<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/NCT01701674</url>
  </required_header>
  <id_info>
    <org_study_id>MCC-17057</org_study_id>
    <secondary_id>CA184-213</secondary_id>
    <nct_id>NCT01701674</nct_id>
  </id_info>
  <brief_title>Ipilimumab With Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Melanoma Mets Pts</brief_title>
  <official_title>Co-stimulation With Ipilimumab to Enhance Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Patients With Metastatic Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>H. Lee Moffitt Cancer Center and Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Iovance Biotherapeutics, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>H. Lee Moffitt Cancer Center and Research Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Purpose of this Pilot Study: The investigators want to study the safety, side effects, and&#xD;
      benefits of tumor infiltrating lymphocytes (TILs), when they are given with the drug&#xD;
      ipilimumab. Ipilimumab is a type of immunotherapy - a drug that is used to boost the ability&#xD;
      of the immune system to fight cancer, infection, and other diseases.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary endpoints of this pilot trial will be the safety and feasibility of administering&#xD;
      ipilimumab with Adoptive Cell Therapy (ACT) using TIL. The data analysis will mainly be&#xD;
      descriptive. All study results will be preliminary and of exploratory in nature due to the&#xD;
      pilot status and small sample size of the trial. Feasibility is defined as the ability to&#xD;
      deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and&#xD;
      successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL. All participants&#xD;
      will be evaluable for toxicity from the time of their first protocol treatment. Toxicity will&#xD;
      be reported by type and severity according to the National Cancer Institute Common Toxicity&#xD;
      Criteria (NCI CTC) version 4.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 9, 2012</start_date>
  <completion_date type="Anticipated">December 15, 2025</completion_date>
  <primary_completion_date type="Actual">April 21, 2016</primary_completion_date>
  <phase>N/A</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>Occurrence of Dose Limiting Toxicity (DLT) Events</measure>
    <time_frame>3 months</time_frame>
    <description>Occurrence of adverse events with dose limiting toxicity, per adverse event category.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rate of Meeting Feasibility Requirements</measure>
    <time_frame>3 months</time_frame>
    <description>Number of participants who were successfully treated with at least 2 doses of ipilimumab and received TIL. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>12 weeks</time_frame>
    <description>Overall Response: Complete Response (CR) + Partial Response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 for target lesions and assessed by computed tomography (CT) scan. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions..</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>42 months</time_frame>
    <description>Progression-free survival (PFS) per RECIST V1.1, defined as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve. Progressive Disease (PD): At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Metastatic Melanoma</condition>
  <arm_group>
    <arm_group_label>Combination Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Pre-treatment with ipilimumab (cycle 1): Before the participant's tumor sample is taken to send to the lab for growing the TILs, they will start their first cycle of ipilimumab. This drug is given as an intravenous infusion (through a vein) over a period of about 90 minutes (an hour and a half). Cycle 2 of ipilimumab: About a week after the sample of the participant's tumor was collected for TIL growth (and 3 weeks after their first cycle of ipilimumab), participants will have their second cycle of ipilimumab. This will be another IV infusion, lasting about 90 minutes.</description>
    <arm_group_label>Combination Therapy</arm_group_label>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Tumor Infiltrating Lymphocytes (TIL)</intervention_name>
    <description>Tumor sample for TIL growth in the lab: About 2 weeks after the participant's first cycle of ipilimumab, a sample of their tumor will be collected and sent to the lab for TIL growth. Growing the TILs takes about 6 weeks. If their sample has grown enough TIL cells, participants will continue with the next part of the study. Depending on how long the TILs take to grow in the lab, they may need to repeat some of their laboratory and imaging tests (blood draws, X-rays, and CT or magnetic resonance imaging [MRI] scans). TIL Infusion (inpatient): After completing lymphodepletion, participants will be admitted back into the hospital for IV infusion of the TIL cells.</description>
    <arm_group_label>Combination Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Administration of Lymphodepletion</intervention_name>
    <description>Lymphodepletion (inpatient hospital stay for about 2 days plus outpatient drug dosing for 5 days): About 4 weeks after their second cycle of ipilimumab, participants will be admitted to the hospital for their first two days of receiving the chemotherapy drug, cyclophosphamide. This drug will be given as an intravenous (IV, meaning through the vein) infusion. After 2 days of receiving cyclophosphamide, if their study doctor thinks that they are well enough, you will be discharged from the hospital and will return for the next 5 days in a row for outpatient IV infusions of the second lymphodepletion chemotherapy, fludarabine.</description>
    <arm_group_label>Combination Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide as Part of Lymphodepletion</intervention_name>
    <arm_group_label>Combination Therapy</arm_group_label>
    <other_name>Cytoxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fludarabine as Part of Lymphodepletion</intervention_name>
    <arm_group_label>Combination Therapy</arm_group_label>
    <other_name>Fludara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>High Dose IL-2</intervention_name>
    <description>High dose IL-2 (continued inpatient): Participants will remain in the hospital following TIL infusion for receiving high dose IL-2 and recovery. The IL-2 will be given three times per day for about 3-5 days as an IV bolus (meaning through the vein, more quickly than other infusions - in about 15 minutes each dose). Participants will remain in the hospital for approximately 7-14 days until they have recovered from the IL-2 treatments.</description>
    <arm_group_label>Combination Therapy</arm_group_label>
    <other_name>Interleukin-2</other_name>
    <other_name>Aldesleukin</other_name>
    <other_name>Proleukin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Adoptive Cell Therapy with TIL</intervention_name>
    <arm_group_label>Combination Therapy</arm_group_label>
    <other_name>ACT</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must have unresectable metastatic stage IV melanoma or stage III&#xD;
             intransit or regional nodal disease, and in the opinion of the institutional PI is an&#xD;
             acceptable candidate for ACT with high dose IL-2&#xD;
&#xD;
          -  Residual measurable disease after resection of target lesion(s) for TIL growth&#xD;
&#xD;
          -  Tumor may have a B-RAF V600 mutation or be BRAF wild type, and patients must not have&#xD;
             been previously treated with ipilimumab&#xD;
&#xD;
          -  Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 - 1. ECOG&#xD;
             performance status of 0-1 will be inferred if the patient's level of energy is ≥ 50%&#xD;
             of baseline.&#xD;
&#xD;
          -  May have been previously treated for metastatic disease, or may have not had prior&#xD;
             systemic treatment. Patients with a V600 BRAF mutated tumor may have previously&#xD;
             received a prior BRAF inhibitor.&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) must have a negative serum pregnancy test&#xD;
             within 7 days of screening.&#xD;
&#xD;
          -  Adequate renal, hepatic and hematologic function, including creatinine of less than or&#xD;
             equal to 1.7 gm/dL, total bilirubin less than or equal to 2.0 mg/dL, except in&#xD;
             patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL,&#xD;
             aspartate aminotransferase (AST) and alanine transaminase (ALT) of less than 3 X&#xD;
             institutional upper limit of normal, hemoglobin of 8 gm/dL or more, white blood count&#xD;
             (WBC) of 3000 per mcL and total granulocytes of 1000 per mcL or more, and platelets of&#xD;
             100,000 per mcL or more.&#xD;
&#xD;
          -  Must have a positive screening Epstein-Barr virus (EBV) antibody titre on screening&#xD;
             test&#xD;
&#xD;
          -  Potential participants with antibiotic allergies per se are not excluded; although the&#xD;
             production of TIL for adoptive transfer includes antibiotics, extensive washing after&#xD;
             harvest will minimize systemic exposure to antibiotics.&#xD;
&#xD;
          -  At screening, patients with ≤ 3 untreated CNS metastases may be included provided none&#xD;
             of the untreated lesions are &gt; 1 cm in greatest dimension, and there is no&#xD;
             peri-tumoral edema present on brain imaging (MRI or CT if MRI is contraindicated).&#xD;
&#xD;
          -  At screening, patients with central nervous system (CNS) metastases treated with&#xD;
             either surgical resection and/or radiation therapy may be included. Patients may be&#xD;
             included if the largest lesion is ≤ 1 cm, and there is no evidence of progressive CNS&#xD;
             disease on brain imaging at least 28 days after treatment.&#xD;
&#xD;
          -  At screening, patients may be included if the largest lesion is &gt; 1 cm or &gt; 3 in&#xD;
             number, and there is no evidence of progressive CNS disease on brain imaging at least&#xD;
             90 days after treatment with surgery and/or radiation therapy.&#xD;
&#xD;
          -  No evidence of ongoing cardiac dysrhythmia ≥ grade 2 (NCI Common Terminology Criteria&#xD;
             for Adverse Events [CTCAE], v4.0)&#xD;
&#xD;
          -  All laboratory and imaging studies must be completed and satisfactory within 30 days&#xD;
             of signing the consent document, with the exceptions of: negative serum pregnancy test&#xD;
             for women of child-bearing potential which must be negative within 7 days of&#xD;
             screening, human leukocyte antigen (HLA) typing which will not be repeated if&#xD;
             performed previously, and pulmonary function tests (PFTs)/cardiac stress tests whose&#xD;
             results are valid for 6 months if performed previously.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Active systemic infections requiring intravenous antibiotics, coagulation disorders or&#xD;
             other major medical illness of the cardiovascular, respiratory or immune system, which&#xD;
             in the opinion of the principal investigator (PI) or treating coinvestigator is not&#xD;
             acceptable risk for ACT, are excluded.&#xD;
&#xD;
          -  Testing positive for HIV titre, Hepatitis B surface antigen, Hepatitis B core&#xD;
             antibody, Hepatitis C antibody, Human T-Lymphotropic Virus (HTLV) I or II antibody, or&#xD;
             both Rapid. Plasma Reagin (RPR) and fluorescent treponemal antibodies (FTA) positive&#xD;
             are excluded.&#xD;
&#xD;
          -  Pregnant or nursing&#xD;
&#xD;
          -  Patients needing chronic, immunosuppressive systemic steroids are excluded&#xD;
&#xD;
          -  History of autoimmune disease that require immunosuppressive medications at the time&#xD;
             of screening&#xD;
&#xD;
          -  Presence of a significant psychiatric disease, which in the opinion of the principal&#xD;
             investigator or his designee, would prevent adequate informed consent or render&#xD;
             immunotherapy unsafe or contraindicated&#xD;
&#xD;
          -  Patients with &gt; 3 untreated CNS metastases or evidence of peri-tumoral edema&#xD;
&#xD;
          -  Patients with ≤ 3 untreated CNS metastases but with at least one lesion &gt;1 cm or&#xD;
             peri-tumoral edema&#xD;
&#xD;
          -  Patients with invasive malignancy other than melanoma at the time of enrollment and&#xD;
             within 2 years prior to the first TIL administration are excluded, except for&#xD;
             adequately treated (with curative intent) basal or squamous cell carcinoma, in situ&#xD;
             carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate&#xD;
             cancer, or limited stage bladder cancer or other cancers from which the patient has&#xD;
             been disease-free for at least 2 years.&#xD;
&#xD;
          -  Patients with treated CNS metastases &gt; 1 cm or &gt; 3 in number will be excluded if there&#xD;
             is evidence of progressive CNS disease on brain imaging at least 90 days after&#xD;
             treatment with surgery and/or radiation therapy.&#xD;
&#xD;
          -  Unable to comprehend and give informed consent&#xD;
&#xD;
          -  Male patients with WOCBP partners who do not agree to use two FDA-accepted forms of&#xD;
             contraception during sexual intercourse with women of child-bearing potential from the&#xD;
             start of ipilimumab and up to at least 6 months after ACT&#xD;
&#xD;
          -  WOCBP who do not agree to use 2 FDA forms of contraception during sexual intercourse&#xD;
             from the start of ipilimumab and up to at least 6 months after ACT&#xD;
&#xD;
          -  Patients who have received ipilimumab in the past&#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>Amod Sarnaik, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>H. Lee Moffitt Cancer Center and Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>H. Lee Moffitt Cancer Center and Research Institute</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>October 3, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 5, 2012</study_first_posted>
  <results_first_submitted>March 22, 2017</results_first_submitted>
  <results_first_submitted_qc>March 22, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">May 2, 2017</results_first_posted>
  <last_update_submitted>April 17, 2023</last_update_submitted>
  <last_update_submitted_qc>April 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>skin cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <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>Fludarabine</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
    <mesh_term>Interleukin-2</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were enrolled at Moffitt Cancer Center, April 2013 through July 2014.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Experimental: Combination Therapy</title>
          <description>The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose 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="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Unable to safely complete treatment</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All participants (13). All evaluable participants (12) may be referenced for some outcome measures.</population>
      <group_list>
        <group group_id="B1">
          <title>Experimental: Combination Therapy</title>
          <description>The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="13"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <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="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="49" lower_limit="22" upper_limit="70"/>
                  </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>
              <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="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Occurrence of Dose Limiting Toxicity (DLT) Events</title>
        <description>Occurrence of adverse events with dose limiting toxicity, per adverse event category.</description>
        <time_frame>3 months</time_frame>
        <population>All participants</population>
        <group_list>
          <group group_id="O1">
            <title>Experimental: Combination Therapy</title>
            <description>The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.</description>
          </group>
        </group_list>
        <measure>
          <title>Occurrence of Dose Limiting Toxicity (DLT) Events</title>
          <description>Occurrence of adverse events with dose limiting toxicity, per adverse event category.</description>
          <population>All participants</population>
          <units>DLT events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Eye-related: Uveitis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Gastrointestinal: Colitis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Rate of Meeting Feasibility Requirements</title>
        <description>Number of participants who were successfully treated with at least 2 doses of ipilimumab and received TIL. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL.</description>
        <time_frame>3 months</time_frame>
        <population>All participants</population>
        <group_list>
          <group group_id="O1">
            <title>Experimental: Combination Therapy</title>
            <description>The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Meeting Feasibility Requirements</title>
          <description>Number of participants who were successfully treated with at least 2 doses of ipilimumab and received TIL. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL.</description>
          <population>All participants</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate (ORR)</title>
        <description>Overall Response: Complete Response (CR) + Partial Response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 for target lesions and assessed by computed tomography (CT) scan. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions..</description>
        <time_frame>12 weeks</time_frame>
        <population>All participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Experimental: Combination Therapy</title>
            <description>The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (ORR)</title>
          <description>Overall Response: Complete Response (CR) + Partial Response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 for target lesions and assessed by computed tomography (CT) scan. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions..</description>
          <population>All participants.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS)</title>
        <description>Progression-free survival (PFS) per RECIST V1.1, defined as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve. Progressive Disease (PD): At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions.</description>
        <time_frame>42 months</time_frame>
        <population>All participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Experimental: Combination Therapy</title>
            <description>The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS)</title>
          <description>Progression-free survival (PFS) per RECIST V1.1, defined as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve. Progressive Disease (PD): At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions.</description>
          <population>All participants.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.4" lower_limit="1.5" upper_limit="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3 years, 6 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Experimental: Combination Therapy</title>
          <description>The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Uveitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Colonic perforation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Small intestinal obstruction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Autoimmune disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Abdominal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Catheter related infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vascular access complication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Investigations - Other, SIADH</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Cystitis non-infective</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders - Other, Cistitis infective</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-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="13" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="82" subjects_affected="12" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Cardiac disorders - Other</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="9" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Endocrine disorders - Other</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Cataract</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Eye disorders - Other</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Uveitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="30" subjects_affected="11" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="31" subjects_affected="13" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="16" subjects_affected="10" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="33" subjects_affected="11" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="12" subjects_affected="7" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other</sub_title>
                <counts group_id="E1" events="15" subjects_affected="7" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="13" subjects_affected="7" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Immune system disorders - Other</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Penile infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Injury, poisoning and procedural complications - Other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vascular access complication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Wound dehiscence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="24" subjects_affected="11" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="18" subjects_affected="9" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="26" subjects_affected="12" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="11" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Cardiac troponin T increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>CPK increased</sub_title>
                <counts group_id="E1" events="9" subjects_affected="6" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>INR increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Investigations - Other</sub_title>
                <counts group_id="E1" events="7" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="45" subjects_affected="12" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lymphocyte count increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="32" subjects_affected="12" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="61" subjects_affected="12" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="49" subjects_affected="12" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Acidosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="37" subjects_affected="12" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="32" subjects_affected="10" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="21" subjects_affected="12" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Myositis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Tumor pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="12" subjects_affected="10" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Bladder spasm</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Cystitis non-infective</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders - Other</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urinary tract pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urine discoloration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Erectile dysfunction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Scrotal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vaginal discharge</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vaginal hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Bronchospasm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="12" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="18" subjects_affected="10" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Postnasal drip</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pulmonary edema</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="18" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="22" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Surgical and medical procedures - Other</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Capillary leak syndrome</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="14" subjects_affected="9" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lymphedema</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vascular disorders - Other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </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>Dr. Amod Sarnaik</name_or_title>
      <organization>H. Lee Moffitt Cancer Center and Research Institute</organization>
      <phone>813-745-8581</phone>
      <email>amod.sarnaik@moffitt.org</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/NCT01701674
org study id: MCC-17057
secondary id: CA184-213
nct id: NCT01701674
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Purpose of this Pilot Study: The investigators want to study the safety, side effects, and
      benefits of tumor infiltrating lymphocytes (TILs), when they are given with the drug
      ipilimumab. Ipilimumab is a type of immunotherapy - a drug that is used to boost the ability
      of the immune system to fight cancer, infection, and other diseases.
The primary endpoints of this pilot trial will be the safety and feasibility of administering
      ipilimumab with Adoptive Cell Therapy (ACT) using TIL. The data analysis will mainly be
      descriptive. All study results will be preliminary and of exploratory in nature due to the
      pilot status and small sample size of the trial. Feasibility is defined as the ability to
      deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and
      successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL. All participants
      will be evaluable for toxicity from the time of their first protocol treatment. Toxicity will
      be reported by type and severity according to the National Cancer Institute Common Toxicity
      Criteria (NCI CTC) version 4.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of Dose Limiting Toxicity (DLT) Events
time frame: 3 months
description: Occurrence of adverse events with dose limiting toxicity, per adverse event category.
measure: Rate of Meeting Feasibility Requirements
time frame: 3 months
description: Number of participants who were successfully treated with at least 2 doses of ipilimumab and received TIL. Feasibility is defined as the ability to deliver at least 50% (i.e., two out of four) of the planned doses of ipilimumab and successfully treat at least 60% (i.e., ≥ 6/10) of the patients with TIL.
measure: Overall Response Rate (ORR)
time frame: 12 weeks
description: Overall Response: Complete Response (CR) + Partial Response (PR), per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1 for target lesions and assessed by computed tomography (CT) scan. CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions..
measure: Progression Free Survival (PFS)
time frame: 42 months
description: Progression-free survival (PFS) per RECIST V1.1, defined as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve. Progressive Disease (PD): At least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum recorded since the treatment started or the appearance of one or more new lesions.
arm group label: Combination Therapy
arm group type: Experimental
description: The combination of ipilimumab followed by lymphodepletion with chemotherapy, TIL infusion, and high dose IL-2.
intervention type: Drug
intervention name: Ipilimumab
description: Pre-treatment with ipilimumab (cycle 1): Before the participant's tumor sample is taken to send to the lab for growing the TILs, they will start their first cycle of ipilimumab. This drug is given as an intravenous infusion (through a vein) over a period of about 90 minutes (an hour and a half). Cycle 2 of ipilimumab: About a week after the sample of the participant's tumor was collected for TIL growth (and 3 weeks after their first cycle of ipilimumab), participants will have their second cycle of ipilimumab. This will be another IV infusion, lasting about 90 minutes.
arm group label: Combination Therapy
other name: Yervoy
intervention type: Procedure
intervention name: Tumor Infiltrating Lymphocytes (TIL)
description: Tumor sample for TIL growth in the lab: About 2 weeks after the participant's first cycle of ipilimumab, a sample of their tumor will be collected and sent to the lab for TIL growth. Growing the TILs takes about 6 weeks. If their sample has grown enough TIL cells, participants will continue with the next part of the study. Depending on how long the TILs take to grow in the lab, they may need to repeat some of their laboratory and imaging tests (blood draws, X-rays, and CT or magnetic resonance imaging [MRI] scans). TIL Infusion (inpatient): After completing lymphodepletion, participants will be admitted back into the hospital for IV infusion of the TIL cells.
arm group label: Combination Therapy
intervention type: Drug
intervention name: Administration of Lymphodepletion
description: Lymphodepletion (inpatient hospital stay for about 2 days plus outpatient drug dosing for 5 days): About 4 weeks after their second cycle of ipilimumab, participants will be admitted to the hospital for their first two days of receiving the chemotherapy drug, cyclophosphamide. This drug will be given as an intravenous (IV, meaning through the vein) infusion. After 2 days of receiving cyclophosphamide, if their study doctor thinks that they are well enough, you will be discharged from the hospital and will return for the next 5 days in a row for outpatient IV infusions of the second lymphodepletion chemotherapy, fludarabine.
arm group label: Combination Therapy
intervention type: Drug
intervention name: Cyclophosphamide as Part of Lymphodepletion
arm group label: Combination Therapy
other name: Cytoxan
intervention type: Drug
intervention name: Fludarabine as Part of Lymphodepletion
arm group label: Combination Therapy
other name: Fludara
intervention type: Drug
intervention name: High Dose IL-2
description: High dose IL-2 (continued inpatient): Participants will remain in the hospital following TIL infusion for receiving high dose IL-2 and recovery. The IL-2 will be given three times per day for about 3-5 days as an IV bolus (meaning through the vein, more quickly than other infusions - in about 15 minutes each dose). Participants will remain in the hospital for approximately 7-14 days until they have recovered from the IL-2 treatments.
arm group label: Combination Therapy
other name: Interleukin-2
other name: Aldesleukin
other name: Proleukin
intervention type: Biological
intervention name: Adoptive Cell Therapy with TIL
arm group label: Combination Therapy
other name: ACT
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Amod Sarnaik, M.D.
role: Principal Investigator
affiliation: H. Lee Moffitt Cancer Center and Research Institute
facility: 
country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Aldesleukin
mesh term: Cyclophosphamide
mesh term: Fludarabine
mesh term: Ipilimumab
mesh term: Interleukin-2
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 