<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/NCT03789110</url>
  </required_header>
  <id_info>
    <org_study_id>18-561</org_study_id>
    <nct_id>NCT03789110</nct_id>
  </id_info>
  <brief_title>NIMBUS: Nivolumab Plus Ipilimumab in Metastatic Hypermutated HER2-negative Breast Cancer</brief_title>
  <official_title>NIMBUS: A Phase II Study of Nivolumab Plus Ipilimumab in Metastatic Hypermutated HER2-negative Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is studying a drug combination of nivolumab and ipilimumab as a possible&#xD;
      treatment for hypermutated HER2 negative breast cancer.&#xD;
&#xD;
      The drugs involved in this study are:&#xD;
&#xD;
        -  Nivolumab (Opdivo ®)&#xD;
&#xD;
        -  Ipilimumab (Yervoy ®)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Phase II clinical trial. Phase II clinical trials test the safety&#xD;
      and effectiveness of an investigational drug to learn whether the drug works in treating a&#xD;
      specific disease. &quot;Investigational&quot; means that the drug is being studied.&#xD;
&#xD;
      Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of&#xD;
      human protein) designed to allow the body's own immune system to destroy tumors. Ipilimumab&#xD;
      is called an anti-CTLA-4 and is a type of antibody that works to prevent your body's immune&#xD;
      system from stopping to fight this specific cancer.&#xD;
&#xD;
      The U.S. Food and Drug Administration (FDA) has not approved nivolumab for this specific&#xD;
      disease but it has been approved for other uses including but not limited to non-small cell&#xD;
      lung cancer, melanoma and renal cell carcinoma.&#xD;
&#xD;
      The U.S. Food and Drug Administration (FDA) has not approved ipilimumab for this specific&#xD;
      disease but it has been approved for other uses such as melanoma and renal cell carcinoma.&#xD;
&#xD;
      The combination of nivolumab with ipilimumab may or may not increase anti-cancer activity by&#xD;
      further boosting the immune system. At this time, the FDA has not approved nivolumab in&#xD;
      combination with ipilimumab for this specific disease although these drugs have been approved&#xD;
      for other uses such as melanoma and renal cell carcinoma.&#xD;
&#xD;
      The purpose of this research study is to determine how nivolumab together with ipilimumab,&#xD;
      works in treating breast cancer that has spread to other parts of the body. The investigators&#xD;
      are also investigating whether there are certain DNA or protein markers in the blood or tumor&#xD;
      tissue that may indicate whether the combination will work in future patients&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 8, 2019</start_date>
  <completion_date type="Anticipated">October 19, 2023</completion_date>
  <primary_completion_date type="Actual">September 30, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Response Rate of Nivolumab in Combination With Ipilimumab</measure>
    <time_frame>2 years</time_frame>
    <description>Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate of the Combination According to Immune-related Response Criteria</measure>
    <time_frame>2 years</time_frame>
    <description>Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by immune-related response criteria (irRC).&#xD;
Per irRC: irComplete Response (irCR): Complete disappearance of all tumor lesions (target an non-target) together with no new measurable/unmeasurable lesions for at least 4 weeks from the date of documentation of complete response.&#xD;
Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular diameters of all target lesions is measured and captured as the SPD baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular diameters of all target lesions and of new measurable lesions are added together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline, of the irSPD compared to the previously SPD baseline of 50% or greater is considered an irPR.; Overall Response (OR) = irCR + irPR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate</measure>
    <time_frame>2 Years</time_frame>
    <description>Clinical Benefit Rate (CBR) will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 24 weeks, per RECIST 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>2 years</time_frame>
    <description>Progression free survival is defined from the study entry to first documented evidence of disease progression by RECIST 1.1 or death of any cause, whichever occurs first. Patients alive with no progression are censored at the last disease assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Participants were followed long-term for survival every 12 weeks from the end of treatment until death or lost to follow-up. Median follow-up in this study cohort was 9.7 months.</time_frame>
    <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Nivolumab+Ipilimumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors</description>
    <arm_group_label>Nivolumab+Ipilimumab</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
    <arm_group_label>Nivolumab+Ipilimumab</arm_group_label>
    <other_name>Yervoy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must have histologically or cytologically confirmed invasive breast&#xD;
             cancer, with metastatic disease. Participants without pathologic or cytologic&#xD;
             confirmation of metastatic disease should have unequivocal evidence of metastasis from&#xD;
             physical examination or radiologic evaluation.&#xD;
&#xD;
          -  Breast cancer must be HER2-negative by IHC or non-amplified as determined by the&#xD;
             current ASCO-CAP criteria. If patient has more than one histological result, the most&#xD;
             recent one will be usedfor inclusion. Participants may be ER/PR positive or negative.&#xD;
&#xD;
          -  Patients must harbor tumors with total mutational burden (TMB) of at least 9 mutations&#xD;
             per megabase assessed by a cancer-gene panel containing more than 300 genes, and&#xD;
             performed in a CLIA verified laboratory. Tests like Foundation One, Oncopanel (DFCI),&#xD;
             or IMPACT (MSKCC) are acceptable for including patients on this trial.&#xD;
&#xD;
          -  Participants must have measurable disease by RECIST version 1.1.&#xD;
&#xD;
          -  Participants must agree to undergo a research biopsy, if tumor is safely accessible,&#xD;
             at baseline and at day 29 cycle 1 (+14 scheduling window). Previously collected&#xD;
             archival tissue will be obtained on all participants. Participants for whom&#xD;
             newly-obtained samples cannot be provided (e.g. inaccessible or participant safety&#xD;
             concern) may submit an archived specimen (block or if not possible, 20 unstained&#xD;
             slides).&#xD;
&#xD;
          -  Prior chemotherapy: Participants may have received 0-3 prior chemotherapeutic regimens&#xD;
             for metastatic breast cancer and must have been off treatment with chemotherapy for at&#xD;
             least 14 days prior to study treatment initiation.&#xD;
&#xD;
          -  Patients with hormone receptor positive breast cancer must have progressed on at least&#xD;
             one prior line of endocrine therapy in the metastatic setting or have disease&#xD;
             recurrence while on adjuvant endocrine therapy.&#xD;
&#xD;
          -  Participants should also be adequately recovered from acute toxicities of prior&#xD;
             treatment, with the exception of alopecia and peripheral sensory neuropathy.&#xD;
&#xD;
          -  Prior biologic therapy: Patients must have discontinued all biologic therapy at least&#xD;
             14 days prior to study treatment initiation.&#xD;
&#xD;
          -  Prior radiation therapy: Patients may have received prior radiation therapy in either&#xD;
             the metastatic or early-stage setting. Radiation therapy must be completed 14 days&#xD;
             prior to study treatment initiation.&#xD;
&#xD;
          -  In all cases, there must be no ongoing complications from prior radiotherapy.&#xD;
&#xD;
          -  The subject is ≥18 years old.&#xD;
&#xD;
          -  ECOG performance status ≤1(Karnofsky ≥70%, see Appendix A).&#xD;
&#xD;
          -  Participants must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  absolute neutrophil count ≥1,000/mcL&#xD;
&#xD;
               -  platelets ≥100,000/mcL&#xD;
&#xD;
               -  hemoglobin ≥ 8 g/dl&#xD;
&#xD;
               -  total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤ 2.0 x ULN&#xD;
                  in patients with documented Gilbert's Syndrome)&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or (≤ 3 × institutional ULN for&#xD;
                  participants with documented liver metastases)&#xD;
&#xD;
               -  creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 40 mL/min (using&#xD;
                  Cockcroft-Gault formula) for participants with creatinine levels above&#xD;
                  institutional ULN.&#xD;
&#xD;
          -  Female subjects of childbearing potential must have a negative pregnancy test (serum&#xD;
             or urine) at screening.&#xD;
&#xD;
          -  Childbearing potential is defined as: participants who have not reached a&#xD;
             postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause&#xD;
             other than menopause) and has not undergone surgical sterilization (removal of ovaries&#xD;
             and/or uterus).&#xD;
&#xD;
          -  Female and male participants of childbearing potential must agree to use an adequate&#xD;
             method of contraception. For women, contraception is required starting with the first&#xD;
             dose of study medication through 150 days (5 months) after the last dose of study&#xD;
             medication. For men who are sexuall active with women of childbearing potential,&#xD;
             contraception is required starting with the first dose of study medication for a&#xD;
             period of 7 months after the last dose of nivolumab. Examples of contraceptive methods&#xD;
             with a failure rate of &lt; 1% per year include bilateral tubal ligation, male&#xD;
             sterilization, established and proper use of hormonal contraceptives that inhibit&#xD;
             ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.&#xD;
             The reliability of sexual abstinence should be evaluated in relation to the duration&#xD;
             of the clinical trial and the preferred and usual lifestyle of the patient. Periodic&#xD;
             abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and&#xD;
             withdrawal are not acceptable methods of contraception.&#xD;
&#xD;
          -  Participants on bisphosphonates may continue receiving bisphosphonate therapy during&#xD;
             study treatment. Initiation of bisphosphonate or RANKL agent is allowed on study.&#xD;
&#xD;
          -  The participant is capable of understanding and complying with the protocol and has&#xD;
             signed the informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Major surgery within 2 weeks before the first dose of study treatment.&#xD;
&#xD;
          -  Concurrent administration of other anti-cancer therapy within 14 days of starting&#xD;
             protocol therapy and during the course of this study.&#xD;
&#xD;
          -  The participant has received another investigational agent within 14 days of the first&#xD;
             dose of study drug.&#xD;
&#xD;
          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or&#xD;
             anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody.&#xD;
&#xD;
          -  Known brain metastases that are untreated, symptomatic, or require therapy to control&#xD;
             symptoms. Participants with a history of treated central nervous system (CNS)&#xD;
             metastases are eligible. Treated brain metastases are defined as those having no&#xD;
             evidence of progression for ≥ 2 weeks after treatment, and no ongoing requirement for&#xD;
             corticosteroids, as ascertained by clinical examination and brain imaging (magnetic&#xD;
             resonance imaging or CT scan) completed during screening. Subject must be either off&#xD;
             corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily (or equivalent)&#xD;
             for at least 7 days prior to first study treatment. Treatment for brain metastases may&#xD;
             include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate&#xD;
             by the treating physician. Participants with CNS metastases treated by neurosurgical&#xD;
             resection or brain biopsy performed within 28 days before study treatment initiation&#xD;
             will be excluded.&#xD;
&#xD;
          -  The subject has uncontrolled, significant intercurrent or recent illness. Individuals&#xD;
             with a history of different malignancy are ineligible except for the following&#xD;
             circumstances. Individuals with a history of other malignancies are eligible if they&#xD;
             have been disease-free for at least 3 years or are deemed by the investigator to be at&#xD;
             low risk for recurrence of that malignancy.&#xD;
&#xD;
          -  Participant has an active infection requiring IV antibiotics at initiation of study&#xD;
             therapy.&#xD;
&#xD;
          -  Patient has a medical condition that requires chronic systemic steroid therapy or on&#xD;
             any other form of immunosuppressive medication. For example, participants with&#xD;
             autoimmune disease that requires systemic steroids or immunosuppression agents should&#xD;
             be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic&#xD;
             corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is&#xD;
             not considered a form of systemic treatment.&#xD;
&#xD;
          -  Subjects with current pneumonitis, or requiring supplementary O2 therapy.&#xD;
&#xD;
          -  The participant is known to be positive for human immunodeficiency virus (HIV),&#xD;
             HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy&#xD;
             are ineligible&#xD;
&#xD;
          -  Participants with any other active malignancy requiring concurrent intervention.&#xD;
&#xD;
          -  Known hypersensitivity to any of the components of ipilimumab or nivolumab.&#xD;
&#xD;
          -  The participant has received a live vaccine within 28 days prior to the first dose of&#xD;
             trial treatment and while participating in the trial. Examples of live vaccines&#xD;
             include, but are not limited to, the following: measles, mumps, rubella,&#xD;
             varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The use of the&#xD;
             inactivated seasonal influenza vaccine (Fluzone®) is allowed.&#xD;
&#xD;
          -  The participant is pregnant or breastfeeding.&#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>Sara Tolaney, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Medical Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>December 26, 2018</study_first_submitted>
  <study_first_submitted_qc>December 26, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 28, 2018</study_first_posted>
  <results_first_submitted>August 30, 2022</results_first_submitted>
  <results_first_submitted_qc>August 30, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">September 27, 2022</results_first_posted>
  <last_update_submitted>May 16, 2023</last_update_submitted>
  <last_update_submitted_qc>May 16, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Sara Tolaney, MD</investigator_full_name>
    <investigator_title>Primary Investigator</investigator_title>
  </responsible_party>
  <keyword>Breast Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast 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>Yes</sharing_ipd>
    <ipd_description>The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>Data can be shared no earlier than 1 year following the date of publication.</ipd_time_frame>
    <ipd_access_criteria>Requests may be directed to: [contact information for Sponsor- Investigator or designee]</ipd_access_criteria>
  </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>January 20, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/10/NCT03789110/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Nivolumab+Ipilimumab</title>
          <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks&#xD;
Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors&#xD;
Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>still on treatment</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Nivolumab+Ipilimumab</title>
          <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks&#xD;
Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors&#xD;
Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
          </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_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="63" lower_limit="36" upper_limit="72"/>
                  </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="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>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="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG Performance Status</title>
          <description>The ECOG (Eastern Cooperative Oncology Group) Scale of Performance Status describes a patient's level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working, etc.). This is a numbering scale of 0 to 5. The higher the number, the worse the performance status. Zero (0) refers to being full active. 5 is dead.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hormone Receptor (HR) Status</title>
          <description>HR+ is defined as ER (Estrogen receptors) positive, or PR (progesterone receptors) positive, or Her2 positive Triple negative is defined as ER negative, and PR negative, and Her2 negative</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>HR +</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Triple Negative</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior lines of chemotherapy in the advanced setting</title>
          <units>line</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.5" lower_limit="0" upper_limit="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>PD-L1 positive cells</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Positive</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Negative</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Missing sample</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Specimen not adequate for evaluation</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>TMB (mut/Mb)</title>
          <description>TMB: Tumor mutational burden</description>
          <units>mut/Mb</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10.9" lower_limit="9" upper_limit="110"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Overall Response Rate of Nivolumab in Combination With Ipilimumab</title>
        <description>Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
        <time_frame>2 years</time_frame>
        <population>The analysis population includes all patients who initiated protocol therapy</population>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab+Ipilimumab</title>
            <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks&#xD;
Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors&#xD;
Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate of Nivolumab in Combination With Ipilimumab</title>
          <description>Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
          <population>The analysis population includes all patients who initiated protocol therapy</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="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate of the Combination According to Immune-related Response Criteria</title>
        <description>Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by immune-related response criteria (irRC).&#xD;
Per irRC: irComplete Response (irCR): Complete disappearance of all tumor lesions (target an non-target) together with no new measurable/unmeasurable lesions for at least 4 weeks from the date of documentation of complete response.&#xD;
Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular diameters of all target lesions is measured and captured as the SPD baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular diameters of all target lesions and of new measurable lesions are added together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline, of the irSPD compared to the previously SPD baseline of 50% or greater is considered an irPR.; Overall Response (OR) = irCR + irPR.</description>
        <time_frame>2 years</time_frame>
        <population>all patients who initiated protocol therapy</population>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab+Ipilimumab</title>
            <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks&#xD;
Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors&#xD;
Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate of the Combination According to Immune-related Response Criteria</title>
          <description>Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by immune-related response criteria (irRC).&#xD;
Per irRC: irComplete Response (irCR): Complete disappearance of all tumor lesions (target an non-target) together with no new measurable/unmeasurable lesions for at least 4 weeks from the date of documentation of complete response.&#xD;
Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular diameters of all target lesions is measured and captured as the SPD baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular diameters of all target lesions and of new measurable lesions are added together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline, of the irSPD compared to the previously SPD baseline of 50% or greater is considered an irPR.; Overall Response (OR) = irCR + irPR.</description>
          <population>all patients who initiated protocol therapy</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="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate</title>
        <description>Clinical Benefit Rate (CBR) will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 24 weeks, per RECIST 1.1</description>
        <time_frame>2 Years</time_frame>
        <population>analysis population includes all patients who initiated protocol therapy</population>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab+Ipilimumab</title>
            <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks&#xD;
Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors&#xD;
Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Benefit Rate</title>
          <description>Clinical Benefit Rate (CBR) will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 24 weeks, per RECIST 1.1</description>
          <population>analysis population includes all patients who initiated protocol therapy</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="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival</title>
        <description>Progression free survival is defined from the study entry to first documented evidence of disease progression by RECIST 1.1 or death of any cause, whichever occurs first. Patients alive with no progression are censored at the last disease assessment.</description>
        <time_frame>2 years</time_frame>
        <population>all patients who initiated protocol therapy</population>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab+Ipilimumab</title>
            <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks&#xD;
Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors&#xD;
Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival</title>
          <description>Progression free survival is defined from the study entry to first documented evidence of disease progression by RECIST 1.1 or death of any cause, whichever occurs first. Patients alive with no progression are censored at the last disease assessment.</description>
          <population>all patients who initiated protocol therapy</population>
          <units>month</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.4" lower_limit="1.3" upper_limit="4.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
        <time_frame>Participants were followed long-term for survival every 12 weeks from the end of treatment until death or lost to follow-up. Median follow-up in this study cohort was 9.7 months.</time_frame>
        <population>All patients who initiated protocol therapy</population>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab+Ipilimumab</title>
            <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks&#xD;
Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors&#xD;
Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
          <population>All patients who initiated protocol therapy</population>
          <units>month</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.3" lower_limit="5.2" upper_limit="NA">Follow-up is not long enough/data is not mature to provide upper bound confidence interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AE data were collected every cycle from the time of the first dose of the study treatment, through the end of the treatment. Vital status was followed even after patients were off treatment. AEs, including overall mortality, were observed up to 30 months.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Nivolumab+Ipilimumab</title>
          <description>Ipilimumab is administered intravenously every 6 weeks&#xD;
Nivolumab is administered intravenously every 2 weeks&#xD;
Nivolumab: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors&#xD;
Ipilimumab: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (5.0)</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="13" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Myocarditis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eyelid function disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Cardiac troponin T increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Myasthenia gravis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (5.0)</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="24" subjects_at_risk="30"/>
              </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="3" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </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>Sara Tolaney</name_or_title>
      <organization>Dana-Farber Cancer Institute</organization>
      <phone>617-632-5743</phone>
      <email>Sara_Tolaney@dfci.harvard.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/NCT03789110
org study id: 18-561
nct id: NCT03789110
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a drug combination of nivolumab and ipilimumab as a possible
      treatment for hypermutated HER2 negative breast cancer.

      The drugs involved in this study are:

        -  Nivolumab (Opdivo ®)

        -  Ipilimumab (Yervoy ®)
This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug to learn whether the drug works in treating a
      specific disease. "Investigational" means that the drug is being studied.

      Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of
      human protein) designed to allow the body's own immune system to destroy tumors. Ipilimumab
      is called an anti-CTLA-4 and is a type of antibody that works to prevent your body's immune
      system from stopping to fight this specific cancer.

      The U.S. Food and Drug Administration (FDA) has not approved nivolumab for this specific
      disease but it has been approved for other uses including but not limited to non-small cell
      lung cancer, melanoma and renal cell carcinoma.

      The U.S. Food and Drug Administration (FDA) has not approved ipilimumab for this specific
      disease but it has been approved for other uses such as melanoma and renal cell carcinoma.

      The combination of nivolumab with ipilimumab may or may not increase anti-cancer activity by
      further boosting the immune system. At this time, the FDA has not approved nivolumab in
      combination with ipilimumab for this specific disease although these drugs have been approved
      for other uses such as melanoma and renal cell carcinoma.

      The purpose of this research study is to determine how nivolumab together with ipilimumab,
      works in treating breast cancer that has spread to other parts of the body. The investigators
      are also investigating whether there are certain DNA or protein markers in the blood or tumor
      tissue that may indicate whether the combination will work in future patients
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate of Nivolumab in Combination With Ipilimumab
time frame: 2 years
description: Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
measure: Overall Response Rate of the Combination According to Immune-related Response Criteria
time frame: 2 years
description: Overall Response Rate (ORR) is defined as the proportion of patients with complete or partial response evaluated by immune-related response criteria (irRC).
Per irRC: irComplete Response (irCR): Complete disappearance of all tumor lesions (target an non-target) together with no new measurable/unmeasurable lesions for at least 4 weeks from the date of documentation of complete response.
Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular diameters of all target lesions is measured and captured as the SPD baseline. At each subsequent tumor assessment, the SPD of the two largest perpendicular diameters of all target lesions and of new measurable lesions are added together to provide the Immune Response Sum of Product Diameters (irSPD). A decrease, relative to baseline, of the irSPD compared to the previously SPD baseline of 50% or greater is considered an irPR.; Overall Response (OR) = irCR + irPR.
measure: Clinical Benefit Rate
time frame: 2 Years
description: Clinical Benefit Rate (CBR) will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 24 weeks, per RECIST 1.1
measure: Progression Free Survival
time frame: 2 years
description: Progression free survival is defined from the study entry to first documented evidence of disease progression by RECIST 1.1 or death of any cause, whichever occurs first. Patients alive with no progression are censored at the last disease assessment.
measure: Overall Survival
time frame: Participants were followed long-term for survival every 12 weeks from the end of treatment until death or lost to follow-up. Median follow-up in this study cohort was 9.7 months.
description: OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
arm group label: Nivolumab+Ipilimumab
arm group type: Experimental
description: Ipilimumab is administered intravenously every 6 weeks
Nivolumab is administered intravenously every 2 weeks
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab is called an anti- PD-1 or a checkpoint inhibitor and is an antibody (a type of human protein) designed to allow the body's own immune system to destroy tumors
arm group label: Nivolumab+Ipilimumab
other name: Opdivo
intervention type: Drug
intervention name: Ipilimumab
description: Ipilimumab is called an anti-CTLA-4 and is a type of antibody that works to prevent the body's immune system from stopping to fight a specific cancer
arm group label: Nivolumab+Ipilimumab
other name: Yervoy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sara Tolaney, MD, MPH
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Sara Tolaney, MD
investigator title: Primary Investigator
mesh term: Breast Neoplasms
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: Yes
ipd description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: Data can be shared no earlier than 1 year following the date of publication.
ipd access criteria: Requests may be directed to: [contact information for Sponsor- Investigator or designee]
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 