<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/NCT04435964</url>
  </required_header>
  <id_info>
    <org_study_id>INT156-19</org_study_id>
    <nct_id>NCT04435964</nct_id>
  </id_info>
  <brief_title>Gender Difference in sidE eFfects of ImmuNotherapy: a Possible Clue to Optimize cancEr tReatment</brief_title>
  <acronym>G-DEFINER</acronym>
  <official_title>Gender Difference in sidE eFfects of ImmuNotherapy: a Possible Clue to Optimize cancEr tReatment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Karolinska University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St Vincent's University Hospital, Ireland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study aim is to investigate the differences between sex and gender in the immune-related&#xD;
      adverse events (irAEs) development associated with immune checkpoint inhibitors (ICI)&#xD;
      treatment. The study will be a multicenter prospective observational study focusing on&#xD;
      biological differences between females and males, possibly affecting discrepant irAEs&#xD;
      incidence.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study aim is to investigate the differences between sex and gender in the immune-related&#xD;
      adverse events (irAEs) development associated with immune checkpoint inhibitors (ICI)&#xD;
      treatment.&#xD;
&#xD;
      In common feeling, sex and gender represent the same concept, that is the traditional&#xD;
      division of individuals into females (F) and males (M) defined by differential organization&#xD;
      of chromosomes, reproductive organs, and sex steroid levels. However, if going beyond these&#xD;
      aspects, which characterize &quot;sex&quot;, it can be observed how the differences between people are&#xD;
      also characterized by behaviors and relationships that are the product of the culture and&#xD;
      sociality typical of human beings. This is what is called &quot;gender&quot;, i.e. the process of&#xD;
      social and cultural construction that determines the behaviors that give life to the status&#xD;
      of an individual. Gender is therefore learned and not innate. Sex and gender do not&#xD;
      constitute two opposing but interdependent dimensions: the process of determining gender&#xD;
      identity is triggered on biological characters. The relationship between sex and gender&#xD;
      varies according to geographical areas, historical periods and cultures.&#xD;
&#xD;
      Sex influences the adaptive immunity, and may influence irAEs types, frequency and severity.&#xD;
      Together with genetic and biological differences, the roots of irAEs inequalities between F&#xD;
      and M could be linked to psycho-social and behavioral determinants. IrAEs usually develop&#xD;
      within the first few weeks to 6 months after treatment initiation; however, they can also&#xD;
      present after cessation of ICI therapy. Most studies indicate that prolonged treatment does&#xD;
      not result in an increased cumulative incidence of irAEs. Accumulating evidences support the&#xD;
      existence of sex-driven differences in immune responses as potential factors contributing to&#xD;
      disease outcome and response to therapy. Increasing use of ICI is associated with&#xD;
      immune-related adverse events caused by non-specific activation of the immune system.&#xD;
&#xD;
      The investigators will conduct a multicenter prospective observational study investigating&#xD;
      sex differences in irAEs in relation to clinical factors and genetic, immunological and&#xD;
      hormonal profiles. By focusing on biological F/M differences possibly affecting discrepant&#xD;
      irAEs incidence, sex inequality will be explicitly addressed and complemented by the&#xD;
      exploration of association between gender dimension and irAEs development. Exploring the&#xD;
      irAEs occurrence in a &quot;real world&quot; (outside RCT) context will be more easily translated in a&#xD;
      ready-to-use personalized approach to irAEs timely diagnosis and treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 25, 2020</start_date>
  <completion_date type="Actual">February 28, 2023</completion_date>
  <primary_completion_date type="Actual">February 28, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Immune-related severe (G≥ 2) adverse events (irAEs)</measure>
    <time_frame>1 year</time_frame>
    <description>The incidence of first severe (G≥ 2) irAEs of any type will be estimated in females and males</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Immune-related adverse events (irAEs)</measure>
    <time_frame>1 year</time_frame>
    <description>The incidence of irAEs of any type and any grade will be estimated in females and males</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">247</enrollment>
  <condition>Melanoma</condition>
  <condition>Lung Cancer</condition>
  <condition>Head and Neck Cancer</condition>
  <condition>Urogenital Neoplasms</condition>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Overall series</arm_group_label>
    <description>Patients treated with immunocheckpoint inhibitors (ICI) irrespective of treatment schedule. No limitations to previous lines of treatment. ICI therapy may be either as single agent or in combination. Concomitant chemotherapy (CT) and radiotherapy (RT) is allowed.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Immunotherapy</intervention_name>
    <description>Patients treated as per clinical prescription with immunocheckpoint inhibitors (ICI) irrespective of treatment schedule, either as single agent or in combination with chemotherapy and/or radiotherapy</description>
    <arm_group_label>Overall series</arm_group_label>
    <other_name>Chemotherapy</other_name>
    <other_name>Radiotherapy</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      -  Gene-expression analysis. Blood samples will be taken in order to identify&#xD;
           immune-related genes in patients with various solid tumors treated with ICI associated&#xD;
           with the development of irAEs.&#xD;
&#xD;
        -  SNPs analysis. Blood samples will be taken in order to perform a preliminary genome wide&#xD;
           association study for the identification of germline variations associated with the&#xD;
           development of irAEs. with the hypothesis that the individual's genetic makeup may be&#xD;
           related to irAEs.&#xD;
&#xD;
        -  Microbiome analysis. Stool collection will be performed to analyze gut microbiota aiming&#xD;
           at performing RNA/DNA sequencing analysis for identifying components associated with the&#xD;
           development of irAEs.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        To allow for balanced sex groups, we will include patients according to the following&#xD;
        stratification : ICI: 100 F/100 M; ICI+ CT/RT: 100 F/100 M. Due to the current ICI use in&#xD;
        clinical practice we are expecting to mainly populate the ICI strata during the first&#xD;
        recruitment period. As the recruitment progresses, the sample will be enriched of ICI+CT&#xD;
        and ICI+RT treated patients, since combinations are expanding for many cancers such for&#xD;
        instance melanoma, lung and head and neck&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed informed consent.&#xD;
&#xD;
          -  Histologically confirmed diagnosis of one of the following cancers: melanoma, lung,&#xD;
             head and neck, urogenital, breast cancer. In addition, other solid tumors&#xD;
             characterized by the presence of microsatellite instability (MSI-high), treated with&#xD;
             immunocheckpoint inhibitors (ICI) irrespective of treatment schedule. It is possible&#xD;
             to include patients treated with Immunotherapy in a compassionate use setting.&#xD;
&#xD;
          -  Any disease stage.&#xD;
&#xD;
          -  Patients eligible for immune checkpoint inhibitors (ICI)-containing regimens: ICI&#xD;
             single agent; Combination of ICIs; ICI-chemotherapy combination; ICI-radiotherapy&#xD;
             combination.&#xD;
&#xD;
          -  Any treatment setting (neoadjuvant, adjuvant, advanced disease, maintenance).&#xD;
&#xD;
          -  Patient age ≥18 years&#xD;
&#xD;
          -  ECOG Performance Status of 0-2.&#xD;
&#xD;
          -  Adequate bone marrow, liver and renal function.&#xD;
&#xD;
          -  Life expectancy of at least 12 weeks.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients not eligible for ICI-containing regimens.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rosalba Miceli, PhD</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>Milano</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>June 11, 2020</study_first_submitted>
  <study_first_submitted_qc>June 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 17, 2020</study_first_posted>
  <last_update_submitted>March 23, 2023</last_update_submitted>
  <last_update_submitted_qc>March 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 24, 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>Urogenital Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunomodulating Agents</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 12, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/64/NCT04435964/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04435964
org study id: INT156-19
nct id: NCT04435964
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
The study aim is to investigate the differences between sex and gender in the immune-related
      adverse events (irAEs) development associated with immune checkpoint inhibitors (ICI)
      treatment. The study will be a multicenter prospective observational study focusing on
      biological differences between females and males, possibly affecting discrepant irAEs
      incidence.
The study aim is to investigate the differences between sex and gender in the immune-related
      adverse events (irAEs) development associated with immune checkpoint inhibitors (ICI)
      treatment.

      In common feeling, sex and gender represent the same concept, that is the traditional
      division of individuals into females (F) and males (M) defined by differential organization
      of chromosomes, reproductive organs, and sex steroid levels. However, if going beyond these
      aspects, which characterize "sex", it can be observed how the differences between people are
      also characterized by behaviors and relationships that are the product of the culture and
      sociality typical of human beings. This is what is called "gender", i.e. the process of
      social and cultural construction that determines the behaviors that give life to the status
      of an individual. Gender is therefore learned and not innate. Sex and gender do not
      constitute two opposing but interdependent dimensions: the process of determining gender
      identity is triggered on biological characters. The relationship between sex and gender
      varies according to geographical areas, historical periods and cultures.

      Sex influences the adaptive immunity, and may influence irAEs types, frequency and severity.
      Together with genetic and biological differences, the roots of irAEs inequalities between F
      and M could be linked to psycho-social and behavioral determinants. IrAEs usually develop
      within the first few weeks to 6 months after treatment initiation; however, they can also
      present after cessation of ICI therapy. Most studies indicate that prolonged treatment does
      not result in an increased cumulative incidence of irAEs. Accumulating evidences support the
      existence of sex-driven differences in immune responses as potential factors contributing to
      disease outcome and response to therapy. Increasing use of ICI is associated with
      immune-related adverse events caused by non-specific activation of the immune system.

      The investigators will conduct a multicenter prospective observational study investigating
      sex differences in irAEs in relation to clinical factors and genetic, immunological and
      hormonal profiles. By focusing on biological F/M differences possibly affecting discrepant
      irAEs incidence, sex inequality will be explicitly addressed and complemented by the
      exploration of association between gender dimension and irAEs development. Exploring the
      irAEs occurrence in a "real world" (outside RCT) context will be more easily translated in a
      ready-to-use personalized approach to irAEs timely diagnosis and treatment.
observational model: Cohort
time perspective: Prospective
measure: Immune-related severe (G≥ 2) adverse events (irAEs)
time frame: 1 year
description: The incidence of first severe (G≥ 2) irAEs of any type will be estimated in females and males
measure: Immune-related adverse events (irAEs)
time frame: 1 year
description: The incidence of irAEs of any type and any grade will be estimated in females and males
arm group label: Overall series
description: Patients treated with immunocheckpoint inhibitors (ICI) irrespective of treatment schedule. No limitations to previous lines of treatment. ICI therapy may be either as single agent or in combination. Concomitant chemotherapy (CT) and radiotherapy (RT) is allowed.
intervention type: Drug
intervention name: Immunotherapy
description: Patients treated as per clinical prescription with immunocheckpoint inhibitors (ICI) irrespective of treatment schedule, either as single agent or in combination with chemotherapy and/or radiotherapy
arm group label: Overall series
other name: Chemotherapy
other name: Radiotherapy
-  Gene-expression analysis. Blood samples will be taken in order to identify
           immune-related genes in patients with various solid tumors treated with ICI associated
           with the development of irAEs.

        -  SNPs analysis. Blood samples will be taken in order to perform a preliminary genome wide
           association study for the identification of germline variations associated with the
           development of irAEs. with the hypothesis that the individual's genetic makeup may be
           related to irAEs.

        -  Microbiome analysis. Stool collection will be performed to analyze gut microbiota aiming
           at performing RNA/DNA sequencing analysis for identifying components associated with the
           development of irAEs.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rosalba Miceli, PhD
role: Principal Investigator
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Urogenital Neoplasms
mesh term: Immunomodulating Agents
sharing ipd: Undecided
provided document: 