<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/NCT02989714</url>
  </required_header>
  <id_info>
    <org_study_id>UMCC 2016.103</org_study_id>
    <secondary_id>HUM00120502</secondary_id>
    <nct_id>NCT02989714</nct_id>
  </id_info>
  <brief_title>Phase Ib/II Trial of Interleukin-2 and PD-1 Checkpoint Inhibitor, Nivolumab In Metastatic Clear Cell Renal Cell Cancer</brief_title>
  <official_title>Phase Ib/II Trial of Interleukin-2 and PD-1 Checkpoint Inhibitor, Nivolumab In Metastatic Clear Cell Renal Cell Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan Rogel Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Michigan Rogel Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This will be a single arm, multi-site phase Ib/II clinical trial of standard doses of High&#xD;
      Dose Interleukin-2 (HD IL2) (600,000 IU/kg/dose intravenously during two 5-day cycles 9 days&#xD;
      apart) in IL-2 eligible clear cell metastatic RCC (Renal Cell Carcinoma) subjects in&#xD;
      combination with Nivolumab.&#xD;
&#xD;
      Investigators hypothesize that concurrent PD-1 inhibition synergistically enhances the&#xD;
      anti-tumor immune response to HD IL-2 in metastatic clear cell RCC. Investigators postulate&#xD;
      that the combination of the two therapies would result in an increase in the overall response&#xD;
      rate, complete response rate, and improved survival outcomes compared to either of the&#xD;
      individual therapies.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 16, 2017</start_date>
  <completion_date type="Actual">June 23, 2020</completion_date>
  <primary_completion_date type="Actual">February 25, 2019</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>The Number of Patients With Grade 3 and Grade 4 Adverse Events of Interest</measure>
    <time_frame>28 days from the first dose of Nivolumab</time_frame>
    <description>This is the primary outcome for the Phase Ib portion of the trial. Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The Number of Patients That Respond to Treatment</measure>
    <time_frame>12 Weeks</time_frame>
    <description>This is the primary outcome for the Phase II portion of the trial. Includes complete response (CR) + partial response (PR), measured by computerized tomography (CT) or magnetic resonance imaging (MRI) scan and assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Grade 3-5 Adverse Events of Interest</measure>
    <time_frame>For the duration of the therapy plus 60 days post treatment</time_frame>
    <description>Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival at 24 Months</measure>
    <time_frame>24 Months</time_frame>
    <description>Overall survival at 24 months following the first dose of study therapy; 24 month estimates were reported using the product limit method of Kaplan and Meier along with 95% confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) at 24 Months</measure>
    <time_frame>24 Months</time_frame>
    <description>PFS is defined as the time from start of study therapy with Nivolumab until progression or death; up to 24 months. Progressive disease is defined as At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD 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>Renal Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>HD IL2 and Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Interleukin-2</intervention_name>
    <description>600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart</description>
    <arm_group_label>HD IL2 and Nivolumab</arm_group_label>
    <other_name>High Dose Interleukin-2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression</description>
    <arm_group_label>HD IL2 and Nivolumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must have a histologic diagnosis of clear cell renal cell carcinoma (pure or&#xD;
             mixed) with radiologic or histologic or cytologic evidence of metastatic disease.&#xD;
&#xD;
          -  Subjects may have received up to 2 prior lines of systemic therapy (excluding any&#xD;
             neoadjuvant/adjuvant therapy) including anti-VEGF or VEGFR inhibitor (e.g. sorafenib,&#xD;
             pazopanib, sunitinib, bevacizumab, axitinib) or mTOR inhibitor (e.g. everolimus or&#xD;
             temsirolimus) for metastatic disease.&#xD;
&#xD;
          -  Age ≥ 18 years at the time of consent.&#xD;
&#xD;
          -  ECOG (Eastern Cooperative Oncology Group) performance status (an attempt to quantify&#xD;
             cancer patients' general well-being and activities of daily life. The score ranges&#xD;
             from 0 to 5 where 0 is asymptomatic and 5 is death.) of 0 or 1&#xD;
&#xD;
          -  Adequate organ and marrow function&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             within 28 days prior to prior to registration. Women of non-childbearing potential are&#xD;
             defined as those who have no uterus, ligation of the fallopian tubes, or permanent&#xD;
             cessation of ovarian function due to ovarian failure or surgical removal of the&#xD;
             ovaries. All others are considered women of child bearing potential.&#xD;
&#xD;
          -  Females and males of childbearing potential must be willing to use an effective method&#xD;
             of contraception (hormonal or barrier method of birth control; abstinence) from the&#xD;
             time consent is signed until 6 months after treatment discontinuation.&#xD;
&#xD;
          -  Subjects must have measurable disease on physical exam or imaging&#xD;
&#xD;
          -  An archived tissue block with the subject's renal cell carcinoma must be identified&#xD;
             prior to registration.&#xD;
&#xD;
          -  Subjects must be considered appropriate candidates for HD IL-2 by one of the treating&#xD;
             investigators listed on the protocol. HD IL-2 candidacy evaluation is per&#xD;
             institutional guidelines at each site and should include a dobutamine stress&#xD;
             echocardiogram or equivalent. Subjects with a positive stress test for cardiac&#xD;
             ischemia would be excluded from this trial.&#xD;
&#xD;
          -  No clinically significant infections or any other medical condition(s) that render the&#xD;
             subject ineligible for high dose IL-2 therapy as judged by the treating investigator.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior interferon or interleukin-2 therapy is NOT allowed.&#xD;
&#xD;
          -  Prior anti-PD-1/PD-L1 targeted therapy is NOT allowed. Prior CTLA-4 therapy or&#xD;
             CD40/CD40L targeted therapy is allowed.&#xD;
&#xD;
          -  Prior systemic treatment must be completed at least 14 calendar days prior to&#xD;
             registration and the subject must have recovered from the toxicities of treatment to&#xD;
             grade 1 or better.&#xD;
&#xD;
          -  Prior radiation therapy is allowed if completed at least 14 calendar days prior to&#xD;
             registration.&#xD;
&#xD;
          -  Treatment with any investigational agent or on an interventional clinical trial within&#xD;
             30 days prior to registration.&#xD;
&#xD;
          -  No prior or concurrent malignancy is allowed except for: adequately treated basal cell&#xD;
             or squamous cell skin cancer, in situ cervical cancer, localized or locally advanced&#xD;
             prostate cancer definitively treated without recurrence or with biochemical recurrence&#xD;
             only, or any other cancer fully treated or from which the subject has been&#xD;
             disease-free for at least 2 years.&#xD;
&#xD;
          -  Current untreated brain metastasi(e)s. If treated history of CNS (central nervous&#xD;
             system) metastases, should have completed radiation or surgery at least 12 weeks prior&#xD;
             and off systemic corticosteroids.&#xD;
&#xD;
          -  Autoimmune diseases such as rheumatoid arthritis are NOT allowed. Vitiligo, mild&#xD;
             psoriasis (topical therapy only) or hypothyroidism are allowed.&#xD;
&#xD;
          -  Medical need for systemic corticosteroids &gt;10mg prednisone daily or equivalent&#xD;
             alternative steroid (except physiologic dose for adrenal replacement therapy) or other&#xD;
             immunosuppressive agents (such as cyclosporine or methotrexate) Topical and inhaled&#xD;
             corticosteroids are allowed if medically needed.&#xD;
&#xD;
          -  History of allergic reaction to interleukin-2 or nivolumab&#xD;
&#xD;
          -  Prior history of psychiatric disorder or seizure disorders which could be exacerbated&#xD;
             by Interleukin-2 as judged by the treating investigator. 3.2.12 Evidence of&#xD;
             significant cardiovascular disease including history of recent (&lt; 6 months prior)&#xD;
             myocardial infarction, congestive heart failure, primary cardiac arrhythmias (not due&#xD;
             to electrolyte disorder or drug toxicity, for example) beyond occasional PVC's&#xD;
             (premature ventricular contractions), angina, positive low-level stress test, or&#xD;
             cerebrovascular accident. All patients should have baseline pulmonary function tests.&#xD;
             Adequate pulmonary function should be documented (FEV1 &gt;2 liters or ≥75% of predicted&#xD;
             for height and age) prior to initiating therapy.&#xD;
&#xD;
          -  Any history of HIV or hepatitis B infection&#xD;
&#xD;
          -  Any other medical or surgical condition or disease that, in the judgment of the&#xD;
             treating physician, renders subject ineligible for High Dose Interleukin-2 therapy.&#xD;
&#xD;
          -  Any history of organ allografts&#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>Ajjai Alva, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan Rogel Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Michigan Comprehensive Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals Seidman Cancer Center</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>December 8, 2016</study_first_submitted>
  <study_first_submitted_qc>December 8, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 12, 2016</study_first_posted>
  <results_first_submitted>February 24, 2020</results_first_submitted>
  <results_first_submitted_qc>February 24, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">March 9, 2020</results_first_posted>
  <last_update_submitted>June 16, 2021</last_update_submitted>
  <last_update_submitted_qc>June 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Renal Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Interleukin-2</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 23, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/14/NCT02989714/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>HD IL2 and Nivolumab</title>
          <description>Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart&#xD;
Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression</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>Started Nivolumab</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </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>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>HD IL2 and Nivolumab</title>
          <description>Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart&#xD;
Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression</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>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="60" lower_limit="43" upper_limit="68"/>
                  </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="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>The Number of Patients With Grade 3 and Grade 4 Adverse Events of Interest</title>
        <description>This is the primary outcome for the Phase Ib portion of the trial. Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.</description>
        <time_frame>28 days from the first dose of Nivolumab</time_frame>
        <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</population>
        <group_list>
          <group group_id="O1">
            <title>HD IL2 and Nivolumab</title>
            <description>Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart&#xD;
Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression</description>
          </group>
        </group_list>
        <measure>
          <title>The Number of Patients With Grade 3 and Grade 4 Adverse Events of Interest</title>
          <description>This is the primary outcome for the Phase Ib portion of the trial. Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.</description>
          <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</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="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>The Number of Patients That Respond to Treatment</title>
        <description>This is the primary outcome for the Phase II portion of the trial. Includes complete response (CR) + partial response (PR), measured by computerized tomography (CT) or magnetic resonance imaging (MRI) scan and assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.</description>
        <time_frame>12 Weeks</time_frame>
        <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</population>
        <group_list>
          <group group_id="O1">
            <title>HD IL2 and Nivolumab</title>
            <description>Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart&#xD;
Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression</description>
          </group>
        </group_list>
        <measure>
          <title>The Number of Patients That Respond to Treatment</title>
          <description>This is the primary outcome for the Phase II portion of the trial. Includes complete response (CR) + partial response (PR), measured by computerized tomography (CT) or magnetic resonance imaging (MRI) scan and assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.</description>
          <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</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="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Grade 3-5 Adverse Events of Interest</title>
        <description>Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.</description>
        <time_frame>For the duration of the therapy plus 60 days post treatment</time_frame>
        <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</population>
        <group_list>
          <group group_id="O1">
            <title>HD IL2 and Nivolumab</title>
            <description>Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart&#xD;
Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Grade 3-5 Adverse Events of Interest</title>
          <description>Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.</description>
          <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</population>
          <units>events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival at 24 Months</title>
        <description>Overall survival at 24 months following the first dose of study therapy; 24 month estimates were reported using the product limit method of Kaplan and Meier along with 95% confidence intervals.</description>
        <time_frame>24 Months</time_frame>
        <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</population>
        <group_list>
          <group group_id="O1">
            <title>HD IL2 and Nivolumab</title>
            <description>Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart.&#xD;
Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival at 24 Months</title>
          <description>Overall survival at 24 months following the first dose of study therapy; 24 month estimates were reported using the product limit method of Kaplan and Meier along with 95% confidence intervals.</description>
          <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="77.1" lower_limit="34.5" upper_limit="93.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS) at 24 Months</title>
        <description>PFS is defined as the time from start of study therapy with Nivolumab until progression or death; up to 24 months. Progressive disease is defined as At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.</description>
        <time_frame>24 Months</time_frame>
        <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</population>
        <group_list>
          <group group_id="O1">
            <title>HD IL2 and Nivolumab</title>
            <description>Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart.&#xD;
Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) at 24 Months</title>
          <description>PFS is defined as the time from start of study therapy with Nivolumab until progression or death; up to 24 months. Progressive disease is defined as At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.</description>
          <population>Patients who received at least 1 dose of Nivolumab and Interleukin-2</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.6" lower_limit="14.7" upper_limit="69.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>60 days after end of treatment (Up to 14 months)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>HD IL2 and Nivolumab</title>
          <description>Interleukin-2: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart&#xD;
Nivolumab: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</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_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="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="25" subjects_affected="11" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenic purpura</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" 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>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Tinnitus</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>Hyperthyroidism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye disorders - Other</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="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="18" subjects_affected="9" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="16" subjects_affected="9" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="14" subjects_affected="8" 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="18" subjects_affected="10" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="14" subjects_affected="11" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Infusion site extravasation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" 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="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Vaginal 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>Fall</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <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>
                <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>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="36" subjects_affected="11" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="16" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="33" subjects_affected="11" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="18" subjects_affected="9" 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="3" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="35" subjects_affected="9" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="32" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Lymphocyte count increased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="20" subjects_affected="8" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urine output decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="4" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" 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="42" subjects_affected="7" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="11" subjects_affected="6" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="35" subjects_affected="10" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="34" subjects_affected="9" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</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="12" subjects_affected="7" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" 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="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Muscle weakness left-sided</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" 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="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Extrapyramidal disorder</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="1" subjects_affected="1" 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>Presyncope</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Insomnia</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>Acute kidney injury</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Chronic kidney disease</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Urinary tract obstruction</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="2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" 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="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Sneezing</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="20" subjects_affected="11" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - 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>Flushing</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="16" subjects_affected="10" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Superficial thrombophlebitis</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>
    <limitations_and_caveats>The trial did not meet criteria for continuation to the second stage.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Ajjai Alva, MD</name_or_title>
      <organization>University of Michigan Rogel Cancer Center</organization>
      <phone>734-936-0091</phone>
      <email>ajjai@umich.edu</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/NCT02989714
org study id: UMCC 2016.103
secondary id: HUM00120502
nct id: NCT02989714
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This will be a single arm, multi-site phase Ib/II clinical trial of standard doses of High
      Dose Interleukin-2 (HD IL2) (600,000 IU/kg/dose intravenously during two 5-day cycles 9 days
      apart) in IL-2 eligible clear cell metastatic RCC (Renal Cell Carcinoma) subjects in
      combination with Nivolumab.

      Investigators hypothesize that concurrent PD-1 inhibition synergistically enhances the
      anti-tumor immune response to HD IL-2 in metastatic clear cell RCC. Investigators postulate
      that the combination of the two therapies would result in an increase in the overall response
      rate, complete response rate, and improved survival outcomes compared to either of the
      individual therapies.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The Number of Patients With Grade 3 and Grade 4 Adverse Events of Interest
time frame: 28 days from the first dose of Nivolumab
description: This is the primary outcome for the Phase Ib portion of the trial. Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.
measure: The Number of Patients That Respond to Treatment
time frame: 12 Weeks
description: This is the primary outcome for the Phase II portion of the trial. Includes complete response (CR) + partial response (PR), measured by computerized tomography (CT) or magnetic resonance imaging (MRI) scan and assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
measure: Number of Grade 3-5 Adverse Events of Interest
time frame: For the duration of the therapy plus 60 days post treatment
description: Events of interest are possibly immune-mediated and occur only after at least one dose of Nivolumab has been administered. Immune-mediated events of interest do not include those that are known to occur during high dose IL-2 monotherapy and are reversible. Grade assessed per CTCAE version 4.0.
measure: Overall Survival at 24 Months
time frame: 24 Months
description: Overall survival at 24 months following the first dose of study therapy; 24 month estimates were reported using the product limit method of Kaplan and Meier along with 95% confidence intervals.
measure: Progression Free Survival (PFS) at 24 Months
time frame: 24 Months
description: PFS is defined as the time from start of study therapy with Nivolumab until progression or death; up to 24 months. Progressive disease is defined as At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.
arm group label: HD IL2 and Nivolumab
arm group type: Experimental
intervention type: Drug
intervention name: Interleukin-2
description: 600,000 IU/kg/dose intravenously during two 5-day cycles 9 days apart
arm group label: HD IL2 and Nivolumab
other name: High Dose Interleukin-2
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab will be administered intravenously at 240 mg/dose over 60 minutes every 14 days, starting 1 week to 3 weeks after the start date of the first cycle of IL2 and continued for up to 48 weeks total in the absence of disease progression
arm group label: HD IL2 and Nivolumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ajjai Alva, M.D.
role: Principal Investigator
affiliation: University of Michigan Rogel Cancer Center
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma, Renal Cell
mesh term: Nivolumab
mesh term: Interleukin-2
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The trial did not meet criteria for continuation to the second stage.
point of contact: 