<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/NCT03304093</url>
  </required_header>
  <id_info>
    <org_study_id>IFCT-1602</org_study_id>
    <nct_id>NCT03304093</nct_id>
  </id_info>
  <brief_title>Immunotherapy by Nivolumab for HIV+ Patients</brief_title>
  <acronym>CHIVA2</acronym>
  <official_title>Immunotherapy by Nivolumab After Prior Chemotherapy for HIV+ Patients With Advanced Non-small Cell Lung Cancer (NSCLC): IFCT-CHIVA2 Phase IIa Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Intergroupe Francophone de Cancerologie Thoracique</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ANRS, Emerging Infectious Diseases</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Intergroupe Francophone de Cancerologie Thoracique</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Two Phase III trials showed superiority in terms of efficacy and tolerance of nivolumab in&#xD;
      second-line treatment compared to docetaxel in metastatic NSCLC in the general population, so&#xD;
      it is important to evaluate this treatment in PLWHIV (Patient Living With HIV) in maximum&#xD;
      security conditions, taking into account their specificities and complex underlying&#xD;
      immunological status. As NSCLC in PLWHIV is a rare tumour, a phase 2 trial, using DCR&#xD;
      (Disease Control Rate) data, would be able to recruit a sufficient number of patients, in a&#xD;
      reasonable period of time, to provide a proof of concept of the safety and efficacy of&#xD;
      nivolumab in this population. Therefore, we think that an open-label, one arm phase 2 trial,&#xD;
      with a rapid accrual, would be currently a crucial approach and a window of opportunity to&#xD;
      explore whether nivolumab could find its place in PLWHIV with NSCLC. Such a trial is&#xD;
      typically a trial for an academic sponsor, experienced in PLWHIV with NSCLC, which previously&#xD;
      showed its ability to recruit patients with such a rare disease as the IFCT did with the&#xD;
      IFCT-1001 CHIVA trial, testing carboplatin plus pemetrexed followed by pemetrexed.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 19, 2017</start_date>
  <completion_date type="Actual">February 18, 2022</completion_date>
  <primary_completion_date type="Actual">February 18, 2021</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease Control Rate</measure>
    <time_frame>8 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>6 months and one year</time_frame>
    <description>Time between the date of inclusion and the first date of documented progression or death due to any cause, whichever occurs first. Subjects who die without a reported progression will be considered to have progressed on the date of their death. Subjects who did not progress or die will be censored on the date of their last evaluable tumor assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>6 months and one year</time_frame>
    <description>Time elapsed between the date of inclusion and death. Subjects who did not die will be censored on the last date a subject was known to be alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tolerance</measure>
    <time_frame>8 weeks, 6 months and one year</time_frame>
    <description>Adverse Events (AEs) grade (NCI-CTC 4.0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Responses rate according to tissue PD-L1 expression</measure>
    <time_frame>8 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life measured by LCSS questionnaire</measure>
    <time_frame>After 2, 3, 5, 7 and 9 cycles (each cycle is 14 days)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>8 weeks, 6 months and one year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>impact on HIV control and immunological, other associated chronic infection susceptible of reactivation and potential occurrence of autoimmunity</measure>
    <time_frame>8 weeks, 6 months and one year</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Monitor HIV, CMV, EBV, HBV, HCV, HHV-8-specific T cell responses in PBMC</measure>
    <time_frame>Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Monitor the HIV reservoirs (HIV-DNA) and the residual HIV replication as well as EBV CMV, HBV, HCV, HHV-8 viral load</measure>
    <time_frame>Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Monitor T cell activation/ exhaustion/differentiation and immune check point expression</measure>
    <time_frame>Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Description of gene mutation that appear to be crucial for the response to immunotherapy or for adverse effects of immunotherapy</measure>
    <time_frame>Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Immune monitoring of adverse effects</measure>
    <time_frame>Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Describe the tumoral microenvironment of NSCLC before nivolumab exposure (CD4, CD8, CD3 infiltrate, PD-1, PD-L1 expression)</measure>
    <time_frame>At enrolment</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Non Small Cell Lung Cancer Metastatic</condition>
  <condition>Non Small Cell Lung Cancer Stage IIIB</condition>
  <condition>HIV/AIDS</condition>
  <arm_group>
    <arm_group_label>Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab 3mg/kg every 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab Injection</intervention_name>
    <description>Nivolumab 3mg/kg every 2 weeks</description>
    <arm_group_label>Nivolumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years old&#xD;
&#xD;
          2. HIV1 or HIV2, regardless of CD4 cell count&#xD;
&#xD;
          3. HIV Viral load &lt;200 copies/mL&#xD;
&#xD;
          4. Proven histologically and/or cytologically, stage IIIB-IV or metastatic relapse&#xD;
             post-surgery non-small cell lung cancer (NSCLC)&#xD;
&#xD;
          5. Disease recurrence or progression during/after at least one prior platinum&#xD;
             doublet-based chemotherapy regimen for advanced or metastatic disease&#xD;
&#xD;
          6. Measurable disease by Computed tomography (CT)/Magnetic resonance imaging (MRI) per&#xD;
             RECIST 1.1 criteria&#xD;
&#xD;
          7. Performance status (PS) 0, 1 or 2&#xD;
&#xD;
          8. Written informed consent&#xD;
&#xD;
          9. Patients must have adequate organ function: creatinine clearance &gt; 40 mL/min&#xD;
             (Cockcroft, MDRD or CKD-Epi formula or 24h Urine Calculate creatinine clearance from a&#xD;
             24h urine collection ), neutrophiles count &gt; 1500/mm3; platelets &gt; 100 000/mm3 ;&#xD;
             hemoglobin &gt; 9 g/dL; hepatic enzymes &lt; 3N with total bilirubin ≤ 1.5 × ULN (upper&#xD;
             limit of normal) except subjects with documented Gilbert's syndrome (≤ 5 × ULN) or&#xD;
             liver metastasis, who must have a baseline total bilirubin ≤ 3.0 mg/dL&#xD;
&#xD;
         10. Patients must receive appropriate care and treatment for HIV infection including ART&#xD;
             when clinically indicated and subjects should be under the care of a physician&#xD;
             experienced in HIV management. In case of recent introduction of cART and CD4 levels&#xD;
             &lt;50 cells/ml, inclusion will be possible provided subjects had at least 4 weeks of&#xD;
             treatment prior to inclusion, to avoid clinical type IRIS (immune inflammatory&#xD;
             syndrome reconstitution). All antiretroviral treatments are allowed.&#xD;
&#xD;
         11. Females of childbearing potential who are sexually active with a nonsterilized male&#xD;
             partner must use a highly effective method of contraception for 28 days prior to the&#xD;
             first dose of investigational product, and must agree to continue using such&#xD;
             precautions for 6 months after the final dose of investigational product; cessation of&#xD;
             contraception after this point should be discussed with the referent physician.&#xD;
             Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable&#xD;
             methods of contraception. They must also refrain from egg cell donation for 6 months&#xD;
             after the final dose of investigational product. Men receiving nivolumab and who are&#xD;
             sexually active with women of childbearing potential will be instructed to adhere to&#xD;
             contraception (appendix I) for a period of 31 weeks after the last dose of nivolumab.&#xD;
&#xD;
         12. Persons deprived of liberty could be eligible because the expected benefice&#xD;
             (improvement of disease control rate) justifies the foreseeable risk (adverse reaction&#xD;
             of nivolumab).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Concurrent malignancies requiring active intervention&#xD;
&#xD;
          2. Active Infection&#xD;
&#xD;
          3. Patient with known EGFR activating tumor mutation or known ALK or ROS1 gene&#xD;
             rearrangement not treated with the appropriate targeted therapy.&#xD;
&#xD;
          4. History of immunological events related to HIV: lymphoid interstitial pneumonitis&#xD;
             (LIP), non-infectious uveitis, encephalitis and other manifestations of CD8 lymphocyte&#xD;
             infiltration syndrome, HIV-associated nephropathy (HIVAN).&#xD;
&#xD;
          5. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo,&#xD;
             type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only&#xD;
             requiring hormone replacement, or conditions not expected to recur in the absence of&#xD;
             an external trigger are permitted to enroll.&#xD;
&#xD;
          6. Active or history of inflammatory bowel disease (eg, diverticulitis, colitis, Crohn's,&#xD;
             coeliac disease or other serious gastrointestinal chronic conditions associated with&#xD;
             diarrhea). Note that diverticulosis is permitted.&#xD;
&#xD;
          7. Symptomatic cerebral metastasis unless treated by brain radiotherapy which will be&#xD;
             completed for at least 15 days before the beginning of the treatment; subjects with&#xD;
             carcinomatous meningitis.&#xD;
&#xD;
          8. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or&#xD;
             any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint&#xD;
             pathways.&#xD;
&#xD;
          9. The last dose of prior chemotherapy or radiation therapy (with the exception of&#xD;
             palliative radiotherapy) was received less than 3 weeks prior to inclusion;&#xD;
&#xD;
         10. History of primary immunodeficiency, history of organ transplant that requires&#xD;
             therapeutic immunosuppression and the use of immunosuppressive agents within 28 days&#xD;
             of inclusion or a prior history of severe (grade 3 or 4) immune mediated toxicity from&#xD;
             other immune therapy.&#xD;
&#xD;
         11. Subjects with a condition requiring systemic treatment with either corticosteroids (&gt;&#xD;
             10 mg daily prednisone equivalent) or other immunosuppressive medications within 14&#xD;
             days of inclusion. Intranasal/inhaled or topical steroids, and adrenal replacement&#xD;
             steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of&#xD;
             active autoimmune disease.&#xD;
&#xD;
         12. Female subjects who are pregnant, breast-feeding or male or female patients of&#xD;
             reproductive potential who are not employing an effective method of birth control.&#xD;
&#xD;
         13. Legally protected adults.&#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>Armelle LAVOLE, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>APHP Hôpital Tenon</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jacques CADRANEL, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>APHP Hôpital Tenon</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CH d'Avignon</name>
      <address>
        <city>Avignon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH de la Côte Basque</name>
      <address>
        <city>Bayonne</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Cahors</name>
      <address>
        <city>Cahors</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH</name>
      <address>
        <city>Colmar</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHI Créteil</name>
      <address>
        <city>Créteil</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier - Pneumologie</name>
      <address>
        <city>Le Mans</city>
        <zip>72000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital de la Croix Rousse</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AP-HM Hôpital Nord</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montpellier - CHRU</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montpellier - ICM</name>
      <address>
        <city>Montpellier</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>APHP - Hopital Tenon - Pneumologie</name>
      <address>
        <city>Paris</city>
        <zip>75020</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Paris - APHP Bichat</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Paris - Pitié-salpêtrière</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH de Pau</name>
      <address>
        <city>Pau</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Brieuc - CHG</name>
      <address>
        <city>Saint Brieuc</city>
        <zip>22000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NHC - Pneumologie</name>
      <address>
        <city>Strasbourg</city>
        <zip>63000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Suresnes - Hopital Foch</name>
      <address>
        <city>Suresnes</city>
        <zip>92151</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Toulouse - Pneumologie</name>
      <address>
        <city>Toulouse</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>October 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 6, 2017</study_first_posted>
  <last_update_submitted>May 11, 2023</last_update_submitted>
  <last_update_submitted_qc>May 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 12, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>IFCT</keyword>
  <keyword>VIH</keyword>
  <keyword>Nivolumab</keyword>
  <keyword>NSCLC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 11, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/93/NCT03304093/Prot_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/NCT03304093
org study id: IFCT-1602
nct id: NCT03304093
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Two Phase III trials showed superiority in terms of efficacy and tolerance of nivolumab in
      second-line treatment compared to docetaxel in metastatic NSCLC in the general population, so
      it is important to evaluate this treatment in PLWHIV (Patient Living With HIV) in maximum
      security conditions, taking into account their specificities and complex underlying
      immunological status. As NSCLC in PLWHIV is a rare tumour, a phase 2 trial, using DCR
      (Disease Control Rate) data, would be able to recruit a sufficient number of patients, in a
      reasonable period of time, to provide a proof of concept of the safety and efficacy of
      nivolumab in this population. Therefore, we think that an open-label, one arm phase 2 trial,
      with a rapid accrual, would be currently a crucial approach and a window of opportunity to
      explore whether nivolumab could find its place in PLWHIV with NSCLC. Such a trial is
      typically a trial for an academic sponsor, experienced in PLWHIV with NSCLC, which previously
      showed its ability to recruit patients with such a rare disease as the IFCT did with the
      IFCT-1001 CHIVA trial, testing carboplatin plus pemetrexed followed by pemetrexed.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease Control Rate
time frame: 8 weeks
measure: Progression Free Survival
time frame: 6 months and one year
description: Time between the date of inclusion and the first date of documented progression or death due to any cause, whichever occurs first. Subjects who die without a reported progression will be considered to have progressed on the date of their death. Subjects who did not progress or die will be censored on the date of their last evaluable tumor assessment.
measure: Overall Survival
time frame: 6 months and one year
description: Time elapsed between the date of inclusion and death. Subjects who did not die will be censored on the last date a subject was known to be alive.
measure: Tolerance
time frame: 8 weeks, 6 months and one year
description: Adverse Events (AEs) grade (NCI-CTC 4.0)
measure: Responses rate according to tissue PD-L1 expression
time frame: 8 weeks
measure: Quality of life measured by LCSS questionnaire
time frame: After 2, 3, 5, 7 and 9 cycles (each cycle is 14 days)
measure: Duration of response
time frame: 8 weeks, 6 months and one year
measure: impact on HIV control and immunological, other associated chronic infection susceptible of reactivation and potential occurrence of autoimmunity
time frame: 8 weeks, 6 months and one year
measure: Monitor HIV, CMV, EBV, HBV, HCV, HHV-8-specific T cell responses in PBMC
time frame: Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)
measure: Monitor the HIV reservoirs (HIV-DNA) and the residual HIV replication as well as EBV CMV, HBV, HCV, HHV-8 viral load
time frame: Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)
measure: Monitor T cell activation/ exhaustion/differentiation and immune check point expression
time frame: Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)
measure: Description of gene mutation that appear to be crucial for the response to immunotherapy or for adverse effects of immunotherapy
time frame: Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)
measure: Immune monitoring of adverse effects
time frame: Cycle 1, 2, 3, 9, 15, 27, 51 and end of treatment (each cycle is 14 days)
measure: Describe the tumoral microenvironment of NSCLC before nivolumab exposure (CD4, CD8, CD3 infiltrate, PD-1, PD-L1 expression)
time frame: At enrolment
arm group label: Nivolumab
arm group type: Experimental
description: Nivolumab 3mg/kg every 2 weeks
intervention type: Drug
intervention name: Nivolumab Injection
description: Nivolumab 3mg/kg every 2 weeks
arm group label: Nivolumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Armelle LAVOLE, MD
role: Principal Investigator
affiliation: APHP Hôpital Tenon
last name: Jacques CADRANEL, MD, PhD
role: Principal Investigator
affiliation: APHP Hôpital Tenon
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Nivolumab
sharing ipd: No
provided document: 