<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/NCT03287674</url>
  </required_header>
  <id_info>
    <org_study_id>GY1721</org_study_id>
    <nct_id>NCT03287674</nct_id>
  </id_info>
  <brief_title>TIL Therapy in Combination With Checkpoint Inhibitors for Metastatic Ovarian Cancer</brief_title>
  <official_title>T-cell Therapy in Combination With Checkpoint Inhibitors for Patients With Advanced Ovarian-, Fallopian Tube- and Primary Peritoneal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Inge Marie Svane</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Herlev Hospital</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>
      Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved&#xD;
      impressive clinical results with durable complete responses in patients with metastatic&#xD;
      melanoma. Recently, the investigators have completed a pilot study treating 6 patients with&#xD;
      metastatic ovarian cancer. The TILs are isolated from patients own tumor tissue followed by&#xD;
      in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients&#xD;
      receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After&#xD;
      TIL infusion Interleukin-2 is administered to support T cell activation and proliferation in&#xD;
      vivo.&#xD;
&#xD;
      The investigators recent pilot study has shown TIL therapy in patients with metastatic&#xD;
      ovarian cancer to be feasible and tolerable. Mainly transient clinical responses where&#xD;
      observed and therefore the investigators plan to combine TIL therapy with checkpoint&#xD;
      inhibitors to potentially increase the clinical effect.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved&#xD;
      impressive clinical results with durable complete responses in patients with metastatic&#xD;
      melanoma. Recently, the investigators have completed a pilot study treating 6 patients with&#xD;
      metastatic ovarian cancer. The TILs are isolated from patients own tumor tissue followed by&#xD;
      in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients&#xD;
      receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After&#xD;
      TIL infusion Interleukin-2 is administered to support T cell activation and proliferation in&#xD;
      vivo.&#xD;
&#xD;
      The investigators recent pilot study has shown TIL therapy in patients with metastatic&#xD;
      ovarian cancer to be feasible and tolerable. Mainly transient clinical responses where&#xD;
      observed and therefore the investigators plan to combine TIL therapy with checkpoint&#xD;
      inhibitors to potentially increase the clinical effect.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      To evaluate safety and feasibility when treating patients with metastatic ovarian cancer with&#xD;
      ACT with TILs in combination with checkpoint inhibitors.&#xD;
&#xD;
      To evaluate treatment related immune responses To evaluate clinical efficacy&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Patients will be screened with a physical exam, medical history, blood samples and ECG.&#xD;
&#xD;
      Patients will be treated with one dose of Ipilimumab 14 days before undergoing surgery to&#xD;
      harvest tumor material for TIL production. Patients is admitted on day -8 in order to undergo&#xD;
      lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7. On day -2&#xD;
      patients will start treatment with Nivolumab every 2 weeks for a total of 4 doses to increase&#xD;
      the activity of the infused TIL product.&#xD;
&#xD;
      On day 0 patients receive TIL infusion and shortly after starts IL-2 stimulation with a daily&#xD;
      subcutaneous dose for a total of 14 days.The patients will followed until progression or up&#xD;
      to 5 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 9, 2017</start_date>
  <completion_date type="Actual">June 1, 2020</completion_date>
  <primary_completion_date type="Actual">June 1, 2020</primary_completion_date>
  <phase>Phase 1/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>Number of Participants With Reported Adverse Events by Type</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Determine the safety of TIL therapy in combination with checkpoint inhibitors for patients with ovarian-, fallopian tube or primary peritoneal cancer by reporting adverse events according to CTCAE v. 4.0.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment Related Immune Responses</measure>
    <time_frame>Until protocol end, until 6 months after TIL infusion</time_frame>
    <description>Ex vivo anti-tumor reactivity of expanded TILs after co-culture measured with flow cytometry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>Assessed up to 12 months after therapy.</time_frame>
    <description>Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CAT scan:&#xD;
Complete Response (CR) Disappearance of all target lesions (sum of all taget lesions=0) Partial Response (PR) &gt;=30% decrease (vs baseline) of sum of all target lesions dimension Progressive Disease (PD) new lesions or &gt;=20% increase (vs smallest sum of target lesions or nadir) Stable Disease (SD) when sum of all target lesions does not qualify for CR/PR/PD</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Up to 3 years after TIL infusion</time_frame>
    <description>Overall Survival (OS), defined as time from TIL infusion to death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>Up to 12 months after TIL infusion</time_frame>
    <description>Progression free survival (PFS): Time from TIL infusion to disease progression, relapse or death due to any cause, which ever comes first, will be used as an event.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Metastatic Ovarian Cancer</condition>
  <arm_group>
    <arm_group_label>Patient group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients receive the same treatment. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks.&#xD;
The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses.&#xD;
The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13.&#xD;
Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>Cyclophosphamide 60 mg/kg is administered i.v. on day -7 and day -6.</description>
    <arm_group_label>Patient group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine</intervention_name>
    <description>Fludarabine 25 mg/m2 is administered on day -5 to day -1.</description>
    <arm_group_label>Patient group</arm_group_label>
    <other_name>Fludarabine phosphate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>TIL infusion</intervention_name>
    <description>The maximum number of expanded TILs are infused over 30-45 minutes on day 0.</description>
    <arm_group_label>Patient group</arm_group_label>
    <other_name>TILs</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Interleukin-2</intervention_name>
    <description>Interleukin-2 is administered as a daily low-dose subcutaneous injection of 2 MIU for a total of 14 days.</description>
    <arm_group_label>Patient group</arm_group_label>
    <other_name>IL-2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>One dose of Ipilimumab 3 mg/kg is administered 14 days prior to surgical removal of tumor tissue for TIL expansion.</description>
    <arm_group_label>Patient group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab 3 mg/kg is administered on day -2 before TIL infusion and every 2 weeks for a total of 4 doses.</description>
    <arm_group_label>Patient group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Only patients within the Danish healthcare system are eligible for enrollment.&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Histological proven advanced ovarian-, fallopian tube or primary peritoneal cancer&#xD;
             with the possibility of surgical removal of tumor tissue of &gt; 1 cm3.&#xD;
&#xD;
          -  Progressive or recurrent resistant disease after platin-based chemotherapy (platinum&#xD;
             resistant) or progressive or recurrent disease after second line or additional&#xD;
             chemotherapy.&#xD;
&#xD;
          -  Age: 18 - 70 years.&#xD;
&#xD;
          -  ECOG performance status of ≤1 (Appendix 2).&#xD;
&#xD;
          -  Life expectancy of &gt; 6 months.&#xD;
&#xD;
          -  At least one measurable parameter in accordance with RECIST 1.1 -criteria's.&#xD;
&#xD;
          -  No significant toxicities or side effects from previous treatments, except sensoric-&#xD;
             and motoric neuropathy and/or alopecia&#xD;
&#xD;
          -  Sufficient renal, hepatic and hematological function&#xD;
&#xD;
          -  Men and women in the fertile age must use effective contraception. This applies from&#xD;
             inclusion and until 6 months after treatment.&#xD;
&#xD;
          -  Able to comprehend the information given and willing to sign informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Other malignancies, unless followed for ≥ 5 years with no sign of disease&#xD;
&#xD;
          -  Known hypersensitivity to one of the active drugs or one or more of the excipients.&#xD;
&#xD;
          -  Severe medical or psychiatric conditions&#xD;
&#xD;
          -  Creatinine clearance &lt; 70 ml/min. In selected cases it can be decided to include a&#xD;
             patient with a GFR &lt; 70 ml/min with the use of a reduced dose of chemotherapy.&#xD;
&#xD;
          -  Acute/chronic infection with HIV, hepatitis, syphilis among others.&#xD;
&#xD;
          -  Severe allergies or previous anaphylactic reactions.&#xD;
&#xD;
          -  Active autoimmune disease&#xD;
&#xD;
          -  Pregnant women and women breastfeeding.&#xD;
&#xD;
          -  Need for immunosuppressive treatment e.g. corticosteroids or methotrexate. In selected&#xD;
             cases a systemic dose of ≤10 mg prednisolone or a transient planned treatment that can&#xD;
             be stopped before TIL therapy can be tolerated.&#xD;
&#xD;
          -  Simultaneous treatment with other experimental drugs.&#xD;
&#xD;
          -  Simultaneous treatment with other systemic anti-cancer treatments.&#xD;
&#xD;
          -  Patients with active and uncontrollable hypercalcaemia.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Inge Marie Svane, Prof., M.D.</last_name>
    <role>Study Director</role>
    <affiliation>Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Magnus Pedersen, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Center for Cancer Immune Therapy Dept. of Hematology/oncology</name>
      <address>
        <city>Copenhagen</city>
        <zip>2730</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>September 14, 2017</study_first_submitted>
  <study_first_submitted_qc>September 15, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 19, 2017</study_first_posted>
  <results_first_submitted>August 10, 2020</results_first_submitted>
  <results_first_submitted_qc>February 25, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">March 22, 2021</results_first_posted>
  <last_update_submitted>February 28, 2023</last_update_submitted>
  <last_update_submitted_qc>February 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Herlev Hospital</investigator_affiliation>
    <investigator_full_name>Inge Marie Svane</investigator_full_name>
    <investigator_title>M.D., Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ovarian Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Ovarian Epithelial</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Fludarabine</mesh_term>
    <mesh_term>Fludarabine phosphate</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
    <mesh_term>Interleukin-2</mesh_term>
  </intervention_browse>
  <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>July 13, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/74/NCT03287674/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>TIL Treated Patients</title>
          <description>Ipilimumab Cyclophospamide Fludarabine Nivolumab TILs IL-2</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>All Treated With TILs</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>TIL Treated Patients</title>
          <description>Ipilimumab Cyclophospamide Fludarabine Nivolumab TILs IL-2</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Denmark</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Reported Adverse Events by Type</title>
        <description>Determine the safety of TIL therapy in combination with checkpoint inhibitors for patients with ovarian-, fallopian tube or primary peritoneal cancer by reporting adverse events according to CTCAE v. 4.0.</description>
        <time_frame>Up to 12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>TIL Treated Patients</title>
            <description>Ipilimumab Cyclophospamide Fludarabine Nivolumab TILs IL-2</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Reported Adverse Events by Type</title>
          <description>Determine the safety of TIL therapy in combination with checkpoint inhibitors for patients with ovarian-, fallopian tube or primary peritoneal cancer by reporting adverse events according to CTCAE v. 4.0.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Performance status drop</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fatigue</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Nausea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Vomiting</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Diarrhea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hyponatremia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Infection</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neutropenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Trombocytopenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Agammaglobulinemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dyspnea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fever</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Colitis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dry skin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment Related Immune Responses</title>
        <description>Ex vivo anti-tumor reactivity of expanded TILs after co-culture measured with flow cytometry.</description>
        <time_frame>Until protocol end, until 6 months after TIL infusion</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Patient Group</title>
            <description>Patients treated with TILs</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment Related Immune Responses</title>
          <description>Ex vivo anti-tumor reactivity of expanded TILs after co-culture measured with flow cytometry.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rate</title>
        <description>Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CAT scan:&#xD;
Complete Response (CR) Disappearance of all target lesions (sum of all taget lesions=0) Partial Response (PR) &gt;=30% decrease (vs baseline) of sum of all target lesions dimension Progressive Disease (PD) new lesions or &gt;=20% increase (vs smallest sum of target lesions or nadir) Stable Disease (SD) when sum of all target lesions does not qualify for CR/PR/PD</description>
        <time_frame>Assessed up to 12 months after therapy.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>TIL Treated Patients</title>
            <description>Ipilimumab Cyclophospamide Fludarabine Nivolumab TILs IL-2</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate</title>
          <description>Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CAT scan:&#xD;
Complete Response (CR) Disappearance of all target lesions (sum of all taget lesions=0) Partial Response (PR) &gt;=30% decrease (vs baseline) of sum of all target lesions dimension Progressive Disease (PD) new lesions or &gt;=20% increase (vs smallest sum of target lesions or nadir) Stable Disease (SD) when sum of all target lesions does not qualify for CR/PR/PD</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Complete response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stabile disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall Survival (OS), defined as time from TIL infusion to death</description>
        <time_frame>Up to 3 years after TIL infusion</time_frame>
        <group_list>
          <group group_id="O1">
            <title>TIL Treated Patients</title>
            <description>Ipilimumab Cyclophospamide Fludarabine Nivolumab TILs IL-2</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Overall Survival (OS), defined as time from TIL infusion to death</description>
          <units>Days</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="247" lower_limit="136" upper_limit="915"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival</title>
        <description>Progression free survival (PFS): Time from TIL infusion to disease progression, relapse or death due to any cause, which ever comes first, will be used as an event.</description>
        <time_frame>Up to 12 months after TIL infusion</time_frame>
        <group_list>
          <group group_id="O1">
            <title>TIL Treated Patients</title>
            <description>Ipilimumab Cyclophospamide Fludarabine Nivolumab TILs IL-2</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival</title>
          <description>Progression free survival (PFS): Time from TIL infusion to disease progression, relapse or death due to any cause, which ever comes first, will be used as an event.</description>
          <units>Days</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="93" lower_limit="84" upper_limit="342"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first therapy and until discontinuation from protocol - up to 12 months after.</time_frame>
      <desc>Adverse event above grade 2 (CTCAE 4.0)</desc>
      <group_list>
        <group group_id="E1">
          <title>TIL Treated Patients</title>
          <description>Ipilimumab Cyclophospamide Fludarabine Nivolumab TILs IL-2</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>colitis</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Agammaglobulimia</sub_title>
                <description>B-cell deficiency</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Trombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</sub_title>
                <description>after ipilimumab</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Infection</sub_title>
                <description>After TILs and immune suppresion</description>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <description>Cyclophosphamide</description>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <description>after TILs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Thyroiditis</sub_title>
                <description>immune related adverse event</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Oral mucositis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Obstipation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Elevated liver enzymes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Anders Kverneland, MD</name_or_title>
      <organization>National Center for Cancer Immune Therapy, Herlev Hospital</organization>
      <phone>38686467</phone>
      <email>anders.kverneland@regionh.dk</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03287674
org study id: GY1721
nct id: NCT03287674
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved
      impressive clinical results with durable complete responses in patients with metastatic
      melanoma. Recently, the investigators have completed a pilot study treating 6 patients with
      metastatic ovarian cancer. The TILs are isolated from patients own tumor tissue followed by
      in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients
      receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After
      TIL infusion Interleukin-2 is administered to support T cell activation and proliferation in
      vivo.

      The investigators recent pilot study has shown TIL therapy in patients with metastatic
      ovarian cancer to be feasible and tolerable. Mainly transient clinical responses where
      observed and therefore the investigators plan to combine TIL therapy with checkpoint
      inhibitors to potentially increase the clinical effect.
Adoptive T cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has achieved
      impressive clinical results with durable complete responses in patients with metastatic
      melanoma. Recently, the investigators have completed a pilot study treating 6 patients with
      metastatic ovarian cancer. The TILs are isolated from patients own tumor tissue followed by
      in vitro expansion and activation for around 4-6 weeks. Before TIL infusion the patients
      receive 1 week of preconditioning chemotherapy with cyclophosphamide and fludarabine. After
      TIL infusion Interleukin-2 is administered to support T cell activation and proliferation in
      vivo.

      The investigators recent pilot study has shown TIL therapy in patients with metastatic
      ovarian cancer to be feasible and tolerable. Mainly transient clinical responses where
      observed and therefore the investigators plan to combine TIL therapy with checkpoint
      inhibitors to potentially increase the clinical effect.

      Objectives:

      To evaluate safety and feasibility when treating patients with metastatic ovarian cancer with
      ACT with TILs in combination with checkpoint inhibitors.

      To evaluate treatment related immune responses To evaluate clinical efficacy

      Design:

      Patients will be screened with a physical exam, medical history, blood samples and ECG.

      Patients will be treated with one dose of Ipilimumab 14 days before undergoing surgery to
      harvest tumor material for TIL production. Patients is admitted on day -8 in order to undergo
      lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7. On day -2
      patients will start treatment with Nivolumab every 2 weeks for a total of 4 doses to increase
      the activity of the infused TIL product.

      On day 0 patients receive TIL infusion and shortly after starts IL-2 stimulation with a daily
      subcutaneous dose for a total of 14 days.The patients will followed until progression or up
      to 5 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Reported Adverse Events by Type
time frame: Up to 12 months
description: Determine the safety of TIL therapy in combination with checkpoint inhibitors for patients with ovarian-, fallopian tube or primary peritoneal cancer by reporting adverse events according to CTCAE v. 4.0.
measure: Treatment Related Immune Responses
time frame: Until protocol end, until 6 months after TIL infusion
description: Ex vivo anti-tumor reactivity of expanded TILs after co-culture measured with flow cytometry.
measure: Objective Response Rate
time frame: Assessed up to 12 months after therapy.
description: Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CAT scan:
Complete Response (CR) Disappearance of all target lesions (sum of all taget lesions=0) Partial Response (PR) >=30% decrease (vs baseline) of sum of all target lesions dimension Progressive Disease (PD) new lesions or >=20% increase (vs smallest sum of target lesions or nadir) Stable Disease (SD) when sum of all target lesions does not qualify for CR/PR/PD
measure: Overall Survival
time frame: Up to 3 years after TIL infusion
description: Overall Survival (OS), defined as time from TIL infusion to death
measure: Progression Free Survival
time frame: Up to 12 months after TIL infusion
description: Progression free survival (PFS): Time from TIL infusion to disease progression, relapse or death due to any cause, which ever comes first, will be used as an event.
arm group label: Patient group
arm group type: Experimental
description: All patients receive the same treatment. All patients are treated with one dose of Ipilimumab 14 days prior to surgical removal of tumor tissue for TIL expansion. Hospitalization for TIL treatment is approximately 3 weeks.
The patients are admitted to hospital on day -8 and receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine= on day -7 to day -1. The first of 4 doses of Nivolumab is administered on day -2 and every 2 weeks for at total of 4 doses.
The TILs are infused on day 0 and Interleukin-2 therapy is administered on day 0 to day 13.
Interleukin-2 is administered as a daily low-dose subcutaneous injection for a total for 14 days.
intervention type: Drug
intervention name: Cyclophosphamide
description: Cyclophosphamide 60 mg/kg is administered i.v. on day -7 and day -6.
arm group label: Patient group
intervention type: Drug
intervention name: Fludarabine
description: Fludarabine 25 mg/m2 is administered on day -5 to day -1.
arm group label: Patient group
other name: Fludarabine phosphate
intervention type: Biological
intervention name: TIL infusion
description: The maximum number of expanded TILs are infused over 30-45 minutes on day 0.
arm group label: Patient group
other name: TILs
intervention type: Drug
intervention name: Interleukin-2
description: Interleukin-2 is administered as a daily low-dose subcutaneous injection of 2 MIU for a total of 14 days.
arm group label: Patient group
other name: IL-2
intervention type: Drug
intervention name: Ipilimumab
description: One dose of Ipilimumab 3 mg/kg is administered 14 days prior to surgical removal of tumor tissue for TIL expansion.
arm group label: Patient group
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab 3 mg/kg is administered on day -2 before TIL infusion and every 2 weeks for a total of 4 doses.
arm group label: Patient group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Inge Marie Svane, Prof., M.D.
role: Study Director
affiliation: Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730
last name: Magnus Pedersen, M.D.
role: Principal Investigator
affiliation: Center for Cancer Immune Therapy, Depth of Hematology/Oncology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730
facility: 
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: Herlev Hospital
investigator full name: Inge Marie Svane
investigator title: M.D., Professor
mesh term: Ovarian Neoplasms
mesh term: Carcinoma, Ovarian Epithelial
mesh term: Cyclophosphamide
mesh term: Nivolumab
mesh term: Fludarabine
mesh term: Fludarabine phosphate
mesh term: Ipilimumab
mesh term: Interleukin-2
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 