<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/NCT03296137</url>
  </required_header>
  <id_info>
    <org_study_id>AA1720</org_study_id>
    <nct_id>NCT03296137</nct_id>
  </id_info>
  <brief_title>Adoptive Cell Therapy Across Cancer Diagnoses</brief_title>
  <official_title>Adoptive Cell Therapy Across Cancer Diagnoses</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will perform tumor-infiltrating lymphocyte (TIL)-based adoptive T-cell therapy in&#xD;
      combination with checkpoint inhibition on cancer patients across all cancer diagnoses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Adoptive cell therapy (ACT) is a personalized form of immunotherapy, where lymphocytes&#xD;
      isolated from the patient's own tumor tissue are expanded 1000-fold ex-vivo and then infused&#xD;
      back into the patient. The lymphocytes are then able to recognize and attack remaining cancer&#xD;
      cells. This approach has shown remarkable clinical results in several trials conducted&#xD;
      worldwide for patients with advanced melanoma - some with durable remissions. Promising&#xD;
      clinical results were obtained in smaller trials where patients with disparate solid tumors&#xD;
      were treated with tumor-infiltrating lymphocytes (TILs). At Center for Cancer Immune Therapy&#xD;
      (CCIT) at Herlev Hospital, there are currently clinical trials undergoing in ovarian and&#xD;
      renal cancer, and internationally ACT is being tested in an increasing number of cancer&#xD;
      diagnoses, some trials are even recruiting patients across cancer types. Studies have shown&#xD;
      that a high intratumoral infiltration with TILs in is correlated to the general clinical&#xD;
      outcome of the disease in virtually all solid tumors, and thus clinical trials with TIL-based&#xD;
      ACT to different cancer diagnoses have been undertaken.&#xD;
&#xD;
      To support the TIL-mediated tumor elimination, in classical ACT protocols patients go through&#xD;
      a highly specialized treatment regime before and after TIL infusion. This regime includes&#xD;
      lymphodepletion with 7 days non-myeloablative chemotherapy, to provide an immunological&#xD;
      window of opportunity for the infused TILs, and concomitant immune stimulation with&#xD;
      interleukin-2 (IL-2). Checkpoint inhibition to support the anti-tumor activity of TILs is&#xD;
      currently under extensive investigation in several other trials worldwide. Thus,&#xD;
      lymphodepletion and IL-2 stimulation are well-established as supportive therapy and already&#xD;
      an integrated part of current ACT protocols and while checkpoint inhibition is a new addition&#xD;
      at CCIT; internationally other centers have ongoing comparable trials.&#xD;
&#xD;
      Drug-based immunotherapy in the form of checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) has&#xD;
      yielded impressive clinical results across tumor histologies. Recent results indicate that&#xD;
      the effect of immunotherapy relies not so much on the cancer diagnoses but rather on the&#xD;
      genomic and immunologic features of the individual patient's cancer disease. Both ACT and&#xD;
      checkpoint inhibition work by tipping the immunological balance in favor of activation and&#xD;
      away from suppression or avoidance by the cancer cells. Scientific evidence now show that&#xD;
      administering anti-CTLA-4 and PD-1 could provide a benefit in the ACT setting, and several&#xD;
      ongoing clinical trials are testing combinations of ACT and checkpoint inhibition. To&#xD;
      synergistically maximize the immunological potential, we wish to combine ACT with an&#xD;
      anti-CTLA-4 antibody (Ipilimumab) prior to tumor resection and an anti-PD-1 antibody&#xD;
      (Nivolumab) in combination with TIL infusion.&#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;
      Available evidence indicates that ACT is a safe and feasible treatment option in an&#xD;
      increasing number of solid tumors, and that it should be tested in all cancer patients&#xD;
      regardless of their cancer diagnosis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">October 13, 2017</start_date>
  <completion_date type="Anticipated">September 30, 2020</completion_date>
  <primary_completion_date type="Actual">March 13, 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 and type of reported adverse events</measure>
    <time_frame>Up to 2,5 years from begin of study</time_frame>
    <description>Determine the safety of the administration of TIL therapy including checkpoint inhibitors, lymphodepleting chemotherapy and Interleukin-2 for patients with cancer by reporting adverse events according to CTCAE v. 4.0.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment response, progressive disease</measure>
    <time_frame>Up to 7 years from begin of study</time_frame>
    <description>Clinical response in progression-free survival to treatment according to RECIST 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment response, surival</measure>
    <time_frame>Up to 7 years from begin of study</time_frame>
    <description>Clinical response in terms of overall survival.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment related immune response</measure>
    <time_frame>3 years from begin of study</time_frame>
    <description>Flow cytometry-based immunological evaluation of peripheral blood</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Cancer</condition>
  <arm_group>
    <arm_group_label>All participants</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Autologous tumor-infiltrating lymphocytes</intervention_name>
    <description>Tumor-infiltrating lymphocytes grown ex-vivo from resected from cancer tissue and reapplied to the patient via an intravenous infusion.</description>
    <arm_group_label>All participants</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>One treatment with ipilimumab (3 mg/kg) prior to tumor resection.</description>
    <arm_group_label>All participants</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>4 doses of nivolumab. Starting 2 days prior to TIL infusion and every 2 weeks hereafter.</description>
    <arm_group_label>All participants</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>proleukin</intervention_name>
    <description>2 MIE s.c. injection, after TIL infusion and continuing for 2 weeks</description>
    <arm_group_label>All participants</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>2 doses (60 mg/kg) prior to TIL infusion</description>
    <arm_group_label>All participants</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludara</intervention_name>
    <description>5 doses (25 mg/m2) prior to TIL infusion</description>
    <arm_group_label>All participants</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Only patients within the Danish Healthcare system are eligible for enrollment.&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically verified metastatic or locally advanced cancer diagnosis&#xD;
&#xD;
          -  At least one lesion (&gt;1 cm3) available for surgical resection&#xD;
&#xD;
          -  Not candidate for standard treatment options&#xD;
&#xD;
          -  Age of 18-70 years&#xD;
&#xD;
          -  Performance status of 1 or 0.&#xD;
&#xD;
          -  Life expectancy &gt; 6 months&#xD;
&#xD;
          -  One or more measurable parameter according to RECIST 1.1.&#xD;
&#xD;
          -  No significant toxicity from previous cancer treatments (CTC≤1). Except aloplecia&#xD;
             (CTC≤2) or neuropathy (CTC≤2)&#xD;
&#xD;
          -  Sufficient organ function, including:&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) ≥ 1.500 /µl&#xD;
&#xD;
          -  Leucocyte count ≥ normal limit&#xD;
&#xD;
          -  Platelets ≥ 100.000 /µl and &lt;700.000 /µl&#xD;
&#xD;
          -  Hemoglobin ≥ 6,0 mmol/l (regardless of prior transfusion)&#xD;
&#xD;
          -  S-creatinine &lt; 140&#xD;
&#xD;
          -  S-bilirubin ≤ 1,5 times upper normal limit&#xD;
&#xD;
          -  ASAT/ALAT ≤ 2,5 times upper normal limit&#xD;
&#xD;
          -  Alkaline phosphatase ≤ 5 times upper normal limit&#xD;
&#xD;
          -  Lactate dehydrogenase (LDH) ≤ 5 times upper normal limit&#xD;
&#xD;
          -  Sufficient coagulation: PP-time&gt;40 and INR&lt;1,5&#xD;
&#xD;
          -  Women in the fertile age must use effective contraception. This applies from inclusion&#xD;
             and until 6 months after treatment. Birth control pills, spiral, depot injection with&#xD;
             gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch&#xD;
             are all considered safe contraceptives.&#xD;
&#xD;
          -  Signed statement of consent after receiving oral and written study information&#xD;
&#xD;
          -  Willingness to participate in the planned treatment and follow-up and capable of&#xD;
             handling toxicities.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A history of prior malignancies. Patients treated for another malignancy can only&#xD;
             participate if they are without signs of disease for a minimum of 3 years after last&#xD;
             treatment.&#xD;
&#xD;
          -  Primary brain tumor or verified brain metastases&#xD;
&#xD;
          -  Known hypersensitivity to one of the active drugs or excipients.&#xD;
&#xD;
          -  Significant medical conditions, including but not limited to severe asthma/COLD,&#xD;
             significant cardiac disease, poorly regulated insulin dependent diabetes mellitus.&#xD;
&#xD;
          -  Creatinine clearance below 70 ml/min .&#xD;
&#xD;
          -  Acute or chronic infections with HIV, hepatitis, syphilis etc.&#xD;
&#xD;
          -  Severe allergies or previous anaphylactic reactions.&#xD;
&#xD;
          -  Active autoimmune disease, such as autoimmune neutropenia/thrombocytopenia or&#xD;
             hemolytic anemia, systemic lupus erythematosus, Sjögren's syndrome, sclerodermia,&#xD;
             myasthenia gravis, goodpastures disease, addison's disease, hashimoto's thyroiditis,&#xD;
             graves' disease etc.&#xD;
&#xD;
          -  Pregnant women and women who are breastfeeding.&#xD;
&#xD;
          -  Simultaneous treatment with systemic immunosuppressive drugs (including prednisolone&#xD;
             methotrexate etc.)&#xD;
&#xD;
          -  Simultaneous treatment with other experimental drugs.&#xD;
&#xD;
          -  Simultaneous treatment with other systemic anti-cancer treatments.&#xD;
&#xD;
          -  Patients with active or uncontrollable hypercalcemia.&#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>Anders H Kverneland, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Cancer Immune Therapy, Herlev Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Inge Marie Svane, MD, Prof.</last_name>
    <role>Study Director</role>
    <affiliation>Center for Cancer Immune Therapy, Herlev Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Center for Cancer immune Therapy (CCIT), Dept. of Hematology and dept. of Oncology</name>
      <address>
        <city>Copenhagen</city>
        <zip>2730</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>September 18, 2017</study_first_submitted>
  <study_first_submitted_qc>September 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 28, 2017</study_first_posted>
  <last_update_submitted>August 10, 2020</last_update_submitted>
  <last_update_submitted_qc>August 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 11, 2020</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>
  <keyword>immune therapy</keyword>
  <keyword>TILs</keyword>
  <keyword>Adoptive cell therapy</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aldesleukin</mesh_term>
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
    <mesh_term>Fludarabine phosphate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>July 20, 2021</submitted>
    <returned>August 11, 2021</returned>
    <submitted>February 28, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03296137
org study id: AA1720
nct id: NCT03296137
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This study will perform tumor-infiltrating lymphocyte (TIL)-based adoptive T-cell therapy in
      combination with checkpoint inhibition on cancer patients across all cancer diagnoses.
Adoptive cell therapy (ACT) is a personalized form of immunotherapy, where lymphocytes
      isolated from the patient's own tumor tissue are expanded 1000-fold ex-vivo and then infused
      back into the patient. The lymphocytes are then able to recognize and attack remaining cancer
      cells. This approach has shown remarkable clinical results in several trials conducted
      worldwide for patients with advanced melanoma - some with durable remissions. Promising
      clinical results were obtained in smaller trials where patients with disparate solid tumors
      were treated with tumor-infiltrating lymphocytes (TILs). At Center for Cancer Immune Therapy
      (CCIT) at Herlev Hospital, there are currently clinical trials undergoing in ovarian and
      renal cancer, and internationally ACT is being tested in an increasing number of cancer
      diagnoses, some trials are even recruiting patients across cancer types. Studies have shown
      that a high intratumoral infiltration with TILs in is correlated to the general clinical
      outcome of the disease in virtually all solid tumors, and thus clinical trials with TIL-based
      ACT to different cancer diagnoses have been undertaken.

      To support the TIL-mediated tumor elimination, in classical ACT protocols patients go through
      a highly specialized treatment regime before and after TIL infusion. This regime includes
      lymphodepletion with 7 days non-myeloablative chemotherapy, to provide an immunological
      window of opportunity for the infused TILs, and concomitant immune stimulation with
      interleukin-2 (IL-2). Checkpoint inhibition to support the anti-tumor activity of TILs is
      currently under extensive investigation in several other trials worldwide. Thus,
      lymphodepletion and IL-2 stimulation are well-established as supportive therapy and already
      an integrated part of current ACT protocols and while checkpoint inhibition is a new addition
      at CCIT; internationally other centers have ongoing comparable trials.

      Drug-based immunotherapy in the form of checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) has
      yielded impressive clinical results across tumor histologies. Recent results indicate that
      the effect of immunotherapy relies not so much on the cancer diagnoses but rather on the
      genomic and immunologic features of the individual patient's cancer disease. Both ACT and
      checkpoint inhibition work by tipping the immunological balance in favor of activation and
      away from suppression or avoidance by the cancer cells. Scientific evidence now show that
      administering anti-CTLA-4 and PD-1 could provide a benefit in the ACT setting, and several
      ongoing clinical trials are testing combinations of ACT and checkpoint inhibition. To
      synergistically maximize the immunological potential, we wish to combine ACT with an
      anti-CTLA-4 antibody (Ipilimumab) prior to tumor resection and an anti-PD-1 antibody
      (Nivolumab) in combination with TIL infusion.

      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.

      Available evidence indicates that ACT is a safe and feasible treatment option in an
      increasing number of solid tumors, and that it should be tested in all cancer patients
      regardless of their cancer diagnosis.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number and type of reported adverse events
time frame: Up to 2,5 years from begin of study
description: Determine the safety of the administration of TIL therapy including checkpoint inhibitors, lymphodepleting chemotherapy and Interleukin-2 for patients with cancer by reporting adverse events according to CTCAE v. 4.0.
measure: Treatment response, progressive disease
time frame: Up to 7 years from begin of study
description: Clinical response in progression-free survival to treatment according to RECIST 1.1
measure: Treatment response, surival
time frame: Up to 7 years from begin of study
description: Clinical response in terms of overall survival.
measure: Treatment related immune response
time frame: 3 years from begin of study
description: Flow cytometry-based immunological evaluation of peripheral blood
arm group label: All participants
arm group type: Experimental
intervention type: Biological
intervention name: Autologous tumor-infiltrating lymphocytes
description: Tumor-infiltrating lymphocytes grown ex-vivo from resected from cancer tissue and reapplied to the patient via an intravenous infusion.
arm group label: All participants
intervention type: Drug
intervention name: Ipilimumab
description: One treatment with ipilimumab (3 mg/kg) prior to tumor resection.
arm group label: All participants
intervention type: Drug
intervention name: Nivolumab
description: 4 doses of nivolumab. Starting 2 days prior to TIL infusion and every 2 weeks hereafter.
arm group label: All participants
intervention type: Drug
intervention name: proleukin
description: 2 MIE s.c. injection, after TIL infusion and continuing for 2 weeks
arm group label: All participants
intervention type: Drug
intervention name: Cyclophosphamide
description: 2 doses (60 mg/kg) prior to TIL infusion
arm group label: All participants
intervention type: Drug
intervention name: Fludara
description: 5 doses (25 mg/m2) prior to TIL infusion
arm group label: All participants
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Anders H Kverneland, MD
role: Principal Investigator
affiliation: Center for Cancer Immune Therapy, Herlev Hospital
last name: Inge Marie Svane, MD, Prof.
role: Study Director
affiliation: Center for Cancer Immune Therapy, Herlev Hospital
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: Aldesleukin
mesh term: Cyclophosphamide
mesh term: Nivolumab
mesh term: Ipilimumab
mesh term: Fludarabine phosphate
sharing ipd: Undecided
submitted: July 20, 2021
returned: August 11, 2021
submitted: February 28, 2023