<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/NCT02221739</url>
  </required_header>
  <id_info>
    <org_study_id>14-00208</org_study_id>
    <nct_id>NCT02221739</nct_id>
  </id_info>
  <brief_title>Study of Combined Ionizing Radiation and Ipilimumab in Metastatic Non-small Cell Lung Cancer (NSCLC)</brief_title>
  <official_title>Phase II Study of Combined Ionizing Radiation and Ipilimumab in Metastatic Non-small Cell Lung Cancer (NSCLC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NYU Langone Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>NYU Langone Health</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to investigate how effective and how safe the combination of&#xD;
      radiation therapy and an investigational medication targeting the immune system known as&#xD;
      Ipilimumab in the treatment of metastatic non-small cell lung cancer (NSCLC).&#xD;
&#xD;
      The investigators would like to see if this combination of radiation and Ipilimumab can&#xD;
      stimulate the body's immune system to stop the growth of tumors that are outside the field of&#xD;
      radiation. The investigators would like see if using this combination of radiation therapy&#xD;
      with Ipilimumab could help the body reject the patient's own tumor or at least help their&#xD;
      immune system to maintain the disease stable and/or slow its growth.&#xD;
&#xD;
      Radiation therapy (RT) is currently a standard procedure for treatment of NSCLC. Ipilimumab&#xD;
      is considered an investigational medication because it is not approved by the Food and Drug&#xD;
      Administration (FDA) for the treatment of NSCLC. Ipilimumab has been approved by the FDA for&#xD;
      the treatment of metastatic melanoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Research Hypothesis:&#xD;
&#xD;
        1. Through a combination of local RT and ipilimumab an anti-tumor immune response is&#xD;
           elicited at the irradiated site, as an in vivo, individualized immunization that is&#xD;
           systemically effective, as reflected by objective responses outside the RT field&#xD;
           (abscopal effect).&#xD;
&#xD;
        2. The immune response can be prospectively monitored among the treated patients.&#xD;
&#xD;
      Objective 1: Evaluate the safety and therapeutic efficacy of anti-cytotoxic&#xD;
      T-lymphocyte-associated protein -4 mono clonal Antibody (anti-CTLA-4 mAb) and concurrent&#xD;
      local RT in NSCLC patients with metastatic disease.&#xD;
&#xD;
      An open label phase II trial will evaluate the preliminary efficacy of the combination of Ipi&#xD;
      and RT, applied to a single metastatic site. Efficacy is measured with respect to systemic&#xD;
      tumor responses (abscopal response, outside the field of therapy) defined by immune-related&#xD;
      Response Criteria (irRC) in all non-irradiated measurable lesions, as a demonstration of an&#xD;
      effective anti-tumor immune response. Secondary endpoints include local response in the RT&#xD;
      treated tumor, progression free survival, and overall survival.&#xD;
&#xD;
      Objective 2: Determine the effects of RT and anti-CTLA-4 mAb on development of anti-tumor&#xD;
      immunity.&#xD;
&#xD;
      The investigators hypothesize that RT will convert the irradiated tumor into an in situ&#xD;
      vaccine and elicit an endogenous tumor-specific cellular and humoral immune response, which&#xD;
      in the presence of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade will promote&#xD;
      immune-mediated destruction of the irradiated and abscopal metastases. Pre- and&#xD;
      post-treatment tumor biopsies will be examined for changes in immune contexture, and blood&#xD;
      for evidence of emerging anti-tumor immune responses. Associations with clinical response&#xD;
      will be explored.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 1, 2014</start_date>
  <completion_date type="Actual">October 27, 2015</completion_date>
  <primary_completion_date type="Actual">April 15, 2015</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>Therapeutic Efficacy of Anti-CTLA-4 mAb and Concurrent Local RT in NSCLC Patients With Metastatic Disease.</measure>
    <time_frame>3 weeks - 6 months post treatment</time_frame>
    <description>Tumor Response will be evaluated using the irRC best response (Partial Response (PR) + Complete Response (CR)). Modified WHO criteria will be used for measurement of tumors. The irradiated lesion will be excluded from the assessment of response.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number pf Patients With Objective Radioactive Responses to Measure the Effects of RT and Anti-CTLA-4 mAb on Development of Anti-tumor Immunity Measured by T Cell Clone Frequency</measure>
    <time_frame>3 weeks - 6 months post-treatment</time_frame>
    <description>The study uses a comprehensive approach to analyze immunological changes that reflect both local and systemic responses, and investigate both general immune activation as well as tumor antigen-specific T- and B-cell responses. The activity of anti-CTLA-1 mAb is thought to be mainly dependent on modulating the quantity and quality of T-cells in cancer patients. A highly extensive analysis of the Cluster of differentiation 4 + (CD4+) and cluster of differentiation 8 + (CD8+) T-cell subsets will be characterized by multi-color flow Cytometry. To facilitate these analyses, serial blood samples will be collected for serum and peripheral blood mononuclear cells (PBMC) at different time points, where, a part of these samples will be used for DNA/RNA extraction. Optional tissue biopsies will be obtained from consenting patients.Tumor tissue will be tested for expression of seven antigens frequently expressed in NSCLC.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">39</enrollment>
  <condition>Non-small Cell Lung Cancer (NSCLC)</condition>
  <arm_group>
    <arm_group_label>Ipilimumab + radiotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <arm_group_label>Ipilimumab + radiotherapy</arm_group_label>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiotherapy (IMRT or 3-D CRT)</intervention_name>
    <arm_group_label>Ipilimumab + radiotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Ability to understand and the willingness to sign a written informed consent document;&#xD;
&#xD;
          2. Histologic diagnosis of metastatic NSCLC;&#xD;
&#xD;
          3. Any Kras or EGFR status is permitted;&#xD;
&#xD;
          4. Patients must have at least two distinct measurable metastatic sites, with one of at&#xD;
             least 1 cm or larger in its largest diameter. Patients may have additional&#xD;
             non-measurable metastatic lesions (e.g., bone metastases);&#xD;
&#xD;
          5. Patients must have prior treatment with at least one line of therapy for metastatic&#xD;
             NSCLC. Any prior therapy is permitted except prior therapy with ipilimumab;&#xD;
&#xD;
          6. An interval of 2 weeks from last previous therapy is required;&#xD;
&#xD;
          7. Patients must have adequate organ and marrow function as defined by initial laboratory&#xD;
             tests:&#xD;
&#xD;
               -  WBC ≥ 2000/uL&#xD;
&#xD;
               -  ANC ≥ 1000/uL&#xD;
&#xD;
               -  Platelets ≥ 50 x 103/uL&#xD;
&#xD;
               -  Hemoglobin ≥ 8 g/dL&#xD;
&#xD;
               -  Creatinine ≤ 3.0 x ULN&#xD;
&#xD;
               -  AST/ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.&#xD;
&#xD;
               -  Bilirubin ≤ 3.0 x ULN (except patients with Gilbert's Syndrome, who must have a&#xD;
                  total bilirubin ≤ 3.0 mg/dL);&#xD;
&#xD;
          8. Performance status ECOG 0-1;&#xD;
&#xD;
          9. Men and women, ages &gt; 18 years of age;&#xD;
&#xD;
         10. Life expectancy &gt; 3 months;&#xD;
&#xD;
         11. Patients may have brain metastases if these are stable for at least 4 weeks, or&#xD;
             greater than 2 weeks post gamma knife therapy and patients are not steroid dependent;&#xD;
&#xD;
         12. Brain Scan (CT/MRI) prior to enrollment&#xD;
&#xD;
         13. Women of childbearing potential (WOCBP) must be using an adequate method of&#xD;
             contraception to avoid pregnancy throughout the study and for up to 8 weeks after the&#xD;
             last dose of Ipi.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients having no lesions outside the field of radiation thus nullifying the ability&#xD;
             to measure an abscopal effect;&#xD;
&#xD;
          2. Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded&#xD;
             from this study as are patients with a history of symptomatic disease (e.g.,&#xD;
             rheumatoid arthritis, progressive systemic sclerosis [scleroderma]), systemic lupus&#xD;
             erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis];&#xD;
&#xD;
          3. Any underlying medical or psychiatric condition, which in the opinion of the&#xD;
             Investigator, will make the administration of study drug hazardous or obscure the&#xD;
             interpretation of adverse events (AEs), such as a condition associated with frequent&#xD;
             diarrhea;&#xD;
&#xD;
          4. Concomitant therapy with any of the following: Interleukin-2 (IL-2), interferon or&#xD;
             other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive&#xD;
             agents; other investigation therapies; or chronic use of systemic corticosteroids;&#xD;
&#xD;
          5. Prior therapy with ipilimumab or another anti-CTLA-4 antagonist;&#xD;
&#xD;
          6. Women who are unwilling or unable to use an acceptable method to avoid pregnancy for&#xD;
             the entire study period and for at least 8 weeks after cessation of study drug, or&#xD;
             have a positive pregnancy test at baseline, or are pregnant or breastfeeding;&#xD;
&#xD;
          7. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for&#xD;
             treatment of either a psychiatric or physical (e.g., infectious) illness.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Abraham Chachoua, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NYU School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NYU Clinical Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NYU Langone Medical Center, Tisch Hospital</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2020</verification_date>
  <study_first_submitted>June 24, 2014</study_first_submitted>
  <study_first_submitted_qc>August 19, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 20, 2014</study_first_posted>
  <results_first_submitted>October 18, 2018</results_first_submitted>
  <results_first_submitted_qc>November 5, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">November 22, 2019</results_first_posted>
  <last_update_submitted>April 22, 2020</last_update_submitted>
  <last_update_submitted_qc>April 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 11, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>lung cancer</keyword>
  <keyword>NSCLC</keyword>
  <keyword>lung</keyword>
  <keyword>cancer</keyword>
  <keyword>radiation</keyword>
  <keyword>immunotherapy</keyword>
  <keyword>metastatic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 4, 2015</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/39/NCT02221739/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Ipilimumab + Radiotherapy</title>
          <description>Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field).&#xD;
Ipilimumab&#xD;
Radiotherapy (IMRT or 3-D CRT)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Ipilimumab + Radiotherapy</title>
          <description>Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field).&#xD;
Ipilimumab&#xD;
Radiotherapy (IMRT or 3-D CRT)</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="39"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <title>Age</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68" lower_limit="48" upper_limit="97"/>
                  </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>
              <title>Gender</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Histology</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Adenocarcinoma</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Squamous Cell Carcinoma</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sarcomatoid</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neuroendocrine</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="39"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Therapeutic Efficacy of Anti-CTLA-4 mAb and Concurrent Local RT in NSCLC Patients With Metastatic Disease.</title>
        <description>Tumor Response will be evaluated using the irRC best response (Partial Response (PR) + Complete Response (CR)). Modified WHO criteria will be used for measurement of tumors. The irradiated lesion will be excluded from the assessment of response.</description>
        <time_frame>3 weeks - 6 months post treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ipilimumab + Radiotherapy</title>
            <description>Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field).&#xD;
Ipilimumab&#xD;
Radiotherapy (IMRT or 3-D CRT)</description>
          </group>
        </group_list>
        <measure>
          <title>Therapeutic Efficacy of Anti-CTLA-4 mAb and Concurrent Local RT in NSCLC Patients With Metastatic Disease.</title>
          <description>Tumor Response will be evaluated using the irRC best response (Partial Response (PR) + Complete Response (CR)). Modified WHO criteria will be used for measurement of tumors. The irradiated lesion will be excluded from the assessment of response.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </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>Number pf Patients With Objective Radioactive Responses to Measure the Effects of RT and Anti-CTLA-4 mAb on Development of Anti-tumor Immunity Measured by T Cell Clone Frequency</title>
        <description>The study uses a comprehensive approach to analyze immunological changes that reflect both local and systemic responses, and investigate both general immune activation as well as tumor antigen-specific T- and B-cell responses. The activity of anti-CTLA-1 mAb is thought to be mainly dependent on modulating the quantity and quality of T-cells in cancer patients. A highly extensive analysis of the Cluster of differentiation 4 + (CD4+) and cluster of differentiation 8 + (CD8+) T-cell subsets will be characterized by multi-color flow Cytometry. To facilitate these analyses, serial blood samples will be collected for serum and peripheral blood mononuclear cells (PBMC) at different time points, where, a part of these samples will be used for DNA/RNA extraction. Optional tissue biopsies will be obtained from consenting patients.Tumor tissue will be tested for expression of seven antigens frequently expressed in NSCLC.</description>
        <time_frame>3 weeks - 6 months post-treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ipilimumab + Radiotherapy</title>
            <description>Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field).&#xD;
Ipilimumab&#xD;
Radiotherapy (IMRT or 3-D CRT)</description>
          </group>
        </group_list>
        <measure>
          <title>Number pf Patients With Objective Radioactive Responses to Measure the Effects of RT and Anti-CTLA-4 mAb on Development of Anti-tumor Immunity Measured by T Cell Clone Frequency</title>
          <description>The study uses a comprehensive approach to analyze immunological changes that reflect both local and systemic responses, and investigate both general immune activation as well as tumor antigen-specific T- and B-cell responses. The activity of anti-CTLA-1 mAb is thought to be mainly dependent on modulating the quantity and quality of T-cells in cancer patients. A highly extensive analysis of the Cluster of differentiation 4 + (CD4+) and cluster of differentiation 8 + (CD8+) T-cell subsets will be characterized by multi-color flow Cytometry. To facilitate these analyses, serial blood samples will be collected for serum and peripheral blood mononuclear cells (PBMC) at different time points, where, a part of these samples will be used for DNA/RNA extraction. Optional tissue biopsies will be obtained from consenting patients.Tumor tissue will be tested for expression of seven antigens frequently expressed in NSCLC.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Objective Radiographic Responses</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Complete Responses (CR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Responses (PR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>60 Months</time_frame>
      <desc>Adverse events as related to Ipilimumab or radiotherapy treatment. Grade of adverse event is shown: 1 - mild, 2 - moderate, 3 - Severe or medically significant but not immediately life-threatening, 4 - Life-threatening consequences, and 5 - Death related to AE.</desc>
      <group_list>
        <group group_id="E1">
          <title>Ipilimumab + Radiotherapy</title>
          <description>Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field).&#xD;
Ipilimumab&#xD;
Radiotherapy (IMRT or 3-D CRT)</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="17" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <description>Patients that progressed or died before completion of treatment</description>
                <counts group_id="E1" events="19" subjects_affected="19" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <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="39" subjects_at_risk="39"/>
              </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="6" subjects_affected="6" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperthyroid</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Hypothyroid</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
              </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="39"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="11" subjects_affected="11" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Peripheral neuropathy</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Pruritis</sub_title>
                <counts group_id="E1" events="17" subjects_affected="17" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="13" subjects_affected="13" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Alkaline Phosphotase</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>ALT</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>AST</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry Skin</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="15" subjects_affected="15" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="30" subjects_affected="30" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="39"/>
              </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="39"/>
              </event>
              <event>
                <sub_title>Edema</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="39"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="39"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>50 dynamic changes of T cell clones in blood were the strongest response predictors, confirming 51 pre-clinical mechanistic data.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Silvia Formenti, M.D.</name_or_title>
      <organization>Weill Cornell Medical College</organization>
      <phone>646-962-4065</phone>
      <email>formenti@med.cornell.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/NCT02221739
org study id: 14-00208
nct id: NCT02221739
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The purpose of this study is to investigate how effective and how safe the combination of
      radiation therapy and an investigational medication targeting the immune system known as
      Ipilimumab in the treatment of metastatic non-small cell lung cancer (NSCLC).

      The investigators would like to see if this combination of radiation and Ipilimumab can
      stimulate the body's immune system to stop the growth of tumors that are outside the field of
      radiation. The investigators would like see if using this combination of radiation therapy
      with Ipilimumab could help the body reject the patient's own tumor or at least help their
      immune system to maintain the disease stable and/or slow its growth.

      Radiation therapy (RT) is currently a standard procedure for treatment of NSCLC. Ipilimumab
      is considered an investigational medication because it is not approved by the Food and Drug
      Administration (FDA) for the treatment of NSCLC. Ipilimumab has been approved by the FDA for
      the treatment of metastatic melanoma.
Research Hypothesis:

        1. Through a combination of local RT and ipilimumab an anti-tumor immune response is
           elicited at the irradiated site, as an in vivo, individualized immunization that is
           systemically effective, as reflected by objective responses outside the RT field
           (abscopal effect).

        2. The immune response can be prospectively monitored among the treated patients.

      Objective 1: Evaluate the safety and therapeutic efficacy of anti-cytotoxic
      T-lymphocyte-associated protein -4 mono clonal Antibody (anti-CTLA-4 mAb) and concurrent
      local RT in NSCLC patients with metastatic disease.

      An open label phase II trial will evaluate the preliminary efficacy of the combination of Ipi
      and RT, applied to a single metastatic site. Efficacy is measured with respect to systemic
      tumor responses (abscopal response, outside the field of therapy) defined by immune-related
      Response Criteria (irRC) in all non-irradiated measurable lesions, as a demonstration of an
      effective anti-tumor immune response. Secondary endpoints include local response in the RT
      treated tumor, progression free survival, and overall survival.

      Objective 2: Determine the effects of RT and anti-CTLA-4 mAb on development of anti-tumor
      immunity.

      The investigators hypothesize that RT will convert the irradiated tumor into an in situ
      vaccine and elicit an endogenous tumor-specific cellular and humoral immune response, which
      in the presence of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade will promote
      immune-mediated destruction of the irradiated and abscopal metastases. Pre- and
      post-treatment tumor biopsies will be examined for changes in immune contexture, and blood
      for evidence of emerging anti-tumor immune responses. Associations with clinical response
      will be explored.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Therapeutic Efficacy of Anti-CTLA-4 mAb and Concurrent Local RT in NSCLC Patients With Metastatic Disease.
time frame: 3 weeks - 6 months post treatment
description: Tumor Response will be evaluated using the irRC best response (Partial Response (PR) + Complete Response (CR)). Modified WHO criteria will be used for measurement of tumors. The irradiated lesion will be excluded from the assessment of response.
measure: Number pf Patients With Objective Radioactive Responses to Measure the Effects of RT and Anti-CTLA-4 mAb on Development of Anti-tumor Immunity Measured by T Cell Clone Frequency
time frame: 3 weeks - 6 months post-treatment
description: The study uses a comprehensive approach to analyze immunological changes that reflect both local and systemic responses, and investigate both general immune activation as well as tumor antigen-specific T- and B-cell responses. The activity of anti-CTLA-1 mAb is thought to be mainly dependent on modulating the quantity and quality of T-cells in cancer patients. A highly extensive analysis of the Cluster of differentiation 4 + (CD4+) and cluster of differentiation 8 + (CD8+) T-cell subsets will be characterized by multi-color flow Cytometry. To facilitate these analyses, serial blood samples will be collected for serum and peripheral blood mononuclear cells (PBMC) at different time points, where, a part of these samples will be used for DNA/RNA extraction. Optional tissue biopsies will be obtained from consenting patients.Tumor tissue will be tested for expression of seven antigens frequently expressed in NSCLC.
arm group label: Ipilimumab + radiotherapy
arm group type: Experimental
description: Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field).
intervention type: Drug
intervention name: Ipilimumab
arm group label: Ipilimumab + radiotherapy
other name: Yervoy
intervention type: Radiation
intervention name: Radiotherapy (IMRT or 3-D CRT)
arm group label: Ipilimumab + radiotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Abraham Chachoua, MD
role: Principal Investigator
affiliation: NYU School of Medicine
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Ipilimumab
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: 50 dynamic changes of T cell clones in blood were the strongest response predictors, confirming 51 pre-clinical mechanistic data.
point of contact: 