<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/NCT03279692</url>
  </required_header>
  <id_info>
    <org_study_id>17-296</org_study_id>
    <nct_id>NCT03279692</nct_id>
  </id_info>
  <brief_title>Phase II Trial of Pembrolizumab in Recurrent or Residual High Grade Meningioma</brief_title>
  <official_title>Phase II Trial of Pembrolizumab in Recurrent or Residual High Grade Meningioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</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 as a possible treatment for High Grade Meningioma.&#xD;
&#xD;
      The drug involved in this study is an immunotherapy drug called pembrolizumab&#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;
      The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this&#xD;
      specific disease but it has been approved for other uses.&#xD;
&#xD;
      In this research study, the investigators are studying pembrolizumab in participants with&#xD;
      meningioma. Research studies have shown that meningioma tumor cells express a gene called&#xD;
      PD-L1. The investigators will be looking to determine whether the study drug may may stop&#xD;
      meningioma tumors from growing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 7, 2017</start_date>
  <completion_date type="Anticipated">March 2025</completion_date>
  <primary_completion_date type="Actual">September 18, 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>Progression-free Survival at 6 Months (PFS6)</measure>
    <time_frame>up to 6 months</time_frame>
    <description>Progression-free survival at 6 months is defined as not having disease progression per RANO (response assessment in neuro-oncology) criteria or death from any cause within six months of the first day of treatment with pembrolizumab.&#xD;
Contrast-enhanced cranial magnetic resonance imaging (MRI) was performed every 6 weeks to assess patient response to treatment. Progressive disease is defined per RANO criteria as the appearance of a new lesion, an increase in the size of a patient's existing lesions, or clear clinical worsening (seizures, medication side effects, complications of therapy, cerebrovascular events, infection, etc.)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 35 months</time_frame>
    <description>OS is defined as the time from protocol registration until death due to any cause. The follow-up of patients who were alive at the time of analysis was censored at the date of last assessment of vital status. 90% confidence intervals for median OS were estimated using log(-log(survival)) methodology.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) at 3 Months</measure>
    <time_frame>3 months</time_frame>
    <description>OS benchmarked at 3 months measures the percentage of participants who are still alive at 3 months, after study registration and receiving study therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>OS benchmarked at 6 months measures the percentage of participants who are still alive at 6 months, after study registration and receiving study therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Treatment-related Adverse Events</measure>
    <time_frame>Up to 26 months</time_frame>
    <description>All adverse events (AEs) recorded during the trial were summarized for all patients who received one or more doses of pembrolizumab. This outcome measure includes adverse events assessed as at least possibly related to study therapy and grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Intracranial Response</measure>
    <time_frame>Up to 25 months</time_frame>
    <description>Intracranial response is defined as complete response (CR), partial response (PR), or stable disease (SD) by RANO (response assessment for neuro-oncology) criteria. Intracranial response was assessed by contrast-enhanced cranial magnetic resonance imaging (MRI) every 6 weeks.&#xD;
CR: complete disappearance of all enhancing measurable and non-measurable disease sustained for 4+ weeks, no new lesions, stable/decreasing corticosteroids, and patient is stable and improved clinically. Participants with non-measurable disease cannot have a CR; the best possible response is SD.&#xD;
PR: greater than or equal to 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for 4+ weeks, no progression of non-measurable disease, no new lesions, stable/decreasing corticosteroids, and patient is stable or improved clinically.&#xD;
SD: does not qualify for CR, PR, or disease progression and patient is stable clinically.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>High Grade Meningioma</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
    <arm_group_label>Pembrolizumab</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        -Documentation Of Disease&#xD;
&#xD;
        --Histologic Documentation: Histologically proven recurrent or residual intracranial or&#xD;
        metastatic meningioma or meningioma with extracranial spread&#xD;
&#xD;
        Progressive OR residual disease, as defined by the following:&#xD;
&#xD;
          -  Progressive disease, as defined as an increase in size of the measurable primary&#xD;
             lesion on imaging by 25% or more (bidirectional area). The change must occur between&#xD;
             scans separated by no more than 24 months.&#xD;
&#xD;
          -  Residual measurable disease: For Grade II or III meningioma, residual measurable&#xD;
             disease immediately after surgery without requirement for progression. Residual&#xD;
             measurable disease will be defined by bidimensionally measurable lesions with clearly&#xD;
             defined margins by MRI scans, with a minimum diameter of 10mm in both dimensions.&#xD;
&#xD;
          -  Post radiation patients: Patients with measurable and progressive meningioma who have&#xD;
             received radiation are potentially eligible, but need to show evidence of progressive&#xD;
             disease in the radiated field after completion of radiation. At least 24 weeks must&#xD;
             have elapsed from completion of radiation to registration. Patients that have&#xD;
             progressive disease outside of the radiation field do not need to wait 24 weeks from&#xD;
             completion of radiation.&#xD;
&#xD;
               -  Measurable Disease: Measurable disease is defined by a bidimensionally measurable&#xD;
                  main lesion on MRI or CT images (MRI preferred) with clearly defined margins and&#xD;
                  ≥ 10 mm. Multifocal disease is allowed as long as one lesion meets criteria for&#xD;
                  measurable disease and progressive disease.&#xD;
&#xD;
        Prior Treatment&#xD;
&#xD;
          -  Prior medical therapy is allowed but not required.&#xD;
&#xD;
          -  Meningioma that have resulted from prior radiation therapy are allowed.&#xD;
&#xD;
          -  No limit on number of prior therapies.&#xD;
&#xD;
          -  No chemotherapy, other investigational agents within 14 days of study treatment.&#xD;
&#xD;
          -  No other concurrent investigational agents or other meningioma-directed therapy&#xD;
             (chemotherapy, radiation) while on study.&#xD;
&#xD;
          -  For patients treated with external beam radiation, interstitial brachytherapy or&#xD;
             radiosurgery, an interval &gt; 24 weeks must have elapsed from completion of XRT to&#xD;
             registration.&#xD;
&#xD;
          -  Stable dose of dexamethasone 2mg or less for 7 days prior to initiation of treatment&#xD;
&#xD;
          -  Recovered to CTCAE grade 1 or less toxicity from other agents with exception of&#xD;
             alopecia and fatigue.&#xD;
&#xD;
          -  No craniotomy within 28 days of registration.&#xD;
&#xD;
               -  Not pregnant and not nursing:&#xD;
&#xD;
               -  A female of childbearing potential is a sexually mature female who: 1) has not&#xD;
                  undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally&#xD;
                  postmenopausal for at least 12 consecutive months (i.e., has had menses at any&#xD;
                  time in the preceding 12 consecutive months). Female subject of childbearing&#xD;
                  potential should have a negative urine or serum pregnancy within 72 hours prior&#xD;
                  to receiving the first dose of study medication. If the urine test is positive or&#xD;
                  cannot be confirmed as negative, a serum pregnancy test will be required. Female&#xD;
                  subjects of childbearing potential should be willing to use 2 methods of birth&#xD;
                  control or be surgically sterile, or abstain from heterosexual activity for the&#xD;
                  course of the study through 120 days after the last dose of study medication.&#xD;
&#xD;
               -  Age ≥ 18 years&#xD;
&#xD;
               -  ECOG Performance Status &lt; 2&#xD;
&#xD;
               -  Patient history: Patients with history of NF may have other stable CNS tumors&#xD;
                  (schwannoma, acoustic neuroma or ependymoma) if lesions have been stable for 6&#xD;
                  months.&#xD;
&#xD;
               -  Metastatic meningiomas (as defined by extracranial meningiomas) and meningioma&#xD;
                  with extra-cranial spread are allowed.&#xD;
&#xD;
               -  Required Initial Laboratory Values&#xD;
&#xD;
               -  Participants must have normal organ and marrow function as defined in Table 1,&#xD;
                  all screening labs should be performed within 14 days of treatment initiation.&#xD;
&#xD;
               -  Required Initial Laboratory Values&#xD;
&#xD;
          -  System Laboratory Value&#xD;
&#xD;
          -  Hematological&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) ≥1,500 /mcL&#xD;
&#xD;
          -  Platelets ≥100,000 / mcL&#xD;
&#xD;
          -  Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days&#xD;
             of assessment)&#xD;
&#xD;
             -Renal&#xD;
&#xD;
          -  Serum creatinine OR&#xD;
&#xD;
          -  Measured or calculated creatinine clearance (GFR can also be used in place of&#xD;
             creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR&#xD;
&#xD;
             ≥60 mL/min for subject with creatinine levels &gt; 1.5 X institutional ULN&#xD;
&#xD;
          -  Hepatic&#xD;
&#xD;
          -  Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total&#xD;
             bilirubin levels &gt; 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN&#xD;
&#xD;
          -  Albumin &gt;2.5 mg/dL&#xD;
&#xD;
          -  Coagulation&#xD;
&#xD;
          -  International Normalized Ratio (INR) or Prothrombin Time (PT)&#xD;
&#xD;
          -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving&#xD;
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use&#xD;
             of anticoagulants&#xD;
&#xD;
             ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is&#xD;
             within therapeutic range of intended use of anticoagulants&#xD;
&#xD;
          -  Creatinine clearance should be calculated per institutional standard.&#xD;
&#xD;
               -  Male subjects should agree to use an adequate method of contraception starting&#xD;
                  with the first dose of study therapy through 120 days after the last dose of&#xD;
                  study therapy.&#xD;
&#xD;
               -  Ability to understand and the willingness to sign a written informed consent&#xD;
                  document.&#xD;
&#xD;
               -  Stable dose of dexamethasone 2mg or less for 7 days prior to initiation of&#xD;
                  treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants who have had chemotherapy, targeted small molecule therapy or study&#xD;
             therapy within 14 days of protocol treatment, or those who have not recovered (i.e., ≤&#xD;
             Grade 1 or at baseline) from adverse events due to agents administered more than 2&#xD;
             weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion&#xD;
             and may qualify for the study. If subject received major surgery, they must have&#xD;
             recovered adequately from the toxicity and/or complications from the intervention&#xD;
             prior to starting therapy.&#xD;
&#xD;
          -  Participants with brainstem lesions&#xD;
&#xD;
          -  Participants who are receiving any other investigational agents.&#xD;
&#xD;
          -  Participants who have a diagnosis of an immunodeficiency.&#xD;
&#xD;
          -  Requires treatment with high dose systemic corticosteroids defined as dexamethasone&#xD;
             &gt;2mg/day or bioequivalent within 7 days of initiating therapy.&#xD;
&#xD;
          -  Has received systemic immunosuppressive treatments, aside from systemic&#xD;
             corticosteroids as described in Section 5.7, within three months of start of study&#xD;
             drug&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or any of its excipients&#xD;
&#xD;
          -  Has a known history of active TB (Bacillus Tuberculosis)&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the pre-screening or screening visit&#xD;
             through 120 days after the last dose of trial treatment.&#xD;
&#xD;
          -  Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy or in situ cervical cancer or&#xD;
             stable NF-related neoplasms (Section 3.1.7).&#xD;
&#xD;
          -  Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment.&#xD;
&#xD;
          -  Has known history of, or any evidence of active, non-infectious pneumonitis.&#xD;
&#xD;
          -  Has an active infection requiring systemic therapy.&#xD;
&#xD;
          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.&#xD;
&#xD;
          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).&#xD;
             HIV-positive participants on combination antiretroviral therapy are ineligible because&#xD;
             of the potential for pharmacokinetic interactions with pembrolizumab. In addition,&#xD;
             these participants are at increased risk of lethal infections when treated with&#xD;
             marrow-suppressive therapy. Appropriate studies will be undertaken in participants&#xD;
             receiving combination antiretroviral therapy when indicated.&#xD;
&#xD;
          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA&#xD;
             [qualitative] is detected).&#xD;
&#xD;
          -  Has received a live vaccine within 30 days of planned start of study therapy. Note:&#xD;
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and&#xD;
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live&#xD;
             attenuated vaccines, and are not allowed.&#xD;
&#xD;
          -  Unable to undergo brain MRI.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Priscilla Brastianos, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02214</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>September 5, 2017</study_first_submitted>
  <study_first_submitted_qc>September 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <results_first_submitted>March 29, 2023</results_first_submitted>
  <results_first_submitted_qc>May 10, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">June 6, 2023</results_first_posted>
  <last_update_submitted>May 10, 2023</last_update_submitted>
  <last_update_submitted_qc>May 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Priscilla Brastianos</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Meningioma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Meningioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</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>January 20, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/92/NCT03279692/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 24, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/92/NCT03279692/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>One patient withdrew consent before receiving pembrolizumab and was excluded from efficacy and safety analyses.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Pembrolizumab</title>
          <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Pembrolizumab</title>
          <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="25"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="60.9" spread="16.5"/>
                  </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="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </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="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </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="0"/>
                  </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="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression-free Survival at 6 Months (PFS6)</title>
        <description>Progression-free survival at 6 months is defined as not having disease progression per RANO (response assessment in neuro-oncology) criteria or death from any cause within six months of the first day of treatment with pembrolizumab.&#xD;
Contrast-enhanced cranial magnetic resonance imaging (MRI) was performed every 6 weeks to assess patient response to treatment. Progressive disease is defined per RANO criteria as the appearance of a new lesion, an increase in the size of a patient's existing lesions, or clear clinical worsening (seizures, medication side effects, complications of therapy, cerebrovascular events, infection, etc.)</description>
        <time_frame>up to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival at 6 Months (PFS6)</title>
          <description>Progression-free survival at 6 months is defined as not having disease progression per RANO (response assessment in neuro-oncology) criteria or death from any cause within six months of the first day of treatment with pembrolizumab.&#xD;
Contrast-enhanced cranial magnetic resonance imaging (MRI) was performed every 6 weeks to assess patient response to treatment. Progressive disease is defined per RANO criteria as the appearance of a new lesion, an increase in the size of a patient's existing lesions, or clear clinical worsening (seizures, medication side effects, complications of therapy, cerebrovascular events, infection, etc.)</description>
          <units>percent of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48" lower_limit="31" upper_limit="66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>OS is defined as the time from protocol registration until death due to any cause. The follow-up of patients who were alive at the time of analysis was censored at the date of last assessment of vital status. 90% confidence intervals for median OS were estimated using log(-log(survival)) methodology.</description>
        <time_frame>Up to 35 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>OS is defined as the time from protocol registration until death due to any cause. The follow-up of patients who were alive at the time of analysis was censored at the date of last assessment of vital status. 90% confidence intervals for median OS were estimated using log(-log(survival)) methodology.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.2" lower_limit="14.8" upper_limit="25.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS) at 3 Months</title>
        <description>OS benchmarked at 3 months measures the percentage of participants who are still alive at 3 months, after study registration and receiving study therapy.</description>
        <time_frame>3 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS) at 3 Months</title>
          <description>OS benchmarked at 3 months measures the percentage of participants who are still alive at 3 months, after study registration and receiving study therapy.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="92" lower_limit="77" upper_limit="97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS) at 6 Months</title>
        <description>OS benchmarked at 6 months measures the percentage of participants who are still alive at 6 months, after study registration and receiving study therapy.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS) at 6 Months</title>
          <description>OS benchmarked at 6 months measures the percentage of participants who are still alive at 6 months, after study registration and receiving study therapy.</description>
          <units>percent of patients</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="84" lower_limit="67" upper_limit="93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Treatment-related Adverse Events</title>
        <description>All adverse events (AEs) recorded during the trial were summarized for all patients who received one or more doses of pembrolizumab. This outcome measure includes adverse events assessed as at least possibly related to study therapy and grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.</description>
        <time_frame>Up to 26 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Treatment-related Adverse Events</title>
          <description>All adverse events (AEs) recorded during the trial were summarized for all patients who received one or more doses of pembrolizumab. This outcome measure includes adverse events assessed as at least possibly related to study therapy and grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Intracranial Response</title>
        <description>Intracranial response is defined as complete response (CR), partial response (PR), or stable disease (SD) by RANO (response assessment for neuro-oncology) criteria. Intracranial response was assessed by contrast-enhanced cranial magnetic resonance imaging (MRI) every 6 weeks.&#xD;
CR: complete disappearance of all enhancing measurable and non-measurable disease sustained for 4+ weeks, no new lesions, stable/decreasing corticosteroids, and patient is stable and improved clinically. Participants with non-measurable disease cannot have a CR; the best possible response is SD.&#xD;
PR: greater than or equal to 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for 4+ weeks, no progression of non-measurable disease, no new lesions, stable/decreasing corticosteroids, and patient is stable or improved clinically.&#xD;
SD: does not qualify for CR, PR, or disease progression and patient is stable clinically.</description>
        <time_frame>Up to 25 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Intracranial Response</title>
          <description>Intracranial response is defined as complete response (CR), partial response (PR), or stable disease (SD) by RANO (response assessment for neuro-oncology) criteria. Intracranial response was assessed by contrast-enhanced cranial magnetic resonance imaging (MRI) every 6 weeks.&#xD;
CR: complete disappearance of all enhancing measurable and non-measurable disease sustained for 4+ weeks, no new lesions, stable/decreasing corticosteroids, and patient is stable and improved clinically. Participants with non-measurable disease cannot have a CR; the best possible response is SD.&#xD;
PR: greater than or equal to 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for 4+ weeks, no progression of non-measurable disease, no new lesions, stable/decreasing corticosteroids, and patient is stable or improved clinically.&#xD;
SD: does not qualify for CR, PR, or disease progression and patient is stable clinically.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>up to 3 years</time_frame>
      <desc>In addition to the clinicaltrials.gov seriousness criteria, the following seriousness criteria are added: (1) new cancer (that is not a condition of the study) and (2) associated with an overdose.</desc>
      <group_list>
        <group group_id="E1">
          <title>Pembrolizumab</title>
          <description>Pembrolizumab will be administered every 3 weeks&#xD;
Pembrolizumab will be administered through IV infusion&#xD;
Pembrolizumab: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells</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="15" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <description>Gallstone</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Skin infection</sub_title>
                <description>Cellulitis</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Lung Infection</sub_title>
                <description>Pneumonia</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Aspartate Aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized Muscle weakness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary Incontinence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other, specify</sub_title>
                <description>Chronic Obstructive Pulmonary Disease Exacerbation</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders - Other, specify</sub_title>
                <description>Basal Cell Carcinoma</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Surgical and medical procedures - Other, specify</sub_title>
                <description>Bifrontal Craniotomy</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </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="25" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="11" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other, specify</sub_title>
                <description>Intermittent Decreased Red Blood Cell Count</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other, specify</sub_title>
                <description>eGFR abnormality</description>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other, specify</sub_title>
                <description>bandemia</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenic purpura</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac disorders - Other, specify</sub_title>
                <description>Systolic Murmur</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Cardiac disorders - Other, specify</sub_title>
                <description>Left Ventricular Outflow Tract Obstruction</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Restrictive cardiomyopathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear Pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hearing impaired</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Adrenal Insufficiency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Eye disorders - Other, specify</sub_title>
                <description>Neurotropic ulcer left eye</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Eye disorders - Other, specify</sub_title>
                <description>Eye Discharge</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Papilledema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Esophagitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <description>Diverticulosis</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <description>Mouth Pain</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <description>Thrush</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Retroperitoneal hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="15" subjects_affected="12" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Ingrown toenail</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Postural Difficulty</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Left Arm Orbiting</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Left Pronator Drift</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Left Pointer Finger inflammation with Drainage</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Hypopituitarism</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Collapsed right nostril</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Upper Right Eyelid Lymphedema</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Right Brow Ptosis</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <description>Right forearm lesion</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatobiliary disorders - Other, specify</sub_title>
                <description>jaundice</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Enterocolitis infectious</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <description>Bilateral toe fungus</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <description>Herpes simplex virus vesicle</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <description>Elevated LDH</description>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Upper Respiratory Infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vaginal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="18" subjects_affected="10" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Spinal fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Aspartate Aminotransferase Increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Blood corticotrophin decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Cholesterol High</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Creatinine Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <description>Decreased free T4</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <description>Decreased free T3</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <description>Elevated Neutrophil Count</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <description>TSH elevated</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <description>Free T4 Elevated</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <description>Decreased TSH</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </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" events="7" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Muscle weakness left-sided</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Muscle weakness right-sided</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Muscle weakness upper limb</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>Cramping, left leg</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>Right ankle pain</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <description>Right calf swelling</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Neck edema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </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>
                <description>Adrenal Adenoma</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Ataxia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Cognitive Disturbance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Concentration Impairment</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Edema cerebral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Facial muscle weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Intracranial hemorrhage</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Numbness, face</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Hypertonicity (worsening)</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Aura</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Staring Spells</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Facial twitch</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Left Ptosis</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Myoclonus</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Right Hemiparesis</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <description>Dysmetria</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" events="10" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Spasticity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Psychiatric disorders - Other, specify</sub_title>
                <description>Panic Attack</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary Incontinence</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary urgency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Reproductive system and breast disorders - Other, specify</sub_title>
                <description>Vaginal lesion</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vaginal dryness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Scalp pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <description>Nail irritation</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <description>Scalp swelling</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <description>Atypical squamous proliferation</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <description>Benign Seborrheic Keratoses</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <description>Actinic keratoses</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <description>Verruca vulgaris</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <description>Scaly skin irritation</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Truncal rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vascular disorders - Other, specify</sub_title>
                <description>Atheroma</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </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>Priscilla Brastianos, MD</name_or_title>
      <organization>Massachusetts General Hospital</organization>
      <phone>617-724-8770</phone>
      <email>pbrastianos@partners.org</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/NCT03279692
org study id: 17-296
nct id: NCT03279692
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a drug as a possible treatment for High Grade Meningioma.

      The drug involved in this study is an immunotherapy drug called pembrolizumab
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.

      The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this
      specific disease but it has been approved for other uses.

      In this research study, the investigators are studying pembrolizumab in participants with
      meningioma. Research studies have shown that meningioma tumor cells express a gene called
      PD-L1. The investigators will be looking to determine whether the study drug may may stop
      meningioma tumors from growing.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free Survival at 6 Months (PFS6)
time frame: up to 6 months
description: Progression-free survival at 6 months is defined as not having disease progression per RANO (response assessment in neuro-oncology) criteria or death from any cause within six months of the first day of treatment with pembrolizumab.
Contrast-enhanced cranial magnetic resonance imaging (MRI) was performed every 6 weeks to assess patient response to treatment. Progressive disease is defined per RANO criteria as the appearance of a new lesion, an increase in the size of a patient's existing lesions, or clear clinical worsening (seizures, medication side effects, complications of therapy, cerebrovascular events, infection, etc.)
measure: Overall Survival (OS)
time frame: Up to 35 months
description: OS is defined as the time from protocol registration until death due to any cause. The follow-up of patients who were alive at the time of analysis was censored at the date of last assessment of vital status. 90% confidence intervals for median OS were estimated using log(-log(survival)) methodology.
measure: Overall Survival (OS) at 3 Months
time frame: 3 months
description: OS benchmarked at 3 months measures the percentage of participants who are still alive at 3 months, after study registration and receiving study therapy.
measure: Overall Survival (OS) at 6 Months
time frame: 6 months
description: OS benchmarked at 6 months measures the percentage of participants who are still alive at 6 months, after study registration and receiving study therapy.
measure: Percentage of Participants With Treatment-related Adverse Events
time frame: Up to 26 months
description: All adverse events (AEs) recorded during the trial were summarized for all patients who received one or more doses of pembrolizumab. This outcome measure includes adverse events assessed as at least possibly related to study therapy and grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.
measure: Number of Participants With Intracranial Response
time frame: Up to 25 months
description: Intracranial response is defined as complete response (CR), partial response (PR), or stable disease (SD) by RANO (response assessment for neuro-oncology) criteria. Intracranial response was assessed by contrast-enhanced cranial magnetic resonance imaging (MRI) every 6 weeks.
CR: complete disappearance of all enhancing measurable and non-measurable disease sustained for 4+ weeks, no new lesions, stable/decreasing corticosteroids, and patient is stable and improved clinically. Participants with non-measurable disease cannot have a CR; the best possible response is SD.
PR: greater than or equal to 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for 4+ weeks, no progression of non-measurable disease, no new lesions, stable/decreasing corticosteroids, and patient is stable or improved clinically.
SD: does not qualify for CR, PR, or disease progression and patient is stable clinically.
arm group label: Pembrolizumab
arm group type: Experimental
description: Pembrolizumab will be administered every 3 weeks
Pembrolizumab will be administered through IV infusion
intervention type: Drug
intervention name: Pembrolizumab
description: pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells
arm group label: Pembrolizumab
other name: Keytruda
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Priscilla Brastianos, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Priscilla Brastianos
investigator title: Principal Investigator
mesh term: Meningioma
mesh term: Pembrolizumab
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 