<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/NCT01689974</url>
  </required_header>
  <id_info>
    <org_study_id>12-02746</org_study_id>
    <nct_id>NCT01689974</nct_id>
  </id_info>
  <brief_title>Phase II Randomized Trial of Ipilimumab Versus Ipilimumab and Radiotherapy in Metastatic Melanoma</brief_title>
  <official_title>Phase II Randomized Trial of Ipilimumab Versus Ipilimumab and Radiotherapy in Metastatic Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NYU Langone Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </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>
      An attractive area of research regards immune manipulations to recover some of the patient's&#xD;
      immune response to his/her tumor, a strategy that has the advantages of being both natural&#xD;
      and potentially long-lasting.[1] We propose to combine immunotherapy with radiotherapy&#xD;
      directed to a metastatic site, to create a &quot;hub&quot; for in vivo immunization to the tumor, to&#xD;
      enable &quot;tumor rejection&quot; at the other metastatic sites. This &quot;in vivo immunization&quot; is&#xD;
      explored as a viable alternative to an individualized vaccine approach. Preclinical data&#xD;
      generated by us and others support a &quot;proof of principle&quot; clinical trial that may open the&#xD;
      field to an alternative use of radiotherapy in a novel partnership with cancer&#xD;
      immunotherapy.[2]&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In addition, we propose to perform immune-monitoring of the patients accrued to the trial to&#xD;
      generate important information for hypothesis-driven research about the mechanisms behind the&#xD;
      clinical findings, to be tested in the laboratory.&#xD;
&#xD;
      An attractive area of research regards immune manipulations to recover some of the patient's&#xD;
      immune response to his/her tumor, a strategy that has the advantages of being both natural&#xD;
      and potentially long-lasting.[1] We propose to combine immunotherapy with radiotherapy&#xD;
      directed to a metastatic site, to create a &quot;hub&quot; for in vivo immunization to the tumor, to&#xD;
      enable &quot;tumor rejection&quot; at the other metastatic sites. This &quot;in vivo immunization&quot; is&#xD;
      explored as a viable alternative to an individualized vaccine approach. Preclinical data&#xD;
      generated by us and others support a &quot;proof of principle&quot; clinical trial that may open the&#xD;
      field to an alternative use of radiotherapy in a novel partnership with cancer&#xD;
      immunotherapy.[2]&#xD;
&#xD;
      In addition, we propose to perform immune-monitoring of the patients accrued to the trial to&#xD;
      generate important information for hypothesis-driven research about the mechanisms behind the&#xD;
      clinical findings, to be tested in the laboratory.&#xD;
&#xD;
      The specific aims of the study are:&#xD;
&#xD;
        1. To explore the induction of immunity-mediated tumor response outside the radiation field&#xD;
           (abscopal effect) after radiation/Ipilimumab in metastatic melanoma, by estimating and&#xD;
           comparing response rates in patients treated with Ipilimumab alone (Arm A) versus&#xD;
           ipilimumab and radiation (Arm B).&#xD;
&#xD;
        2. To compare the induction of a T-cell response in patients with metastatic melanoma&#xD;
           treated with either ipilimumab alone or in combination with radiation.&#xD;
&#xD;
      All patients with metastatic melanoma with at least 2 measurable sites of disease are&#xD;
      eligible. Extent of metastatic disease is recorded by CT scanning or MRI before therapy.&#xD;
      Patients will then be randomized to Ipilimumab 3 mg/kg IV over 90 minutes alone versus&#xD;
      Ipilimumab 3 mg/kg IV over 90 minutes plus radiotherapy to one of their measurable lesions, 6&#xD;
      Gy delivered daily x 5 days (Monday through Friday) (conformally or by IMRT/IGRT, to&#xD;
      maximally spare normal tissue), for a total of 30 Gy. For patients assigned to the&#xD;
      Ipilimumab/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4&#xD;
      from the first radiotherapy fraction. All patients will then have ipilimumab infusions&#xD;
      repeated on Days 25, 46 and 67. Patients will be re-imaged (CT imaging or MRI) on Week 12 and&#xD;
      evaluated for response (defined as an objective response of another metastatic site outside&#xD;
      the radiation field).&#xD;
&#xD;
      The main immunological end-point will be the induction or boosting of treatment induced T&#xD;
      cells (CD4+ and CD8+) and B cells for defined antigen approaches. In addition, the magnitude&#xD;
      and duration of T- and B-cell responses will be examined. Treatment-induced responses will be&#xD;
      calculated as the difference between the pre-treatment measurement and the measurement at the&#xD;
      different time points at which blood will be collected (time of evaluation) in the same&#xD;
      patient. The percentage of patients with the induction of treatment-induced T- and B-cell&#xD;
      responses will be reported.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Study terminated because PI left institution. Planned Statistical analysis not available&#xD;
  </why_stopped>
  <start_date>January 2013</start_date>
  <completion_date type="Actual">March 2015</completion_date>
  <primary_completion_date type="Actual">March 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Response Rates of Ipilimumab Alone and of Ipilimumab With Radiation Therapy and to Estimate the Difference Between Response Rates With Ipilimumab Alone and Ipilimumab With Radiation Therapy</measure>
    <time_frame>2 years</time_frame>
    <description>Eligible patients have metastatic melanoma with at least 2 measurable sites of disease. All patients with metastatic melanoma are eligible to be randomly assigned to Ipilimumab 3mg/kg IV over 90 minutes versus Ipilimumab 3 mg/kg IV over 90 minutes and radiotherapy to one of their measurable lesions, 6 Gy X5 (conformally or by IMRT/IGRT, to maximally spare normal tissue). For patients assigned to the Ipi/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4 from the first radiotherapy fraction and repeated on Days 25, 46 and 67. Patients will be re-imaged on Week 12 and evaluated for response (defined as an objective response of another metastatic site outside the radiation field). This response will be evaluated assessing clinical and CT responses in the non-irradiated measurable metastatic sites.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Metastatic Melanoma</condition>
  <arm_group>
    <arm_group_label>Arm A: Ipilimumab</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Ipilimumab administered alone Day 4, 25, 46, and 67</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B: Ipilimumab and Radiation</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Radiation Therapy and Ipilimumab. Radiation treatment is administered for 5 fractions (sessions) over 1 week. On Day 4 treatment with Ipilimumab begins and continues on Days 25, 46, and 67.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Ipilimumab will be administered alone on day 4, 25, 46 and 67.</description>
    <arm_group_label>Arm A: Ipilimumab</arm_group_label>
    <arm_group_label>Arm B: Ipilimumab and Radiation</arm_group_label>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiation Therapy</intervention_name>
    <description>Radiation is given over one week interval On the fourth day of radiation (day 4)Ipilimumab is administered and repeated on Days 25, 46 and 67.</description>
    <arm_group_label>Arm B: Ipilimumab and Radiation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document;&#xD;
&#xD;
          -  Histologic diagnosis of locally unresectable, metastatic melanoma.&#xD;
&#xD;
          -  Any BRAF status is permitted&#xD;
&#xD;
          -  Any prior therapy is permitted except prior therapy with ipilimumab.&#xD;
&#xD;
          -  Patients must have at least 2 distinct measurable metastatic sites, with one of at&#xD;
             least 1 cm or larger in its largest diameter and may have additional non-measurable&#xD;
             but established metastatic lesions (i.e. bone metastases).&#xD;
&#xD;
          -  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 for patients without liver metastasis&#xD;
&#xD;
               -  Bilirubin 3.0 x ULN, (except patients with Gilbert's Syndrome, who must have a&#xD;
                  total bilirubin less than 3.0 mg/dL;&#xD;
&#xD;
          -  Performance status ECOG 0-1 or Karnofsky &gt; 50%;&#xD;
&#xD;
          -  Men and women, ages &gt; 18 year old of age;&#xD;
&#xD;
          -  Life expectancy &gt; 3 months&#xD;
&#xD;
          -  Stable brain metastases for at least 4 weeks and not steroid dependent;&#xD;
&#xD;
          -  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;
             study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients having no lesions outside the field of radiation thus nullifying the ability&#xD;
             to measure an abscopal effect;&#xD;
&#xD;
          -  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, systemic progressive sclerosis [scleroderma], Systemic Lupus&#xD;
             Erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis;&#xD;
&#xD;
          -  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 AEs, such as a condition associated with frequent diarrhea;&#xD;
&#xD;
          -  Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to&#xD;
             one month prior to or after any dose of ipilimumab);&#xD;
&#xD;
          -  Concomitant therapy with any of the following: IL-2, interferon or other non-study&#xD;
             immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other&#xD;
             investigation therapies; or chronic use of systemic corticosteroids;&#xD;
&#xD;
          -  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;
          -  Persons of reproductive potential must agree to use and utilize an adequate method of&#xD;
             contraception throughout treatment and for at least 8 weeks after study drug is&#xD;
             stopped;&#xD;
&#xD;
          -  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>19 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Silvia C. Formenti, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>NYULMC Department Radiation Oncology</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_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>September 18, 2012</study_first_submitted>
  <study_first_submitted_qc>September 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 21, 2012</study_first_posted>
  <results_first_submitted>August 29, 2017</results_first_submitted>
  <results_first_submitted_qc>January 26, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">February 23, 2018</results_first_posted>
  <last_update_submitted>January 26, 2018</last_update_submitted>
  <last_update_submitted_qc>January 26, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 23, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Metastatic Melanoma</keyword>
  <keyword>Radiation Therapy</keyword>
  <keyword>Immunology</keyword>
  <keyword>Abscopal</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Arm A: Ipilimumab</title>
          <description>Ipilimumab administered alone Day 4, 25, 46, and 67&#xD;
Ipilimumab: Ipilimumab will be administered alone on day 4, 25, 46 and 67.</description>
        </group>
        <group group_id="P2">
          <title>Arm B: Ipilimumab and Radiation</title>
          <description>Radiation Therapy and Ipilimumab. Radiation treatment is administered for 5 fractions (sessions) over 1 week. On Day 4 treatment with Ipilimumab begins and continues on Days 25, 46, and 67.&#xD;
Radiation Therapy and Ipilimumab: Radiation is given over one week interval On the fourth day of radiation (day 4)Ipilimumab is administered and repeated on Days 25, 46 and 67.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Termination of Study</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Arm A: Ipilimumab</title>
          <description>Ipilimumab administered alone Day 4, 25, 46, and 67&#xD;
Ipilimumab: Ipilimumab will be administered alone on day 4, 25, 46 and 67.</description>
        </group>
        <group group_id="B2">
          <title>Arm B: Ipilimumab and Radiation</title>
          <description>Radiation Therapy and Ipilimumab. Radiation treatment is administered for 5 fractions (sessions) over 1 week. On Day 4 treatment with Ipilimumab begins and continues on Days 25, 46, and 67.&#xD;
Radiation Therapy and Ipilimumab: Radiation is given over one week interval On the fourth day of radiation (day 4)Ipilimumab is administered and repeated on Days 25, 46 and 67.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="5"/>
            <count group_id="B2" value="5"/>
            <count group_id="B3" value="10"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Response Rates of Ipilimumab Alone and of Ipilimumab With Radiation Therapy and to Estimate the Difference Between Response Rates With Ipilimumab Alone and Ipilimumab With Radiation Therapy</title>
        <description>Eligible patients have metastatic melanoma with at least 2 measurable sites of disease. All patients with metastatic melanoma are eligible to be randomly assigned to Ipilimumab 3mg/kg IV over 90 minutes versus Ipilimumab 3 mg/kg IV over 90 minutes and radiotherapy to one of their measurable lesions, 6 Gy X5 (conformally or by IMRT/IGRT, to maximally spare normal tissue). For patients assigned to the Ipi/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4 from the first radiotherapy fraction and repeated on Days 25, 46 and 67. Patients will be re-imaged on Week 12 and evaluated for response (defined as an objective response of another metastatic site outside the radiation field). This response will be evaluated assessing clinical and CT responses in the non-irradiated measurable metastatic sites.</description>
        <time_frame>2 years</time_frame>
        <population>Study terminated because PI left institution. Data cannot be reported because 2 year data were not collected and were not analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A: Ipilimumab</title>
            <description>Ipilimumab administered alone Day 4, 25, 46, and 67&#xD;
Ipilimumab: Ipilimumab will be administered alone on day 4, 25, 46 and 67.</description>
          </group>
          <group group_id="O2">
            <title>Arm B: Ipilimumab and Radiation</title>
            <description>Radiation Therapy and Ipilimumab. Radiation treatment is administered for 5 fractions (sessions) over 1 week. On Day 4 treatment with Ipilimumab begins and continues on Days 25, 46, and 67.&#xD;
Radiation Therapy and Ipilimumab: Radiation is given over one week interval On the fourth day of radiation (day 4)Ipilimumab is administered and repeated on Days 25, 46 and 67.</description>
          </group>
        </group_list>
        <measure>
          <title>Response Rates of Ipilimumab Alone and of Ipilimumab With Radiation Therapy and to Estimate the Difference Between Response Rates With Ipilimumab Alone and Ipilimumab With Radiation Therapy</title>
          <description>Eligible patients have metastatic melanoma with at least 2 measurable sites of disease. All patients with metastatic melanoma are eligible to be randomly assigned to Ipilimumab 3mg/kg IV over 90 minutes versus Ipilimumab 3 mg/kg IV over 90 minutes and radiotherapy to one of their measurable lesions, 6 Gy X5 (conformally or by IMRT/IGRT, to maximally spare normal tissue). For patients assigned to the Ipi/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4 from the first radiotherapy fraction and repeated on Days 25, 46 and 67. Patients will be re-imaged on Week 12 and evaluated for response (defined as an objective response of another metastatic site outside the radiation field). This response will be evaluated assessing clinical and CT responses in the non-irradiated measurable metastatic sites.</description>
          <population>Study terminated because PI left institution. Data cannot be reported because 2 year data were not collected and were not analyzed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Arm A: Ipilimumab</title>
          <description>Ipilimumab administered alone Day 4, 25, 46, and 67&#xD;
Ipilimumab: Ipilimumab will be administered alone on day 4, 25, 46 and 67.</description>
        </group>
        <group group_id="E2">
          <title>Arm B: Ipilimumab and Radiation</title>
          <description>Radiation Therapy and Ipilimumab. Radiation treatment is administered for 5 fractions (sessions) over 1 week. On Day 4 treatment with Ipilimumab begins and continues on Days 25, 46, and 67.&#xD;
Radiation Therapy and Ipilimumab: Radiation is given over one week interval On the fourth day of radiation (day 4)Ipilimumab is administered and repeated on Days 25, 46 and 67.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Sylvia Formenti, MD</name_or_title>
      <organization>New York University School of Medicine</organization>
      <phone>646.962.4073</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/NCT01689974
org study id: 12-02746
nct id: NCT01689974
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
An attractive area of research regards immune manipulations to recover some of the patient's
      immune response to his/her tumor, a strategy that has the advantages of being both natural
      and potentially long-lasting.[1] We propose to combine immunotherapy with radiotherapy
      directed to a metastatic site, to create a "hub" for in vivo immunization to the tumor, to
      enable "tumor rejection" at the other metastatic sites. This "in vivo immunization" is
      explored as a viable alternative to an individualized vaccine approach. Preclinical data
      generated by us and others support a "proof of principle" clinical trial that may open the
      field to an alternative use of radiotherapy in a novel partnership with cancer
      immunotherapy.[2]
In addition, we propose to perform immune-monitoring of the patients accrued to the trial to
      generate important information for hypothesis-driven research about the mechanisms behind the
      clinical findings, to be tested in the laboratory.

      An attractive area of research regards immune manipulations to recover some of the patient's
      immune response to his/her tumor, a strategy that has the advantages of being both natural
      and potentially long-lasting.[1] We propose to combine immunotherapy with radiotherapy
      directed to a metastatic site, to create a "hub" for in vivo immunization to the tumor, to
      enable "tumor rejection" at the other metastatic sites. This "in vivo immunization" is
      explored as a viable alternative to an individualized vaccine approach. Preclinical data
      generated by us and others support a "proof of principle" clinical trial that may open the
      field to an alternative use of radiotherapy in a novel partnership with cancer
      immunotherapy.[2]

      In addition, we propose to perform immune-monitoring of the patients accrued to the trial to
      generate important information for hypothesis-driven research about the mechanisms behind the
      clinical findings, to be tested in the laboratory.

      The specific aims of the study are:

        1. To explore the induction of immunity-mediated tumor response outside the radiation field
           (abscopal effect) after radiation/Ipilimumab in metastatic melanoma, by estimating and
           comparing response rates in patients treated with Ipilimumab alone (Arm A) versus
           ipilimumab and radiation (Arm B).

        2. To compare the induction of a T-cell response in patients with metastatic melanoma
           treated with either ipilimumab alone or in combination with radiation.

      All patients with metastatic melanoma with at least 2 measurable sites of disease are
      eligible. Extent of metastatic disease is recorded by CT scanning or MRI before therapy.
      Patients will then be randomized to Ipilimumab 3 mg/kg IV over 90 minutes alone versus
      Ipilimumab 3 mg/kg IV over 90 minutes plus radiotherapy to one of their measurable lesions, 6
      Gy delivered daily x 5 days (Monday through Friday) (conformally or by IMRT/IGRT, to
      maximally spare normal tissue), for a total of 30 Gy. For patients assigned to the
      Ipilimumab/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4
      from the first radiotherapy fraction. All patients will then have ipilimumab infusions
      repeated on Days 25, 46 and 67. Patients will be re-imaged (CT imaging or MRI) on Week 12 and
      evaluated for response (defined as an objective response of another metastatic site outside
      the radiation field).

      The main immunological end-point will be the induction or boosting of treatment induced T
      cells (CD4+ and CD8+) and B cells for defined antigen approaches. In addition, the magnitude
      and duration of T- and B-cell responses will be examined. Treatment-induced responses will be
      calculated as the difference between the pre-treatment measurement and the measurement at the
      different time points at which blood will be collected (time of evaluation) in the same
      patient. The percentage of patients with the induction of treatment-induced T- and B-cell
      responses will be reported.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Response Rates of Ipilimumab Alone and of Ipilimumab With Radiation Therapy and to Estimate the Difference Between Response Rates With Ipilimumab Alone and Ipilimumab With Radiation Therapy
time frame: 2 years
description: Eligible patients have metastatic melanoma with at least 2 measurable sites of disease. All patients with metastatic melanoma are eligible to be randomly assigned to Ipilimumab 3mg/kg IV over 90 minutes versus Ipilimumab 3 mg/kg IV over 90 minutes and radiotherapy to one of their measurable lesions, 6 Gy X5 (conformally or by IMRT/IGRT, to maximally spare normal tissue). For patients assigned to the Ipi/RT arm, Ipilimumab treatment starts after radiotherapy, with a dose given on day 4 from the first radiotherapy fraction and repeated on Days 25, 46 and 67. Patients will be re-imaged on Week 12 and evaluated for response (defined as an objective response of another metastatic site outside the radiation field). This response will be evaluated assessing clinical and CT responses in the non-irradiated measurable metastatic sites.
arm group label: Arm A: Ipilimumab
arm group type: Other
description: Ipilimumab administered alone Day 4, 25, 46, and 67
arm group label: Arm B: Ipilimumab and Radiation
arm group type: Other
description: Radiation Therapy and Ipilimumab. Radiation treatment is administered for 5 fractions (sessions) over 1 week. On Day 4 treatment with Ipilimumab begins and continues on Days 25, 46, and 67.
intervention type: Drug
intervention name: Ipilimumab
description: Ipilimumab will be administered alone on day 4, 25, 46 and 67.
arm group label: Arm A: Ipilimumab
arm group label: Arm B: Ipilimumab and Radiation
other name: Yervoy
intervention type: Radiation
intervention name: Radiation Therapy
description: Radiation is given over one week interval On the fourth day of radiation (day 4)Ipilimumab is administered and repeated on Days 25, 46 and 67.
arm group label: Arm B: Ipilimumab and Radiation
criteria: 
gender: All
minimum age: 19 Years
maximum age: 80 Years
healthy volunteers: No
last name: Silvia C. Formenti, M.D.
role: Principal Investigator
affiliation: NYULMC Department Radiation Oncology
facility: 
country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Ipilimumab
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 