Therapy (IMRT) may allow a more rapid hematologic&#xD;
      recovery. In addition to this immunosuppressive microenvironment, a significant number of&#xD;
      tumor-infiltrating lymphocytes (TILs) are detected in cervical cancer tissue, highlighting&#xD;
      interactions between tumor and immune cells.&#xD;
&#xD;
      Another issue is the fact that cancer cells develop different strategies to bypass the immune&#xD;
      surveillance, such as a down-regulation of class I human leucocyte antigen (HLA) on tumor&#xD;
      cells surface.&#xD;
&#xD;
      Furthermore, there is growing evidence of the importance of immune cells in response to&#xD;
      cervical cancer treatment. TILs have been correlated with cervical cancer patients' outcome.&#xD;
      More precisely, the location and type of these immune cells seem to be of great importance&#xD;
      for the tumor response to treatment.&#xD;
&#xD;
      Receptors with negative regulatory function have been identified on the surface of those T&#xD;
      cells, including CTLA4 and PD1 and seem to play a great role in tumor escape to treatment.&#xD;
&#xD;
      The presence of circulating tumor cells (CTCs) was shown to be correlated with a poor&#xD;
      patient's prognosis in many cancers. A recent study suggested a potential mechanism of immune&#xD;
      escape of these CTCs resulting in metastasis spreading.&#xD;
&#xD;
      The hypothesis of this study is that the frequency of PD1+,CD39+, specific phenotype of the&#xD;
      non-regulatory CD4+ and CD8+ T cells among TILs is involved with the lack of response to the&#xD;
      treatment and correlates with an early relapse after the treatment (i.e. patients with a very&#xD;
      poor prognosis).&#xD;
&#xD;
      Perspectives:&#xD;
&#xD;
        -  To set-up another clinical trial with this specific phenotype as the main stratification&#xD;
           factor. Therefore a more aggressive or a more specific systemic treatment (with or&#xD;
           without an immunomodulator) could be proposed to those selected patients in the field of&#xD;
           personalized medicine.&#xD;
&#xD;
        -  To evaluate the use of the smear as a surrogate non-invasive technique to biopsy for&#xD;
           immunomonitoring.&#xD;
&#xD;
        -  To use the CTC/PD-L1 assay as a liquid biopsy in future clinical trials for&#xD;
           stratification and monitoring of cancer patients undergoing immune checkpoint&#xD;
           treatments. This specific subset of CTCs might represent metastatic cells with a high&#xD;
           potential to escape T cell-mediated lysis and might therefore be the actual targets of&#xD;
           immunotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 15, 2017</start_date>
  <completion_date type="Anticipated">July 2024</completion_date>
  <primary_completion_date type="Actual">June 16, 2022</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>radiothérapy with concomittant chemotherapy</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Expression of CD8+CD39+PD1+ lymphocytes infiltrate on cervix biopsies</measure>
    <time_frame>through study completion, an average of 1 year disease free survival</time_frame>
    <description>Cervix biopsies analysis</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Effect on 1-year DFS of other putative biomarkers (CD73, CD39, PD1 and Tim3) on the non-regulatory CD4+ and CD8+ lymphocytes</measure>
    <time_frame>through study completion, an average of 1 year disease free survival</time_frame>
    <description>Cervix biopsies and blood samples analysis</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>Cervical Cancer</condition>
  <arm_group>
    <arm_group_label>Cisplatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Weekly cisplatin (40 mg/m²) will be administered during radiotherapy. At least 3 cycles of cisplatin should be performed according to the hematological and renal functions but not mandatory.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin injection</intervention_name>
    <description>Weekly cisplatin (40 mg/m²) will be administered during radiotherapy. At least 3 cycles of cisplatin should be performed according to the hematological and renal functions but not mandatory.</description>
    <arm_group_label>Cisplatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>radiotherapy</intervention_name>
    <description>A total dose of 45Gy in 25 fractions to the PTV is considered standard but simultaneous integrated boost or two steps boost to specific volumes (positive lymph nodes for example) are accepted and left to the investigator's discretion).</description>
    <arm_group_label>Cisplatin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years.&#xD;
&#xD;
          -  HPV-positive cervical cancer proven* by biopsy.&#xD;
&#xD;
          -  All FIGO stages cervical cancers which are the matter for radio-chemotherapy and&#xD;
             exclusive brachytherapy indications.&#xD;
&#xD;
          -  ECOG performance status ≤2.&#xD;
&#xD;
          -  Ability to give informed consent.&#xD;
&#xD;
          -  Patients must be affiliated to a Social Security System.&#xD;
&#xD;
          -  Patient information and written informed consent form signed.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Adenocarcinoma of cervix.&#xD;
&#xD;
          -  Known autoimmune disorder.&#xD;
&#xD;
          -  History of HIV and/ or hepatitis infection.&#xD;
&#xD;
          -  History of pelvic radiation or radio-chemotherapy.&#xD;
&#xD;
          -  Recurrent or metastatic cervical cancer.&#xD;
&#xD;
          -  Contra-indication for cisplatin.&#xD;
&#xD;
          -  Patient pregnant and/or breastfeeding.&#xD;
&#xD;
          -  History of other malignancy within the previous 5 years (except for appropriately&#xD;
             treated melanoma skin carcinoma).&#xD;
&#xD;
          -  Patients with psychological, familial, sociological or geographical condition&#xD;
             potentially hampering compliance with the study protocol and follow-up schedule&#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>Riou Olivier, MD</last_name>
    <role>Study Chair</role>
    <affiliation>ICM Val d'Aurelle</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinique Beausoleil</name>
      <address>
        <city>Montpellier</city>
        <zip>34070</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU Montpellier</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moussin Aurore</name>
      <address>
        <city>Montpellier</city>
        <zip>34298</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
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    <citation>Steinert G, Scholch S, Niemietz T, Iwata N, Garcia SA, Behrens B, Voigt A, Kloor M, Benner A, Bork U, Rahbari NN, Buchler MW, Stoecklein NH, Weitz J, Koch M. Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res. 2014 Mar 15;74(6):1694-704. doi: 10.1158/0008-5472.CAN-13-1885. Epub 2014 Mar 5.</citation>
    <PMID>24599131</PMID>
  </reference>
  <reference>
    <citation>Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, Rossille D, Maudelonde T, Fest T, Alix-Panabieres C. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 2015 Nov;9(9):1773-82. doi: 10.1016/j.molonc.2015.05.009. Epub 2015 Jun 9.</citation>
    <PMID>26093818</PMID>
  </reference>
  <reference>
    <citation>Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol. 2015 Jan;25(1):11-7. doi: 10.1016/j.semradonc.2014.07.005.</citation>
    <PMID>25481261</PMID>
  </reference>
  <reference>
    <citation>Delgado FG, Martinez E, Cespedes MA, Bravo MM, Navas MC, Combita Rojas AL. Increase of human papillomavirus-16 E7-specific T helper type 1 response in peripheral blood of cervical cancer patients after radiotherapy. Immunology. 2009 Apr;126(4):523-34. doi: 10.1111/j.1365-2567.2008.02912.x. Epub 2008 Sep 5.</citation>
    <PMID>18778290</PMID>
  </reference>
  <reference>
    <citation>Lim K, Small W Jr, Portelance L, Creutzberg C, Jurgenliemk-Schulz IM, Mundt A, Mell LK, Mayr N, Viswanathan A, Jhingran A, Erickson B, De los Santos J, Gaffney D, Yashar C, Beriwal S, Wolfson A, Taylor A, Bosch W, El Naqa I, Fyles A; Gyn IMRT Consortium. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):348-55. doi: 10.1016/j.ijrobp.2009.10.075. Epub 2010 May 14.</citation>
    <PMID>20472347</PMID>
  </reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>August 10, 2017</study_first_submitted>
  <study_first_submitted_qc>August 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 21, 2017</study_first_posted>
  <last_update_submitted>June 6, 2023</last_update_submitted>
  <last_update_submitted_qc>June 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 7, 2023</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>Uterine Cervical Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cisplatin</mesh_term>
  </intervention_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/NCT03255252
org study id: ICM-URC 2015/27
nct id: NCT03255252
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Perspectives:

        -  To set-up another clinical trial with this specific phenotype as the main stratification
           factor. Therefore a more aggressive or a more specific systemic treatment (with or
           without an immunomodulator) could be proposed to those selected patients in the field of
           personalized medicine.

        -  To evaluate the use of the smear as a surrogate non-invasive technique to biopsy for
           immunomonitoring.

        -  To use the CTC/PD-L1 assay as a liquid biopsy in future clinical trials for
           stratification and monitoring of cancer patients undergoing immune checkpoint
           treatments. This specific subset of CTCs might represent metastatic cells with a high
           potential to escape T cell-mediated lysis and might therefore be the actual targets of
           immunotherapy.
Cervical cancer is a real worldwide health care issue. High-risk human papillomavirus
      (HR-HPV) chronic infection is a co-factor in the development of the cervical cancer.

      The HR-HPV genome encodes two oncoproteins (E6 and E7) which are required to sustain the
      malignant phenotype of pre-neoplastic lesions and are considered as foreign antigens
      recognized by the immune system, Many studies have suggested that local immunologic escape
      can cause the emergence of HPV-induced cervical cancer Radio-chemotherapy is the gold
      standard treatment for locally advanced cervical cancer, resulting in 2 year-control rates of
      about 70 to 85 %. A better and earlier understanding of the reasons for tumor escape may
      hopefully help to improve these outcomes.

      Both radiation and chemotherapy are myelosuppressive treatments, but new treatment modalities
      such as Intensity-Modulated Radiation Therapy (IMRT) may allow a more rapid hematologic
      recovery. In addition to this immunosuppressive microenvironment, a significant number of
      tumor-infiltrating lymphocytes (TILs) are detected in cervical cancer tissue, highlighting
      interactions between tumor and immune cells.

      Another issue is the fact that cancer cells develop different strategies to bypass the immune
      surveillance, such as a down-regulation of class I human leucocyte antigen (HLA) on tumor
      cells surface.

      Furthermore, there is growing evidence of the importance of immune cells in response to
      cervical cancer treatment. TILs have been correlated with cervical cancer patients' outcome.
      More precisely, the location and type of these immune cells seem to be of great importance
      for the tumor response to treatment.

      Receptors with negative regulatory function have been identified on the surface of those T
      cells, including CTLA4 and PD1 and seem to play a great role in tumor escape to treatment.

      The presence of circulating tumor cells (CTCs) was shown to be correlated with a poor
      patient's prognosis in many cancers. A recent study suggested a potential mechanism of immune
      escape of these CTCs resulting in metastasis spreading.

      The hypothesis of this study is that the frequency of PD1+,CD39+, specific phenotype of the
      non-regulatory CD4+ and CD8+ T cells among TILs is involved with the lack of response to the
      treatment and correlates with an early relapse after the treatment (i.e. patients with a very
      poor prognosis).

      Perspectives:

        -  To set-up another clinical trial with this specific phenotype as the main stratification
           factor. Therefore a more aggressive or a more specific systemic treatment (with or
           without an immunomodulator) could be proposed to those selected patients in the field of
           personalized medicine.

        -  To evaluate the use of the smear as a surrogate non-invasive technique to biopsy for
           immunomonitoring.

        -  To use the CTC/PD-L1 assay as a liquid biopsy in future clinical trials for
           stratification and monitoring of cancer patients undergoing immune checkpoint
           treatments. This specific subset of CTCs might represent metastatic cells with a high
           potential to escape T cell-mediated lysis and might therefore be the actual targets of
           immunotherapy.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: radiothérapy with concomittant chemotherapy
primary purpose: Treatment
masking: None (Open Label)
measure: Expression of CD8+CD39+PD1+ lymphocytes infiltrate on cervix biopsies
time frame: through study completion, an average of 1 year disease free survival
description: Cervix biopsies analysis
measure: Effect on 1-year DFS of other putative biomarkers (CD73, CD39, PD1 and Tim3) on the non-regulatory CD4+ and CD8+ lymphocytes
time frame: through study completion, an average of 1 year disease free survival
description: Cervix biopsies and blood samples analysis
arm group label: Cisplatin
arm group type: Experimental
description: Weekly cisplatin (40 mg/m²) will be administered during radiotherapy. At least 3 cycles of cisplatin should be performed according to the hematological and renal functions but not mandatory.
intervention type: Drug
intervention name: Cisplatin injection
description: Weekly cisplatin (40 mg/m²) will be administered during radiotherapy. At least 3 cycles of cisplatin should be performed according to the hematological and renal functions but not mandatory.
arm group label: Cisplatin
intervention type: Combination Product
intervention name: radiotherapy
description: A total dose of 45Gy in 25 fractions to the PTV is considered standard but simultaneous integrated boost or two steps boost to specific volumes (positive lymph nodes for example) are accepted and left to the investigator's discretion).
arm group label: Cisplatin
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Riou Olivier, MD
role: Study Chair
affiliation: ICM Val d'Aurelle
facility: 
facility: 
facility: 
country: France
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citation: Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, Rossille D, Maudelonde T, Fest T, Alix-Panabieres C. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 2015 Nov;9(9):1773-82. doi: 10.1016/j.molonc.2015.05.009. Epub 2015 Jun 9.
PMID: 26093818
citation: Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol. 2015 Jan;25(1):11-7. doi: 10.1016/j.semradonc.2014.07.005.
PMID: 25481261
citation: Delgado FG, Martinez E, Cespedes MA, Bravo MM, Navas MC, Combita Rojas AL. Increase of human papillomavirus-16 E7-specific T helper type 1 response in peripheral blood of cervical cancer patients after radiotherapy. Immunology. 2009 Apr;126(4):523-34. doi: 10.1111/j.1365-2567.2008.02912.x. Epub 2008 Sep 5.
PMID: 18778290
citation: Lim K, Small W Jr, Portelance L, Creutzberg C, Jurgenliemk-Schulz IM, Mundt A, Mell LK, Mayr N, Viswanathan A, Jhingran A, Erickson B, De los Santos J, Gaffney D, Yashar C, Beriwal S, Wolfson A, Taylor A, Bosch W, El Naqa I, Fyles A; Gyn IMRT Consortium. Consensus guidelines for delineation of clinical target volume for intensity-modulated pelvic radiotherapy for the definitive treatment of cervix cancer. Int J Radiat Oncol Biol Phys. 2011 Feb 1;79(2):348-55. doi: 10.1016/j.ijrobp.2009.10.075. Epub 2010 May 14.
PMID: 20472347
responsible party type: Sponsor
mesh term: Uterine Cervical Neoplasms
mesh term: Cisplatin
sharing ipd: No