<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/NCT04434560</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00103812</org_study_id>
    <secondary_id>CA184-583</secondary_id>
    <nct_id>NCT04434560</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Immunotherapy in Brain Metastases</brief_title>
  <official_title>A Phase II Trial of Surgery and Stereotactic Radiosurgery With Neoadjuvant Nivolumab and Ipilimumab in Patients With Surgically-resectable, Solid Tumor Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sarah Sammons, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this phase 2 study is to assess the feasibility and efficacy of neoadjuvant&#xD;
      immunotherapy in patients with previously untreated, surgically-resectable, solid tumor brain&#xD;
      metastases. The primary objectives of this study are to 1) assess the feasibility of&#xD;
      neoadjuvant ipilimumab and nivolumab treatment before surgery and stereotactic radiosurgery&#xD;
      (SRS) in patients with solid tumor brain metastases as measured by the proportion of patients&#xD;
      who have their surgery delayed or surgery never occurs, and 2) demonstrate that neoadjuvant&#xD;
      immunotherapy will increase proliferation of circulating T-cells compared to baseline&#xD;
      measurements. Exploratory objectives include describing patient progression free survival and&#xD;
      overall survival, time to local and distant intracranial progression, and the rate of&#xD;
      radiation necrosis. The rate of radionecrosis will also be explored, as immune expression&#xD;
      profiles.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Forty patients planned for standard of care resection of at least one solid tumor brain&#xD;
      metastasis will be enrolled onto the study after providing informed consent. Primary tumor&#xD;
      histology types are restricted to those known to extracranially respond to immunotherapy, and&#xD;
      will include, but not be limited to, squamous non-small cell lung cancer (NSCLC),&#xD;
      non-squamous NSCLC without known anaplastic lymphoma kinase (ALK), epidermal growth factor&#xD;
      receptor (EGFR), and ROS mutation, renal cell carcinoma (RCC), melanoma, and triple negative&#xD;
      breast cancer (TNBC) that is programmed death-ligand 1 positive (PD-L1 +). All participants&#xD;
      will receive neoadjuvant immunotherapy and will receive a single infusion of nivolumab at a&#xD;
      dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg 7 days (±3 days) prior to surgical&#xD;
      resection of their metastases. Approximately three weeks after resection, patients in will&#xD;
      then receive SRS per standard of care guidelines. Patients will be followed for 18 months&#xD;
      after initiating study treatment. Up to 20 participants will be recruited and treated. Blood&#xD;
      will be collected periodically during the study for correlative assessments.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Poor enrollment&#xD;
  </why_stopped>
  <start_date type="Actual">November 4, 2020</start_date>
  <completion_date type="Actual">June 17, 2021</completion_date>
  <primary_completion_date type="Actual">June 17, 2021</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>Proportion of Patients Who Have Their Surgery Delayed by More Than 4 Days or Surgery Never Occurs as a Direct or Indirect Result of Ipilimumab and Nivolumab Treatment.</measure>
    <time_frame>10 days</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Proliferation of Circulating T-cells as Measured by Mean Fold-change Between Baseline and Day 1 in Ki67 Levels.</measure>
    <time_frame>baseline to day 1</time_frame>
    <description>Ki-67 is a nuclear protein involved in cell proliferation regulation.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Brain Metastases, Adult</condition>
  <arm_group>
    <arm_group_label>Standard of Care (no neoadjuvant immunotherapy)</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Neoadjuvant Immunotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab will be given at the FDA-approved dose of 3 mg/kg.</description>
    <arm_group_label>Neoadjuvant Immunotherapy</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.</description>
    <arm_group_label>Neoadjuvant Immunotherapy</arm_group_label>
    <other_name>Yervoy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1. Patients must have at least 1 previously untreated, solid tumor brain metastases&#xD;
             that are ≤4 cm in the largest direction. At least one of the metastases must be&#xD;
             surgically resectable. All metastases must be planned for treatment with SRS. Primary&#xD;
             tumor histology must be one of the following:&#xD;
&#xD;
               1. Squamous NSCLC&#xD;
&#xD;
               2. Non-squamous NSCLC without known ALK, EGFR, and ROS mutation&#xD;
&#xD;
               3. RCC&#xD;
&#xD;
               4. Urothelial carcinoma&#xD;
&#xD;
               5. Ovarian carcinoma&#xD;
&#xD;
               6. Melanoma&#xD;
&#xD;
               7. Triple negative breast cancer that is PD-L1 positive&#xD;
&#xD;
               8. Other solid tumor histologies may be eligible at the discretion of the PI if they&#xD;
                  are known to respond to immunotherapy containing regimens.&#xD;
&#xD;
          -  2. Patient must be asymptomatic or minimally symptomatic, requiring the equivalent of&#xD;
             ≤ 4 mg dexamethasone daily for at least 7 days prior to enrollment&#xD;
&#xD;
          -  3. Patient or partner(s) meets one of the following criteria:&#xD;
&#xD;
               1. Non-childbearing potential (i.e. not sexually active, physiologically incapable&#xD;
                  of becoming pregnant, including any female who is post-menopausal or surgically&#xD;
                  sterile, or any male who has had a vasectomy). Surgically sterile females are&#xD;
                  defined as those with a documented hysterectomy and/or bilateral oophorectomy or&#xD;
                  tubal ligation. Postmenopausal for purposes of this study is defined as 1 year&#xD;
                  without menses.; or&#xD;
&#xD;
               2. Childbearing potential and agrees to use one of the following methods of birth&#xD;
                  control: approved hormonal contraceptives (e.g. birth control pills, patches,&#xD;
                  implants, or infusions), an intrauterine device, or a barrier method of&#xD;
                  contraception (e.g. a condom or diaphragm) used with spermicide.&#xD;
&#xD;
          -  4. Age ≥ 18 years of age at the time of entry into the study&#xD;
&#xD;
          -  5. Karnofsky Performance Score (KPS) ≥ 70&#xD;
&#xD;
          -  6. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to resection&#xD;
&#xD;
          -  7. Neutrophil count ≥ 1000 prior to resection&#xD;
&#xD;
          -  8. Hemoglobin ≥ 9 g/dl prior to resection&#xD;
&#xD;
          -  9. Platelet count ≥ 100,000/µl unsupported is necessary for eligibility on the study;&#xD;
             however, because of risks of intracranial hemorrhage during resection, platelet count&#xD;
             ≥ 125,000/µl is required for the patient to undergo resection, which can be attained&#xD;
             with the help of platelet transfusion&#xD;
&#xD;
          -  10. Creatinine ≤ 1.5 x ULN (upper limit of normal) prior to resection&#xD;
&#xD;
          -  11. A signed informed consent form approved by the Institutional Review Board (IRB)&#xD;
             will be required for patient enrollment into the study. Patients must be able to read&#xD;
             and understand the informed consent document and must sign the informed consent&#xD;
             indicating that they are aware of the investigational nature of this study&#xD;
&#xD;
          -  12. Ability to undergo MRI&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. Females who are pregnant or breast-feeding&#xD;
&#xD;
          -  2. Patients with an impending, life-threatening cerebral herniation syndrome, based on&#xD;
             the assessment of the study neurosurgeons or their designate&#xD;
&#xD;
          -  3. Patients with severe, active co-morbidity, defined as follow:&#xD;
&#xD;
               1. Patients with an active infection requiring intravenous treatment or having an&#xD;
                  unexplained febrile illness (Tmax &gt; 99.5°F/37.5°C)&#xD;
&#xD;
               2. Patients with known immunosuppressive disease or known uncontrolled human&#xD;
                  immunodeficiency virus infection&#xD;
&#xD;
               3. Patients with unstable or severe intercurrent medical conditions such as severe&#xD;
                  heart disease (New York Heart Association Class 3 or 4)&#xD;
&#xD;
          -  4. Patients who have not recovered from the toxic effects of prior chemo- and/or&#xD;
             radiation therapy. Guidelines for this recovery period are dependent upon the specific&#xD;
             therapeutic agent being used:&#xD;
&#xD;
          -  5. Patients must not have received immunotherapy within 3 months prior to enrollment&#xD;
&#xD;
          -  6. Patients with prior, unrelated malignancy requiring current active treatment in the&#xD;
             last 3 years with the exception of cervical carcinoma in situ and adequately treated&#xD;
             basal cell or squamous cell carcinoma of the skin&#xD;
&#xD;
          -  7. Patients with a known history of hypersensitivity to nivolumab, or any components&#xD;
             of nivolumab&#xD;
&#xD;
          -  8. Patients with a known history of hypersensitivity to ipilimumab, or any components&#xD;
             of ipilimumab&#xD;
&#xD;
          -  9. Patients with active autoimmune disease requiring systemic immunomodulatory&#xD;
             treatment within the past 3 months.&#xD;
&#xD;
          -  10. History and/or confirmed pneumonitis, or extensive bilateral lung disease on high&#xD;
             resolution/spiral CT scan.&#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>Sarah Sammons, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://tischbraintumorcenter.duke.edu/</url>
    <description>The Preston Robert Tisch Brain Tumor Center</description>
  </link>
  <link>
    <url>http://www.dukehealth.org/clinical-trials</url>
    <description>Duke Health</description>
  </link>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>June 12, 2020</study_first_submitted>
  <study_first_submitted_qc>June 12, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 17, 2020</study_first_posted>
  <results_first_submitted>June 10, 2022</results_first_submitted>
  <results_first_submitted_qc>July 22, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">July 26, 2022</results_first_posted>
  <last_update_submitted>July 22, 2022</last_update_submitted>
  <last_update_submitted_qc>July 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Duke University</investigator_affiliation>
    <investigator_full_name>Sarah Sammons, MD</investigator_full_name>
    <investigator_title>Assistant Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Pro00103812</keyword>
  <keyword>Sammons</keyword>
  <keyword>Non-small-cell lung carcinoma</keyword>
  <keyword>Renal cell carcinoma</keyword>
  <keyword>Urothelial carcinoma</keyword>
  <keyword>Melanoma</keyword>
  <keyword>Ovarian carcinoma</keyword>
  <keyword>Triple negative breast cancer</keyword>
  <keyword>Solid tumor</keyword>
  <keyword>Brain metastases</keyword>
  <keyword>Nivolumab</keyword>
  <keyword>Ipilimumab</keyword>
  <keyword>Opdivo</keyword>
  <keyword>Yervoy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 19, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT04434560/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>In a Memo to File dated March 4, 2021, the removal of randomization in favor of a single-arm study in which all patients will receive neoadjuvant immunotherapy prior to their resection and SRS was proposed. One patient had already been randomized to receive standard of care surgery and SRS without neoadjuvant immunotherapy. This patient is not part of the analyses for the primary or secondary outcomes, as after the protocol amendment all patients were to receive neoadjuvant immunotherapy.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Standard of Care (no Neoadjuvant Immunotherapy)</title>
          <description>Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.</description>
        </group>
        <group group_id="P2">
          <title>Neoadjuvant Immunotherapy</title>
          <description>Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.&#xD;
Nivolumab: Nivolumab will be given at the FDA-approved dose of 3 mg/kg.&#xD;
Ipilimumab: Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>No participants were enrolled in the Neoadjuvant Immunotherapy group.</population>
      <group_list>
        <group group_id="B1">
          <title>Standard of Care (no Neoadjuvant Immunotherapy)</title>
          <description>Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.</description>
        </group>
        <group group_id="B2">
          <title>Neoadjuvant Immunotherapy</title>
          <description>Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.&#xD;
Nivolumab: Nivolumab will be given at the FDA-approved dose of 3 mg/kg.&#xD;
Ipilimumab: Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.</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="1"/>
            <count group_id="B2" value="0"/>
            <count group_id="B3" value="1"/>
          </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="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</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>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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Proportion of Patients Who Have Their Surgery Delayed by More Than 4 Days or Surgery Never Occurs as a Direct or Indirect Result of Ipilimumab and Nivolumab Treatment.</title>
        <time_frame>10 days</time_frame>
        <population>Outcome measure only applies to Neoadjuvant Immunotherapy; no participants were enrolled in the Neoadjuvant Immunotherapy group.</population>
        <group_list>
          <group group_id="O1">
            <title>Standard of Care (no Neoadjuvant Immunotherapy)</title>
            <description>Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.</description>
          </group>
          <group group_id="O2">
            <title>Neoadjuvant Immunotherapy</title>
            <description>Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.&#xD;
Nivolumab: Nivolumab will be given at the FDA-approved dose of 3 mg/kg.&#xD;
Ipilimumab: Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Patients Who Have Their Surgery Delayed by More Than 4 Days or Surgery Never Occurs as a Direct or Indirect Result of Ipilimumab and Nivolumab Treatment.</title>
          <population>Outcome measure only applies to Neoadjuvant Immunotherapy; no participants were enrolled in the Neoadjuvant Immunotherapy group.</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>
        <type>Primary</type>
        <title>Proliferation of Circulating T-cells as Measured by Mean Fold-change Between Baseline and Day 1 in Ki67 Levels.</title>
        <description>Ki-67 is a nuclear protein involved in cell proliferation regulation.</description>
        <time_frame>baseline to day 1</time_frame>
        <population>Outcome measure only applies to Neoadjuvant Immunotherapy; no participants were enrolled in the Neoadjuvant Immunotherapy group.</population>
        <group_list>
          <group group_id="O1">
            <title>Standard of Care (no Neoadjuvant Immunotherapy)</title>
            <description>Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.</description>
          </group>
          <group group_id="O2">
            <title>Neoadjuvant Immunotherapy</title>
            <description>Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.&#xD;
Nivolumab: Nivolumab will be given at the FDA-approved dose of 3 mg/kg.&#xD;
Ipilimumab: Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Proliferation of Circulating T-cells as Measured by Mean Fold-change Between Baseline and Day 1 in Ki67 Levels.</title>
          <description>Ki-67 is a nuclear protein involved in cell proliferation regulation.</description>
          <population>Outcome measure only applies to Neoadjuvant Immunotherapy; no participants were enrolled in the Neoadjuvant Immunotherapy group.</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>
      <time_frame>Approximately 10 days</time_frame>
      <desc>No participants were enrolled in the Neoadjuvant Immunotherapy group.</desc>
      <group_list>
        <group group_id="E1">
          <title>Standard of Care (no Neoadjuvant Immunotherapy)</title>
          <description>Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.</description>
        </group>
        <group group_id="E2">
          <title>Neoadjuvant Immunotherapy</title>
          <description>Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.&#xD;
Nivolumab: Nivolumab will be given at the FDA-approved dose of 3 mg/kg.&#xD;
Ipilimumab: Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Pyramidal tract syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Concentration impairment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Pyramidal tract syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </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>Sarah Sammons, MD</name_or_title>
      <organization>Duke University</organization>
      <phone>919-684-4563</phone>
      <email>sarah.sammons@duke.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/NCT04434560
org study id: Pro00103812
secondary id: CA184-583
nct id: NCT04434560
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this phase 2 study is to assess the feasibility and efficacy of neoadjuvant
      immunotherapy in patients with previously untreated, surgically-resectable, solid tumor brain
      metastases. The primary objectives of this study are to 1) assess the feasibility of
      neoadjuvant ipilimumab and nivolumab treatment before surgery and stereotactic radiosurgery
      (SRS) in patients with solid tumor brain metastases as measured by the proportion of patients
      who have their surgery delayed or surgery never occurs, and 2) demonstrate that neoadjuvant
      immunotherapy will increase proliferation of circulating T-cells compared to baseline
      measurements. Exploratory objectives include describing patient progression free survival and
      overall survival, time to local and distant intracranial progression, and the rate of
      radiation necrosis. The rate of radionecrosis will also be explored, as immune expression
      profiles.
Forty patients planned for standard of care resection of at least one solid tumor brain
      metastasis will be enrolled onto the study after providing informed consent. Primary tumor
      histology types are restricted to those known to extracranially respond to immunotherapy, and
      will include, but not be limited to, squamous non-small cell lung cancer (NSCLC),
      non-squamous NSCLC without known anaplastic lymphoma kinase (ALK), epidermal growth factor
      receptor (EGFR), and ROS mutation, renal cell carcinoma (RCC), melanoma, and triple negative
      breast cancer (TNBC) that is programmed death-ligand 1 positive (PD-L1 +). All participants
      will receive neoadjuvant immunotherapy and will receive a single infusion of nivolumab at a
      dose of 3 mg/kg and ipilimumab at a dose of 1 mg/kg 7 days (±3 days) prior to surgical
      resection of their metastases. Approximately three weeks after resection, patients in will
      then receive SRS per standard of care guidelines. Patients will be followed for 18 months
      after initiating study treatment. Up to 20 participants will be recruited and treated. Blood
      will be collected periodically during the study for correlative assessments.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of Patients Who Have Their Surgery Delayed by More Than 4 Days or Surgery Never Occurs as a Direct or Indirect Result of Ipilimumab and Nivolumab Treatment.
time frame: 10 days
measure: Proliferation of Circulating T-cells as Measured by Mean Fold-change Between Baseline and Day 1 in Ki67 Levels.
time frame: baseline to day 1
description: Ki-67 is a nuclear protein involved in cell proliferation regulation.
arm group label: Standard of Care (no neoadjuvant immunotherapy)
arm group type: No Intervention
description: Patients will proceed to surgical resection with no nivolumab/ipilimumab given prior to surgery.
arm group label: Neoadjuvant Immunotherapy
arm group type: Experimental
description: Patients will receive a single dose of neoadjuvant nivolumab and ipilimumab 7 days (± 3 days) prior to surgical resection.
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab will be given at the FDA-approved dose of 3 mg/kg.
arm group label: Neoadjuvant Immunotherapy
other name: Opdivo
intervention type: Drug
intervention name: Ipilimumab
description: Ipilimumab will be given at the FDA-approved dose of 1 mg/kg.
arm group label: Neoadjuvant Immunotherapy
other name: Yervoy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sarah Sammons, MD
role: Principal Investigator
affiliation: Duke University
facility: 
country: United States
url: http://tischbraintumorcenter.duke.edu/
description: The Preston Robert Tisch Brain Tumor Center
url: http://www.dukehealth.org/clinical-trials
description: Duke Health
responsible party type: Sponsor-Investigator
investigator affiliation: Duke University
investigator full name: Sarah Sammons, MD
investigator title: Assistant Professor of Medicine
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 