<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/NCT01703507</url>
  </required_header>
  <id_info>
    <org_study_id>12P.314</org_study_id>
    <secondary_id>2012-43</secondary_id>
    <nct_id>NCT01703507</nct_id>
  </id_info>
  <brief_title>Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma</brief_title>
  <official_title>Phase I Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Cancer Center at Thomas Jefferson University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Thomas Jefferson University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of ipilimumab when given together&#xD;
      with whole brain radiation therapy or stereotactic radiosurgery in treating patients with&#xD;
      melanoma with brain metastases. Monoclonal antibodies, such as ipilimumab, can block tumor&#xD;
      growth in different ways. Some block the ability of the tumor to grow and spread. Others find&#xD;
      Tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy,&#xD;
      such uses high-energy x-rays and other types of radiation to kill tumor cells. Giving&#xD;
      radiation therapy in different ways may kill more tumor cells. Giving ipilimumab together&#xD;
      with whole-brain radiation therapy or stereotactic radiosurgery may kill more tumor cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Melanoma patients with brain metastases have a very poor outcome. Most patients with brain&#xD;
      metastases will die from CNS related death. Radiation therapy is an effective treatment for&#xD;
      patients with brain metastases for symptom palliation and survival benefit. Patients with&#xD;
      multiple metastases are typically treated with whole brain radiation treatment (WBRT). For&#xD;
      patients with a few metastases, stereotactic radiosurgery (SRS) alone can be used as an&#xD;
      alternative. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) antibody, Ipilimumab has shown&#xD;
      efficacy in metastatic melanoma and unresectable melanoma. Treatment with high doses of&#xD;
      radiation therapy would result in tumor cell death, releasing tumor debris and liberating&#xD;
      potential tumor antigens. We hypothesize that combining radiation therapy with Ipilimumab&#xD;
      will facilitate immune recognition of these novel tumor-specific antigens, yielding a&#xD;
      synergistic effect. Further, the hypothesis of this study is that this combination could&#xD;
      focus the immune system on tumor antigens and minimize the aberrant immune activation in&#xD;
      normal tissues, consequently reducing the incidence of irAE's (immune related adverse&#xD;
      effect). Combination of radiation treatment with Ipilimumab will likely result in better&#xD;
      local control, decrease the risk of developing new brain metastases, and improved overall&#xD;
      survival. However, the safety profile and toxicities of combining Ipilimumab with brain&#xD;
      radiation treatment are unknown. The current phase I study will assess the safety profile of&#xD;
      combining different doses of Ipilimumab with standard dose radiation treatment either with&#xD;
      WBRT or SRS. The MTD (maximum tolerated dose) will be determined, as well as a recommended&#xD;
      phase II trial dose of Ipilimumab.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 9, 2012</start_date>
  <completion_date type="Actual">April 11, 2018</completion_date>
  <primary_completion_date type="Actual">May 20, 2015</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) of Ipilimumab</measure>
    <time_frame>30 days following the completion of radiation therapy</time_frame>
    <description>(MTD) when combined with WBRT or SRS, defined as the last dose studied or the previous dose, based on clinical judgment of the degree of toxicity seen at the last dose</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of Developing New Brain Metastases in Each Arm</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response of Extracranial Disease</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>Extracranial disease is assessed through repeated computed tomography of the chest, abdomen, and pelvis. The purpose of this scan is to determine if there is any evidence of disease outside of the brain.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) Rate</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) Rate</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>PFS rate based on Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related response criteria (irRC) criteria based on the brain MRI and systematic assessment by the treating physician</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events and Serious Adverse Events</measure>
    <time_frame>4 weeks following the last dose of ipilimumab</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Recurrent Melanoma</condition>
  <condition>Stage IV Melanoma</condition>
  <condition>Tumors Metastatic to Brain</condition>
  <arm_group>
    <arm_group_label>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B (Ipilimumab and Stereotactic Radiosurgery)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</arm_group_label>
    <arm_group_label>Arm B (Ipilimumab and Stereotactic Radiosurgery)</arm_group_label>
    <other_name>MDX-010</other_name>
    <other_name>MDX-101</other_name>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Whole-Brain Radiation Therapy (WBRT)</intervention_name>
    <description>Undergo WBRT</description>
    <arm_group_label>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</arm_group_label>
    <other_name>WBRT</other_name>
    <other_name>Whole-brain radiotherapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic Radiosurgery (SRS)</intervention_name>
    <description>Undergo SRS</description>
    <arm_group_label>Arm B (Ipilimumab and Stereotactic Radiosurgery)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient age is &gt;= 18 years&#xD;
&#xD;
          2. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, or&#xD;
             1.&#xD;
&#xD;
          3. Ability to provide written informed consent obtained prior to participation in the&#xD;
             study and any related procedures being performed&#xD;
&#xD;
          4. Patients must meet the following laboratory criteria:&#xD;
&#xD;
               -  WBC &gt;= 2000/uL&#xD;
&#xD;
               -  ANC &gt;= 1000/uL&#xD;
&#xD;
               -  Platelets &gt;= 75 x 10^3/uL&#xD;
&#xD;
               -  Hemoglobin &gt;= 9 g/dL (&gt;= 80 g/L; may be transfused)&#xD;
&#xD;
               -  AST/ALT &lt;= 2.5 x ULN for patients without liver metastasis&#xD;
&#xD;
               -  AST/ALT &lt;= 5 times for liver metastases&#xD;
&#xD;
               -  Bilirubin &lt;= 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a&#xD;
                  total bilirubin less than 3.0 mg/dL)&#xD;
&#xD;
               -  Serum creatinine &lt;= 2.0 x ULN or 24-hour creatinine clearance &gt;= 50 ml/min&#xD;
&#xD;
               -  Total serum calcium (corrected for serum albumin) or ionized calcium &gt;= lower&#xD;
                  limit of normal (LLN)&#xD;
&#xD;
               -  Serum potassium &gt;= LLN&#xD;
&#xD;
               -  Serum sodium &gt;= LLN&#xD;
&#xD;
               -  Serum albumin &gt;= LLN or 3g/dl&#xD;
&#xD;
               -  Patients with any elevated Alkaline Phosphatase due to bone metastases can be&#xD;
                  enrolled&#xD;
&#xD;
          5. No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.&#xD;
&#xD;
          6. Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone&#xD;
             supplements to treat underlying hypothyroidism.&#xD;
&#xD;
          7. Women of childbearing potential (WOCBP) must be using an adequate method of&#xD;
             contraception to avoid pregnancy throughout the study and for up to 26 weeks after the&#xD;
             last dose of investigational product, in such a manner that the risk of pregnancy is&#xD;
             minimized. WOCBP include any female who has experienced menarche and who has not&#xD;
             undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,&#xD;
             or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as:&#xD;
&#xD;
               -  Amenorrhea &gt;= 12 consecutive months without another cause, or&#xD;
&#xD;
               -  For women with irregular menstrual periods and taking hormone replacement therapy&#xD;
                  (HRT), a documented serum follicle stimulating hormone (FSH) level &gt;= 35 mIU/mL.&#xD;
&#xD;
               -  Women who are using oral contraceptives, other hormonal contraceptives (vaginal&#xD;
                  products, skin patches, or implanted or injectable products), or mechanical&#xD;
                  products such as an intrauterine device or barrier methods (diaphragm, condoms,&#xD;
                  spermicides) to prevent pregnancy, or are practicing abstinence or where their&#xD;
                  partner is sterile (eg, vasectomy) should be considered to be of childbearing&#xD;
                  potential.&#xD;
&#xD;
               -  WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25&#xD;
                  IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab.&#xD;
&#xD;
          8. Men of fathering potential must be using an adequate method of contraception to avoid&#xD;
             conception throughout the study (and for up to 26 weeks after the last dose of&#xD;
             investigational product) in such a manner that the risk of pregnancy is minimized.&#xD;
&#xD;
          9. A pathological diagnosis of melanoma is required, from either the primary or a&#xD;
             metastasis. This also includes uveal melanoma.&#xD;
&#xD;
         10. A radiological diagnosis (CT or MRI) of one or more brain metastases is required.&#xD;
&#xD;
         11. Resolution of all acute toxic effects of prior chemotherapy or radiotherapy or&#xD;
             surgical procedures to NCI CTCAE Version 4.0 grade &lt;= 1.&#xD;
&#xD;
         12. Specific eligibility criteria for the two arms&#xD;
&#xD;
               -  Arm A WBRT and Ipilimumab:&#xD;
&#xD;
                    -  Patients have 5 or more brain metastases, or patients have any brain&#xD;
                       metastases exceeding the limit for SRS (maximum diameter is &gt; 4 cm).&#xD;
&#xD;
                    -  OR Patient has only one brain metastasis and completely resected, the&#xD;
                       resection cavity is &gt; 4 cm in diameter.&#xD;
&#xD;
               -  Arm B SRS and Ipilimumab:&#xD;
&#xD;
                    -  Patients have 4 or fewer brain metastases. All the brain metastases are &lt;= 4&#xD;
                       cm in diameter.&#xD;
&#xD;
                    -  Patients have only one brain metastasis and completely resected, the&#xD;
                       resection cavity is &lt;= 4 cm in diameter.&#xD;
&#xD;
                    -  OR If a patient is found to have progression of brain metastases that exceed&#xD;
                       4 cm in diameter based on the MRI scan on the time of SRS procedure, the&#xD;
                       patient should be re-assigned to WBRT arm or withdrawn from the study. The&#xD;
                       study PI should be notified.&#xD;
&#xD;
                    -  OR If a patient is found to have progression of brain metastases that exceed&#xD;
                       4 lesions based on the MRI scan on the time of the SRS procedure, the&#xD;
                       patient can either be treated with SRS to all the lesions (up to 10&#xD;
                       lesions), re-assigned to WBRT arm, or withdrawn from the study per the&#xD;
                       treating physician. The study PI should be notified.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient with leptomeningeal carcinomatosis.&#xD;
&#xD;
          2. Autoimmune disease: Patients with a history of inflammatory bowel disease, including&#xD;
             ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients&#xD;
             with a history of symptomatic disease (eg, rheumatoid arthritis, systemic progressive&#xD;
             sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg,&#xD;
             Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (e.g.&#xD;
             Guillain-Barre Syndrome and Myasthenia Gravis).&#xD;
&#xD;
          3. Major surgery or radiation therapy within 2 weeks of starting the study treatment.&#xD;
&#xD;
          4. If patients are receiving chemotherapy or other investigational drugs, they must be&#xD;
             discontinued 4 weeks prior to enrollment.&#xD;
&#xD;
          5. NCI CTCAE grade 3 hemorrhage within 4 weeks of starting the study treatment.&#xD;
&#xD;
          6. Any of the following within the 6 months prior to study drug administration:&#xD;
&#xD;
             myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass&#xD;
             graft, symptomatic congestive heart failure, cerebrovascular accident or transient&#xD;
             ischemic attack, or pulmonary embolism. Patients with known cardiac disease will be&#xD;
             required to have an ECHO or MUGA scan at baseline and at the completion of study.&#xD;
&#xD;
          7. Ongoing cardiac dysrhythmias of NCI CTCAE grade &gt;= 2.&#xD;
&#xD;
          8. Hypertension that cannot be controlled by medications (&gt;150/100 mm Hg despite optimal&#xD;
             medical therapy).&#xD;
&#xD;
          9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in&#xD;
             the normal range with medication.&#xD;
&#xD;
         10. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome&#xD;
             (AIDS)-related illness or other active infection.&#xD;
&#xD;
         11. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be&#xD;
             postmenopausal, or must agree to use effective contraception during the period of&#xD;
             therapy. All female subjects with reproductive potential must have a negative&#xD;
             pregnancy test (serum or urine) prior to enrollment. Male subjects must be surgically&#xD;
             sterile or must agree to use effective contraception during the period of therapy. The&#xD;
             definition of effective contraception will be based on the judgment of the principal&#xD;
             investigator or a designated associate.&#xD;
&#xD;
         12. Other severe acute or chronic medical or psychiatric condition or laboratory&#xD;
             abnormality that may increase the risk associated with study participation or study&#xD;
             drug administration, or may interfere with the interpretation of study results, and in&#xD;
             the judgment of the investigator would make the subject inappropriate for entry into&#xD;
             this study.&#xD;
&#xD;
         13. Concomitant therapy with any of the following: IL-2, interferon, or other non-study&#xD;
             immunotherapy regimens, cytotoxic chemotherapy, immunosuppressive agents,&#xD;
             vermurafenib, or other investigational therapies.&#xD;
&#xD;
         14. All efforts need to be taken to avoid/minimize the use of cortical steroid during&#xD;
             radiation period (1 week prior to start radiation, during radiation, and 1 week after&#xD;
             finishing radiation). Any steroid used considered necessary by the treating physician&#xD;
             should be closely documented, including medication, route of administration, dose, and&#xD;
             duration.&#xD;
&#xD;
         15. Active infection with hepatitis B, or hepatitis C.&#xD;
&#xD;
         16. Patients who had prior brain radiation treatment.&#xD;
&#xD;
         17. Patients are excluded if they have a history of any other malignancy from which the&#xD;
             patient has been disease-free for less than 2 years, with the exception of adequately&#xD;
             treated basal or squamous cell carcinoma of skin, superficial bladder cancer or&#xD;
             carcinoma in situ of cervix, AJCC (version 7.0) stage 0 or I breast cancer, AJCC&#xD;
             (version 7.0) stage I, or II prostate cancer.&#xD;
&#xD;
         18. Patients are excluded if they have a history of autoimmune disease, as follows:&#xD;
             Patients with a history of inflammatory bowel disease are excluded from this study as&#xD;
             are patients with a history of symptomatic disease (e.g., rheumatoid arthritis,&#xD;
             systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune&#xD;
             vasculitis [e.g., Wegener's Granulomatosis]). Patients with motor neuropathy&#xD;
             considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis)&#xD;
             are excluded. Patients with a history of autoimmune thyroiditis are eligible if their&#xD;
             current thyroid disorder is treated and stable with replacement or other medical&#xD;
             therapy.&#xD;
&#xD;
         19. Patients who are allergic to Ipilimumab.&#xD;
&#xD;
         20. Patients who received ipilimumab before.&#xD;
&#xD;
         21. Patients who are allergic to MRI contrast agent or have contraindication for MRI.&#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>Wenyin Shi, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Thomas Jefferson University</affiliation>
  </overall_official>
  <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>
    <facility>
      <name>Thomas Jefferson University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.JeffersonHospital.org</url>
    <description>Thomas Jefferson University Hospitals</description>
  </link>
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  <verification_date>July 2019</verification_date>
  <study_first_submitted>October 5, 2012</study_first_submitted>
  <study_first_submitted_qc>October 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <results_first_submitted>April 30, 2019</results_first_submitted>
  <results_first_submitted_qc>July 12, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">August 19, 2019</results_first_posted>
  <last_update_submitted>July 12, 2019</last_update_submitted>
  <last_update_submitted_qc>July 12, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 19, 2019</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>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>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
          <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
        </group>
        <group group_id="P2">
          <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
          <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
          <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
        </group>
        <group group_id="B2">
          <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
          <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</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="6"/>
            <count group_id="B2" value="11"/>
            <count group_id="B3" value="17"/>
          </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="1"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="8"/>
                  </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="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="12"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</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>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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</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>Native Hawaiian or Other Pacific Islander</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>Black or African American</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>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</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>Unknown or Not Reported</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>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of Ipilimumab</title>
        <description>(MTD) when combined with WBRT or SRS, defined as the last dose studied or the previous dose, based on clinical judgment of the degree of toxicity seen at the last dose</description>
        <time_frame>30 days following the completion of radiation therapy</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
            <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
            <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of Ipilimumab</title>
          <description>(MTD) when combined with WBRT or SRS, defined as the last dose studied or the previous dose, based on clinical judgment of the degree of toxicity seen at the last dose</description>
          <units>mg/kg</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Developing New Brain Metastases in Each Arm</title>
        <time_frame>Up to 5 years</time_frame>
        <population>Of the enrolled participants, only 7 developed new Brain Metastases (BMs) and were included in this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
            <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
            <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Developing New Brain Metastases in Each Arm</title>
          <population>Of the enrolled participants, only 7 developed new Brain Metastases (BMs) and were included in this analysis.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.2" lower_limit="8.2" upper_limit="8.2"/>
                    <measurement group_id="O2" value="1.9" lower_limit="0.97" upper_limit="8.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Response of Extracranial Disease</title>
        <description>Extracranial disease is assessed through repeated computed tomography of the chest, abdomen, and pelvis. The purpose of this scan is to determine if there is any evidence of disease outside of the brain.</description>
        <time_frame>Up to 5 years</time_frame>
        <population>Of the enrolled participants, only 4 out of 5 participants on Arm A and 9 out of 11 participants on Arm B had Extracranial Disease. Only these participants were included in this analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
            <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
            <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</description>
          </group>
        </group_list>
        <measure>
          <title>Response of Extracranial Disease</title>
          <description>Extracranial disease is assessed through repeated computed tomography of the chest, abdomen, and pelvis. The purpose of this scan is to determine if there is any evidence of disease outside of the brain.</description>
          <population>Of the enrolled participants, only 4 out of 5 participants on Arm A and 9 out of 11 participants on Arm B had Extracranial Disease. Only these participants were included in this analysis</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="4"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS) Rate</title>
        <time_frame>Up to 5 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
            <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
            <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS) Rate</title>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8" lower_limit="3.5" upper_limit="24.1"/>
                    <measurement group_id="O2" value="10.5" lower_limit="1.8" upper_limit="36.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS) Rate</title>
        <description>PFS rate based on Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related response criteria (irRC) criteria based on the brain MRI and systematic assessment by the treating physician</description>
        <time_frame>Up to 5 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
            <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
            <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) Rate</title>
          <description>PFS rate based on Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related response criteria (irRC) criteria based on the brain MRI and systematic assessment by the treating physician</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="5"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events and Serious Adverse Events</title>
        <time_frame>4 weeks following the last dose of ipilimumab</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
            <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
            <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events and Serious Adverse Events</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>30 days after completion of radiation therapy (RT)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Arm A (Ipilimumab and Whole Brain Radiation Therapy)</title>
          <description>Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.&#xD;
Ipilimumab: Given IV&#xD;
Whole-Brain Radiation Therapy (WBRT): Undergo WBRT</description>
        </group>
        <group group_id="E2">
          <title>Arm B (Ipilimumab and Stereotactic Radiosurgery)</title>
          <description>Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.&#xD;
Ipilimumab: Given IV&#xD;
Stereotactic Radiosurgery (SRS): Undergo SRS</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="3" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Lymphopenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Changes in Hearing</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision Changes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>hot flashes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Lipase Increase</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anoerexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Facial Palsy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>hypertension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Wenyin Shi</name_or_title>
      <organization>Sidney Kimmel Cancer Center at Thomas Jefferson University</organization>
      <phone>215-955-6702</phone>
      <email>Wenyin.Shi@jefferson.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/NCT01703507
org study id: 12P.314
secondary id: 2012-43
nct id: NCT01703507
lead sponsor: 
collaborator: 
has dmc: Yes
This phase I trial studies the side effects and best dose of ipilimumab when given together
      with whole brain radiation therapy or stereotactic radiosurgery in treating patients with
      melanoma with brain metastases. Monoclonal antibodies, such as ipilimumab, can block tumor
      growth in different ways. Some block the ability of the tumor to grow and spread. Others find
      Tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy,
      such uses high-energy x-rays and other types of radiation to kill tumor cells. Giving
      radiation therapy in different ways may kill more tumor cells. Giving ipilimumab together
      with whole-brain radiation therapy or stereotactic radiosurgery may kill more tumor cells.
Melanoma patients with brain metastases have a very poor outcome. Most patients with brain
      metastases will die from CNS related death. Radiation therapy is an effective treatment for
      patients with brain metastases for symptom palliation and survival benefit. Patients with
      multiple metastases are typically treated with whole brain radiation treatment (WBRT). For
      patients with a few metastases, stereotactic radiosurgery (SRS) alone can be used as an
      alternative. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) antibody, Ipilimumab has shown
      efficacy in metastatic melanoma and unresectable melanoma. Treatment with high doses of
      radiation therapy would result in tumor cell death, releasing tumor debris and liberating
      potential tumor antigens. We hypothesize that combining radiation therapy with Ipilimumab
      will facilitate immune recognition of these novel tumor-specific antigens, yielding a
      synergistic effect. Further, the hypothesis of this study is that this combination could
      focus the immune system on tumor antigens and minimize the aberrant immune activation in
      normal tissues, consequently reducing the incidence of irAE's (immune related adverse
      effect). Combination of radiation treatment with Ipilimumab will likely result in better
      local control, decrease the risk of developing new brain metastases, and improved overall
      survival. However, the safety profile and toxicities of combining Ipilimumab with brain
      radiation treatment are unknown. The current phase I study will assess the safety profile of
      combining different doses of Ipilimumab with standard dose radiation treatment either with
      WBRT or SRS. The MTD (maximum tolerated dose) will be determined, as well as a recommended
      phase II trial dose of Ipilimumab.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of Ipilimumab
time frame: 30 days following the completion of radiation therapy
description: (MTD) when combined with WBRT or SRS, defined as the last dose studied or the previous dose, based on clinical judgment of the degree of toxicity seen at the last dose
measure: Rate of Developing New Brain Metastases in Each Arm
time frame: Up to 5 years
measure: Response of Extracranial Disease
time frame: Up to 5 years
description: Extracranial disease is assessed through repeated computed tomography of the chest, abdomen, and pelvis. The purpose of this scan is to determine if there is any evidence of disease outside of the brain.
measure: Overall Survival (OS) Rate
time frame: Up to 5 years
measure: Progression Free Survival (PFS) Rate
time frame: Up to 5 years
description: PFS rate based on Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related response criteria (irRC) criteria based on the brain MRI and systematic assessment by the treating physician
measure: Number of Participants With Adverse Events and Serious Adverse Events
time frame: 4 weeks following the last dose of ipilimumab
arm group label: Arm A (Ipilimumab and Whole Brain Radiation Therapy)
arm group type: Experimental
description: Patients receive ipilimumab IV over 90 minutes once in weeks 1, 4, 7, and 10. Patients also undergo WBRT 5 days a week in weeks 1-2.
arm group label: Arm B (Ipilimumab and Stereotactic Radiosurgery)
arm group type: Experimental
description: Patients receive ipilimumab IV over 90 minutes as in Arm A. Patients also undergo SRS on day 1 in week 1.
intervention type: Drug
intervention name: Ipilimumab
description: Given IV
arm group label: Arm A (Ipilimumab and Whole Brain Radiation Therapy)
arm group label: Arm B (Ipilimumab and Stereotactic Radiosurgery)
other name: MDX-010
other name: MDX-101
other name: Yervoy
intervention type: Radiation
intervention name: Whole-Brain Radiation Therapy (WBRT)
description: Undergo WBRT
arm group label: Arm A (Ipilimumab and Whole Brain Radiation Therapy)
other name: WBRT
other name: Whole-brain radiotherapy
intervention type: Radiation
intervention name: Stereotactic Radiosurgery (SRS)
description: Undergo SRS
arm group label: Arm B (Ipilimumab and Stereotactic Radiosurgery)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Wenyin Shi, MD, PhD
role: Principal Investigator
affiliation: Thomas Jefferson University
facility: 
facility: 
country: United States
url: http://www.JeffersonHospital.org
description: Thomas Jefferson University Hospitals
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responsible party type: Sponsor
mesh term: Melanoma
mesh term: Ipilimumab
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 