<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/NCT03767465</url>
  </required_header>
  <id_info>
    <org_study_id>PembroHIV</org_study_id>
    <nct_id>NCT03767465</nct_id>
  </id_info>
  <brief_title>Treatment With Immunological Checkpoint Inhibitors of HIV-infected Subjects With Cancer</brief_title>
  <acronym>PembroHIV</acronym>
  <official_title>Treatment With Immunological Checkpoint Inhibitors of HIV-infected Subjects With Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IrsiCaixa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>IrsiCaixa</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      It has been reported that peripheral and lymph node resident Cluster of Differentiation 4&#xD;
      (CD4)+ T cells expressing Programmed cell death protein 1 (PD-1) contribute to Human&#xD;
      Immunodeficiency Virus (HIV) persistence during Antiretroviral Therapy (ART). In HIV-infected&#xD;
      individuals, PD-1 expression on CD4+ T cells correlates with HIV disease progression, and&#xD;
      loss of HIV-specific CD4+ T cell function can be reversed in vitro by PD-1 blockade. There&#xD;
      are only a limited number of case reports describing the evolution of HIV-infected patients&#xD;
      with concurrent oncological disease treated with immunological checkpoint inhibitors.&#xD;
      However, this case provides very limited information on the effect of pembrolizumab on the&#xD;
      HIV reservoir. Here, the investigators aim at describing changes in the HIV reservoir and in&#xD;
      the HIV-specific immunity in HIV-infected patients on ART who receive immunological&#xD;
      checkpoint inhibitors for the treatment of cancer, especially for metastatic melanoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Long-lived latently infected resting CD4+ T cells are the main reason why current&#xD;
      antiretroviral therapy (ART) is unable to cure HIV infection. Recent work has suggested that&#xD;
      the expression of immune checkpoint markers, such as the programmed death-1 (PD1) or the&#xD;
      cytotoxic T-lymphocyte antigen 4 (CTL-4), may play a role in viral persistence on ART via&#xD;
      either suppression of virus transcription and/or reduced HIV-specific T cell activity, but&#xD;
      the in vivo role of immune checkpoint markers in HIV persistence on ART is not clear.&#xD;
&#xD;
      Immunological checkpoint inhibitors are humanized monoclonal Immunoglobulin G (IgG)&#xD;
      antibodies directed against several cell surface receptors, including PD-1 that inhibits&#xD;
      binding of PD-1, expressed on activated T cells to its ligands PD-L1, overexpressed on&#xD;
      certain cancer cells, and PD-L2, which is primarily expressed on antigen presenting cells.&#xD;
      Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion&#xD;
      from host immunity antigen presenting cells. Immunological checkpoint inhibitors can also&#xD;
      target CTL-4, which is constitutively expressed in Treg cells but only upregulated in&#xD;
      conventional T cells after activation, a phenomenon which is particularly notable in cancers.&#xD;
      These drugs are used to treat oncology diseases, including metastatic melanoma, and have been&#xD;
      associated with multiple changes in immune function thought to enhance antitumor T cell&#xD;
      function.&#xD;
&#xD;
      This exploratory study will include HIV-infected subjects with advanced melanoma or other&#xD;
      oncological conditions in which the use of immunological checkpoint inhibitors is clinically&#xD;
      indicated. The study is conceptually observational as the patients will be in regular&#xD;
      clinical treatment with immunological checkpoint inhibitors for oncological conditions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 26, 2018</start_date>
  <completion_date type="Actual">October 11, 2019</completion_date>
  <primary_completion_date type="Actual">March 18, 2019</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>Other</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Quantification of total HIV DNA</measure>
    <time_frame>At the end of recruitment (up to one year after inclusion)</time_frame>
    <description>Measurement of HIV viral latency by quantification of total HIV DNA in purified CD4+ T cells, using digital droplet PCR (ddPCR)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Quantification of cell-associated HIV RNA</measure>
    <time_frame>At the end of recruitment (up to one year after inclusion)</time_frame>
    <description>Measurement of viral transcription by quantification of cell-associated unspliced HIV RNA in purified CD4+ T cells, using ddPCR</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Quantification of ultrasensitive HIV viral load</measure>
    <time_frame>At the end of recruitment (up to one year after inclusion)</time_frame>
    <description>Measurement of ultrasensitive viremia in plasma using single copy assay</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Analysis of changes in HIV-specific cellular responses</measure>
    <time_frame>At the end of recruitment (up to one year after inclusion)</time_frame>
    <description>Changes in the ability of Peripheral Blood Mononuclear Cells (PBMCs) to release Interferon gamma (IFNγ) in response to viral antigen stimulation (ELISPOT assay).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Analysis of changes in immune-phenotype of cellular populations</measure>
    <time_frame>At the end of recruitment (up to one year after inclusion)</time_frame>
    <description>Study of changes in multiple cell membrane markers related with cell function, including T-cell activation and proliferation, T-cell exhaustion, T-cell subpopulations and release of specific cytokines in response to HIV stimuli (multicolor flow cytometry).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Analysis of changes in HIV inhibition capacity in vitro</measure>
    <time_frame>At the end of recruitment (up to one year after inclusion)</time_frame>
    <description>Changes in the ex vivo ability of cluster of differentiation 8 (CD8)+ T cells to inhibit superinfected autologous CD4+ T cells (virus inhibition assay).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Supervision of changes on the standard blood analysis for oncologic follow-up</measure>
    <time_frame>At the end of recruitment (up to one year after inclusion)</time_frame>
    <description>Blood analysis will be revised for oncologic follow-up</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Analysis of changes in imaging of the oncological focus</measure>
    <time_frame>At the end of recruitment (up to one year after inclusion)</time_frame>
    <description>Positron Emission Tomography (PET) scan will be analyzed for oncologic follow-up</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">1</enrollment>
  <condition>HIV Infection</condition>
  <condition>Cancer</condition>
  <arm_group>
    <arm_group_label>PembroHIV</arm_group_label>
    <description>HIV-infected subjects with advanced melanoma or other oncological conditions in which the use of immunological checkpoint inhibitors is clinically indicated</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Criopreserved peripheral blood mononuclear cells (PBMCs) Frozen plasma&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        HIV-infected subjects with advanced melanoma or other oncological conditions in which the&#xD;
        use of immunological checkpoint inhibitors is clinically indicated&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV-infected subjects with advanced melanoma or other oncological conditions in which&#xD;
             the use of immunological checkpoint inhibitors is clinically indicated&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  None&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>Javier Martinez-Picado, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>IrsiCaixa</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitari Germans Trias i Pujol</name>
      <address>
        <city>Badalona</city>
        <state>Barcelona</state>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>December 3, 2018</study_first_submitted>
  <study_first_submitted_qc>December 5, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 6, 2018</study_first_posted>
  <last_update_submitted>January 15, 2020</last_update_submitted>
  <last_update_submitted_qc>January 15, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>Cancer</keyword>
  <keyword>Checkpoint inhibitors</keyword>
  <keyword>HIV reservoir</keyword>
  <keyword>Immunity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>HIV Infections</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/NCT03767465
org study id: PembroHIV
nct id: NCT03767465
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: Yes
It has been reported that peripheral and lymph node resident Cluster of Differentiation 4
      (CD4)+ T cells expressing Programmed cell death protein 1 (PD-1) contribute to Human
      Immunodeficiency Virus (HIV) persistence during Antiretroviral Therapy (ART). In HIV-infected
      individuals, PD-1 expression on CD4+ T cells correlates with HIV disease progression, and
      loss of HIV-specific CD4+ T cell function can be reversed in vitro by PD-1 blockade. There
      are only a limited number of case reports describing the evolution of HIV-infected patients
      with concurrent oncological disease treated with immunological checkpoint inhibitors.
      However, this case provides very limited information on the effect of pembrolizumab on the
      HIV reservoir. Here, the investigators aim at describing changes in the HIV reservoir and in
      the HIV-specific immunity in HIV-infected patients on ART who receive immunological
      checkpoint inhibitors for the treatment of cancer, especially for metastatic melanoma.
Long-lived latently infected resting CD4+ T cells are the main reason why current
      antiretroviral therapy (ART) is unable to cure HIV infection. Recent work has suggested that
      the expression of immune checkpoint markers, such as the programmed death-1 (PD1) or the
      cytotoxic T-lymphocyte antigen 4 (CTL-4), may play a role in viral persistence on ART via
      either suppression of virus transcription and/or reduced HIV-specific T cell activity, but
      the in vivo role of immune checkpoint markers in HIV persistence on ART is not clear.

      Immunological checkpoint inhibitors are humanized monoclonal Immunoglobulin G (IgG)
      antibodies directed against several cell surface receptors, including PD-1 that inhibits
      binding of PD-1, expressed on activated T cells to its ligands PD-L1, overexpressed on
      certain cancer cells, and PD-L2, which is primarily expressed on antigen presenting cells.
      Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion
      from host immunity antigen presenting cells. Immunological checkpoint inhibitors can also
      target CTL-4, which is constitutively expressed in Treg cells but only upregulated in
      conventional T cells after activation, a phenomenon which is particularly notable in cancers.
      These drugs are used to treat oncology diseases, including metastatic melanoma, and have been
      associated with multiple changes in immune function thought to enhance antitumor T cell
      function.

      This exploratory study will include HIV-infected subjects with advanced melanoma or other
      oncological conditions in which the use of immunological checkpoint inhibitors is clinically
      indicated. The study is conceptually observational as the patients will be in regular
      clinical treatment with immunological checkpoint inhibitors for oncological conditions.
observational model: Cohort
time perspective: Other
measure: Quantification of total HIV DNA
time frame: At the end of recruitment (up to one year after inclusion)
description: Measurement of HIV viral latency by quantification of total HIV DNA in purified CD4+ T cells, using digital droplet PCR (ddPCR)
measure: Quantification of cell-associated HIV RNA
time frame: At the end of recruitment (up to one year after inclusion)
description: Measurement of viral transcription by quantification of cell-associated unspliced HIV RNA in purified CD4+ T cells, using ddPCR
measure: Quantification of ultrasensitive HIV viral load
time frame: At the end of recruitment (up to one year after inclusion)
description: Measurement of ultrasensitive viremia in plasma using single copy assay
measure: Analysis of changes in HIV-specific cellular responses
time frame: At the end of recruitment (up to one year after inclusion)
description: Changes in the ability of Peripheral Blood Mononuclear Cells (PBMCs) to release Interferon gamma (IFNγ) in response to viral antigen stimulation (ELISPOT assay).
measure: Analysis of changes in immune-phenotype of cellular populations
time frame: At the end of recruitment (up to one year after inclusion)
description: Study of changes in multiple cell membrane markers related with cell function, including T-cell activation and proliferation, T-cell exhaustion, T-cell subpopulations and release of specific cytokines in response to HIV stimuli (multicolor flow cytometry).
measure: Analysis of changes in HIV inhibition capacity in vitro
time frame: At the end of recruitment (up to one year after inclusion)
description: Changes in the ex vivo ability of cluster of differentiation 8 (CD8)+ T cells to inhibit superinfected autologous CD4+ T cells (virus inhibition assay).
measure: Supervision of changes on the standard blood analysis for oncologic follow-up
time frame: At the end of recruitment (up to one year after inclusion)
description: Blood analysis will be revised for oncologic follow-up
measure: Analysis of changes in imaging of the oncological focus
time frame: At the end of recruitment (up to one year after inclusion)
description: Positron Emission Tomography (PET) scan will be analyzed for oncologic follow-up
arm group label: PembroHIV
description: HIV-infected subjects with advanced melanoma or other oncological conditions in which the use of immunological checkpoint inhibitors is clinically indicated
Criopreserved peripheral blood mononuclear cells (PBMCs) Frozen plasma
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
last name: Javier Martinez-Picado, PhD
role: Principal Investigator
affiliation: IrsiCaixa
facility: 
country: Spain
responsible party type: Sponsor
mesh term: HIV Infections
sharing ipd: Undecided