<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/NCT01675765</url>
  </required_header>
  <id_info>
    <org_study_id>ADU-CL-02</org_study_id>
    <nct_id>NCT01675765</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Listeria in Combination With Chemotherapy as Front-line Treatment for Malignant Pleural Mesothelioma</brief_title>
  <official_title>A Phase 1B Study to Evaluate the Safety and Induction of Immune Response of CRS-207 in Combination With Pemetrexed and Cisplatin as Front-line Therapy in Adults With Malignant Pleural Mesothelioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Aduro Biotech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Aduro Biotech, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical trial will evaluate the safety and immune response of the sequential&#xD;
      administration cancer vaccine CRS-207 (with or without cyclophosphamide) followed by standard&#xD;
      of care chemotherapy (pemetrexed and cisplatin). CRS-207 is a weakened (attenuated) form of&#xD;
      Listeria monocytogenes that has been genetically-modified to reduce its capacity to cause&#xD;
      disease, while maintaining its ability to stimulate potent immune responses. CRS-207 has been&#xD;
      engineered to elicit an immune response against the tumor-associated antigen mesothelin,&#xD;
      which has been shown to be present at higher levels on certain tumor cells (such as&#xD;
      mesothelioma) than on normal cells. Pemetrexed and cisplatin are the standard chemotherapy&#xD;
      regimen to treat malignant pleural mesothelioma. This trial will evaluate whether giving&#xD;
      CRS-207 cancer vaccine with chemotherapy will induce anti-tumor immune responses and/or&#xD;
      objective tumor response.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Up to 60 subjects will be enrolled in this study. Eligible subjects will receive 2 prime&#xD;
      vaccinations of CRS-207 (1×10^9 colony-forming units [CFU] given intravenously [i.v.] over 2&#xD;
      hours) (with or without cyclophosphamide) 2 weeks apart followed 2 weeks later by up to 6&#xD;
      cycles of pemetrexed and cisplatin 21 days apart. Three weeks after completion of&#xD;
      chemotherapy, subjects will receive an additional 2 infusions (boost vaccinations) of CRS-207&#xD;
      3 weeks apart. Subjects will be followed every 8 weeks until disease progression by&#xD;
      immune-related response criteria. Subjects who continue to meet dosing eligibility may&#xD;
      receive additional CRS-207 (with or without cyclophosphamide) infusions (maintenance&#xD;
      vaccinations) at each follow-up visit.&#xD;
&#xD;
      Study assessments include blood draws for safety and immune response monitoring and CT scans&#xD;
      [with optional fluorodeoxyglucose positron emission tomography (FDG-PET)] or magnetic&#xD;
      resonance imaging (MRI) to monitor disease status. In addition, optional tumor biopsies may&#xD;
      be performed before, during and after treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 3, 2014</start_date>
  <completion_date type="Actual">August 19, 2019</completion_date>
  <primary_completion_date type="Actual">September 5, 2018</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Subjects Reporting Adverse Events</measure>
    <time_frame>From first study dose until 28 days after the final dose (an average of 44 weeks)</time_frame>
    <description>Count of subjects with incidences of adverse events.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Induction of Immune Response to Mesothelin by Enzyme-linked Immunosorbent Spot (ELISPOT) Assay</measure>
    <time_frame>Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Tumor Response</measure>
    <time_frame>Baseline to measured disease progression or death (up to 12 months or longer)</time_frame>
    <description>Objective tumor response was measured using modified Response Evaluation Criteria in Solid Tumors (mRECIST) for assessment of response in malignant pleural mesothelioma (MPM). Per mRECIST for target lesions and assessed by CT: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Stable Disease, those who fulfilled the criteria for neither PR nor PD; Progressive Disease (PD), &gt;=20% increase in the sum of the longest diameter of target lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Progression</measure>
    <time_frame>From date of randomization until date of documented progression (by modified RECIST or immune-related response criteria) or death, assessed up to 12 months or longer</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Mesothelin as Correlate of Therapeutic Response</measure>
    <time_frame>Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Malignant Pleural Mesothelioma</condition>
  <arm_group>
    <arm_group_label>Immunotherapy plus chemotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Immunotherapy with cyclophosphamide plus chemotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Immunotherapy plus chemotherapy</intervention_name>
    <description>live attenuated double deleted Lm</description>
    <arm_group_label>Immunotherapy plus chemotherapy</arm_group_label>
    <other_name>CRS-207</other_name>
    <other_name>Listeria</other_name>
    <other_name>pemetrexed</other_name>
    <other_name>cisplatin</other_name>
    <other_name>ALIMTA</other_name>
    <other_name>Platinol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Immunotherapy with cyclophosphamide plus chemotherapy</intervention_name>
    <description>live attenuated double deleted Lm</description>
    <arm_group_label>Immunotherapy with cyclophosphamide plus chemotherapy</arm_group_label>
    <other_name>CRS-207</other_name>
    <other_name>Cytoxan</other_name>
    <other_name>pemetrexed</other_name>
    <other_name>cisplatin</other_name>
    <other_name>ALIMTA</other_name>
    <other_name>Platinol</other_name>
    <other_name>Listeria</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Have histologically confirmed epithelial or biphasic MPM not amenable to potentially&#xD;
             curative surgical resection (subjects with biphasic tumors that have a predominantly&#xD;
             (≥50%) sarcomatoid component will be excluded)&#xD;
&#xD;
          -  Be at least 18 years of age&#xD;
&#xD;
          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          -  Have an anticipated life expectancy of greater than 6 months&#xD;
&#xD;
          -  For women and men of childbearing potential, a medically acceptable method of highly&#xD;
             effective contraception (oral hormonal contraceptive, condom plus spermicide, or&#xD;
             hormone implants) must be used throughout the study period and for 28 days after their&#xD;
             final vaccine administration. (A barrier method of contraception must be employed by&#xD;
             all subjects [male and female], regardless of other methods.)&#xD;
&#xD;
          -  Be willing and able to give written informed consent, and be able to comply with all&#xD;
             study procedures&#xD;
&#xD;
          -  Have adequate organ function as defined by specified laboratory values&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A candidate for curative surgery&#xD;
&#xD;
          -  Surgery within 2 weeks prior to dosing&#xD;
&#xD;
          -  Prior radiotherapy or biologic therapy&#xD;
&#xD;
          -  Treatment with an investigational agent within 4 weeks before dosing&#xD;
&#xD;
          -  Prior systemic chemotherapy&#xD;
&#xD;
          -  Currently have or have history of certain study-specified heart, liver, kidney, lung,&#xD;
             neurological, immune or other medical conditions&#xD;
&#xD;
          -  Documented and ongoing brain metastases&#xD;
&#xD;
          -  Have any evidence of hepatic cirrhosis or clinical or radiographic ascites&#xD;
&#xD;
          -  Have clinically significant and/or malignant pleural effusion&#xD;
&#xD;
          -  Known or suspected allergy or hypersensitivity to yeast or any other component of&#xD;
             CRS-207 (e.g., glycerol), Platinol or platinum-containing compounds, or pemetrexed&#xD;
&#xD;
          -  Used any systemic steroids within 28 days of study treatment&#xD;
&#xD;
          -  Use more than 3 g/d of acetaminophen&#xD;
&#xD;
          -  An artificial (prosthetic) joint or other artificial implant or device that cannot be&#xD;
             easily removed (with some exceptions for dental and breast implants and biliary stents&#xD;
             and mediports)&#xD;
&#xD;
          -  Infection with HIV or hepatitis B or C at screening&#xD;
&#xD;
          -  Any immunodeficiency disease or immunocompromised state or active autoimmune disease&#xD;
             or history of autoimmune disease requiring systemic steroids or other&#xD;
             immunosuppressive treatment&#xD;
&#xD;
          -  Be a woman who is pregnant or breastfeeding&#xD;
&#xD;
          -  Unable to avoid close contact with another individual known to be at high risk of&#xD;
             listeriosis (e.g., newborn infant, pregnant woman, HIV-positive individual) during the&#xD;
             course of CRS-207 treatment until completion of antibiotic regimen&#xD;
&#xD;
          -  Conditions, including alcohol or drug dependence, intercurrent illness, or lack of&#xD;
             sufficient peripheral venous access, that would affect the patient's ability to comply&#xD;
             with study visits and procedures&#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>Raffit Hassan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California at San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>H. Lee Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Chicago Medical Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Cancer Institute</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania Abramson Cancer Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Le DT, Dubenksy TW Jr, Brockstedt DG. Clinical development of Listeria monocytogenes-based immunotherapies. Semin Oncol. 2012 Jun;39(3):311-22. doi: 10.1053/j.seminoncol.2012.02.008.</citation>
    <PMID>22595054</PMID>
  </reference>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>August 23, 2012</study_first_submitted>
  <study_first_submitted_qc>August 28, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 30, 2012</study_first_posted>
  <results_first_submitted>September 2, 2020</results_first_submitted>
  <results_first_submitted_qc>September 28, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">September 30, 2020</results_first_posted>
  <last_update_submitted>September 28, 2020</last_update_submitted>
  <last_update_submitted_qc>September 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cancer</keyword>
  <keyword>Cancer vaccine</keyword>
  <keyword>Listeria monocytogenes</keyword>
  <keyword>Listeria-based vaccines</keyword>
  <keyword>Pemetrexed</keyword>
  <keyword>Cisplatin</keyword>
  <keyword>T regulatory cells</keyword>
  <keyword>Mesothelin</keyword>
  <keyword>Malignant Pleural Mesothelioma</keyword>
  <keyword>Chemotherapy</keyword>
  <keyword>Standard of care</keyword>
  <keyword>Naive</keyword>
  <keyword>Front-line</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>MPM</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mesothelioma</mesh_term>
    <mesh_term>Mesothelioma, Malignant</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclophosphamide</mesh_term>
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Pemetrexed</mesh_term>
    <mesh_term>Immunologic Factors</mesh_term>
    <mesh_term>Immunomodulating Agents</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 8, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/65/NCT01675765/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 4, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/65/NCT01675765/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Immunotherapy Plus Chemotherapy</title>
          <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy plus chemotherapy: live attenuated double deleted Lm</description>
        </group>
        <group group_id="P2">
          <title>Immunotherapy With Cyclophosphamide Plus Chemotherapy</title>
          <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="38"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="27"/>
                <participants group_id="P2" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Progressive disease</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Clinical progression</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Immunotherapy Plus Chemotherapy</title>
          <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy plus chemotherapy: live attenuated double deleted Lm</description>
        </group>
        <group group_id="B2">
          <title>Immunotherapy With Cyclophosphamide Plus Chemotherapy</title>
          <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="38"/>
            <count group_id="B2" value="22"/>
            <count group_id="B3" value="60"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>&lt;65 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>&gt;=65 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="45"/>
                  </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="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="51"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="37"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="59"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="81.63" spread="16.203"/>
                    <measurement group_id="B2" value="73.83" spread="12.340"/>
                    <measurement group_id="B3" value="78.77" spread="15.271"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>cm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="174.51" spread="8.295"/>
                    <measurement group_id="B2" value="168.41" spread="7.102"/>
                    <measurement group_id="B3" value="172.28" spread="8.359"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26.702" spread="4.3292"/>
                    <measurement group_id="B2" value="26.076" spread="4.4584"/>
                    <measurement group_id="B3" value="26.473" spread="4.3498"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Surface Area</title>
          <units>m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.982" spread="0.2230"/>
                    <measurement group_id="B2" value="1.852" spread="0.1756"/>
                    <measurement group_id="B3" value="1.935" spread="0.2148"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Subjects Reporting Adverse Events</title>
        <description>Count of subjects with incidences of adverse events.</description>
        <time_frame>From first study dose until 28 days after the final dose (an average of 44 weeks)</time_frame>
        <population>Safety Analysis Set (all participants who received &gt;= 1 dose of study treatment)</population>
        <group_list>
          <group group_id="O1">
            <title>Immunotherapy Plus Chemotherapy</title>
            <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
          <group group_id="O2">
            <title>Immunotherapy With Cyclophosphamide Plus Chemotherapy</title>
            <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects Reporting Adverse Events</title>
          <description>Count of subjects with incidences of adverse events.</description>
          <population>Safety Analysis Set (all participants who received &gt;= 1 dose of study treatment)</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38"/>
                    <measurement group_id="O2" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Induction of Immune Response to Mesothelin by Enzyme-linked Immunosorbent Spot (ELISPOT) Assay</title>
        <time_frame>Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)</time_frame>
        <population>Immune response to mesothelin was not assessed.</population>
        <group_list>
          <group group_id="O1">
            <title>Immunotherapy Plus Chemotherapy</title>
            <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
          <group group_id="O2">
            <title>Immunotherapy With Cyclophosphamide Plus Chemotherapy</title>
            <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
        </group_list>
        <measure>
          <title>Induction of Immune Response to Mesothelin by Enzyme-linked Immunosorbent Spot (ELISPOT) Assay</title>
          <population>Immune response to mesothelin was not assessed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Tumor Response</title>
        <description>Objective tumor response was measured using modified Response Evaluation Criteria in Solid Tumors (mRECIST) for assessment of response in malignant pleural mesothelioma (MPM). Per mRECIST for target lesions and assessed by CT: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Stable Disease, those who fulfilled the criteria for neither PR nor PD; Progressive Disease (PD), &gt;=20% increase in the sum of the longest diameter of target lesions.</description>
        <time_frame>Baseline to measured disease progression or death (up to 12 months or longer)</time_frame>
        <population>Safety analysis set: all enrolled subjects who received at least one dose of study treatment and had measurable disease.</population>
        <group_list>
          <group group_id="O1">
            <title>Immunotherapy Plus Chemotherapy</title>
            <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
          <group group_id="O2">
            <title>Immunotherapy With Cyclophosphamide Plus Chemotherapy</title>
            <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Tumor Response</title>
          <description>Objective tumor response was measured using modified Response Evaluation Criteria in Solid Tumors (mRECIST) for assessment of response in malignant pleural mesothelioma (MPM). Per mRECIST for target lesions and assessed by CT: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Stable Disease, those who fulfilled the criteria for neither PR nor PD; Progressive Disease (PD), &gt;=20% increase in the sum of the longest diameter of target lesions.</description>
          <population>Safety analysis set: all enrolled subjects who received at least one dose of study treatment and had measurable disease.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="36"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Assessable</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Progression</title>
        <time_frame>From date of randomization until date of documented progression (by modified RECIST or immune-related response criteria) or death, assessed up to 12 months or longer</time_frame>
        <population>Time to progression was not assessed.</population>
        <group_list>
          <group group_id="O1">
            <title>Immunotherapy Plus Chemotherapy</title>
            <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
          <group group_id="O2">
            <title>Immunotherapy With Cyclophosphamide Plus Chemotherapy</title>
            <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Progression</title>
          <population>Time to progression was not assessed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Serum Mesothelin as Correlate of Therapeutic Response</title>
        <time_frame>Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)</time_frame>
        <population>Predictive value of serum mesothelin was not assessed.</population>
        <group_list>
          <group group_id="O1">
            <title>Immunotherapy Plus Chemotherapy</title>
            <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
          <group group_id="O2">
            <title>Immunotherapy With Cyclophosphamide Plus Chemotherapy</title>
            <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm</description>
          </group>
        </group_list>
        <measure>
          <title>Serum Mesothelin as Correlate of Therapeutic Response</title>
          <population>Predictive value of serum mesothelin was not assessed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the start of the first study drug administration until 28 days after the last study drug dose, assessed up to 5 years from the date of randomization.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Immunotherapy Plus Chemotherapy</title>
          <description>Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: CRS-207&#xD;
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy plus chemotherapy: live attenuated double deleted Lm</description>
        </group>
        <group group_id="E2">
          <title>Immunotherapy With Cyclophosphamide Plus Chemotherapy</title>
          <description>Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)&#xD;
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)&#xD;
Weeks 23 and 26: cyclophosphamide one day before CRS-207&#xD;
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression&#xD;
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (15.0)</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="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Diverticular perforation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Gastric ulcer haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Large intestine perforation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pancreatitis acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Small intestinal obstruction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Polyarthritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Spinal cord neoplasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Haemothorax</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pleuritic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (15.0)</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="38" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Leukocytosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Lacrimation increased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="37" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="37" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Oedema</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Mucosal inflammation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Haemoglobin decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Blood urea increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Weight increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Blood albumin decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Haematocrit decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypophosphataemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal impairment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dyspnoea exertional</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dysphonia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Tachypnoea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Throat irritation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Night sweats</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Jugular vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Disclosure restriction - study results first published in a joint multi-center paper unless (a) no multi-center publication, or (b) ≥18 months has passed since completion of the study. Thereafter, Investigator may publish provided that Investigator: (i) provides a copy of the publication to Aduro ≥ 30 days in advance of submission for publication; (ii) deletes Aduro Confidential Information (other than the Study results) and (iii) submission may be delayed up to 90 days to permit IP filings.&quot;</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Corporate Communications</name_or_title>
      <organization>Aduro Biotech, Inc.</organization>
      <phone>510-848-4400</phone>
      <email>press@aduro.com</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/NCT01675765
org study id: ADU-CL-02
nct id: NCT01675765
lead sponsor: 
has dmc: No
This clinical trial will evaluate the safety and immune response of the sequential
      administration cancer vaccine CRS-207 (with or without cyclophosphamide) followed by standard
      of care chemotherapy (pemetrexed and cisplatin). CRS-207 is a weakened (attenuated) form of
      Listeria monocytogenes that has been genetically-modified to reduce its capacity to cause
      disease, while maintaining its ability to stimulate potent immune responses. CRS-207 has been
      engineered to elicit an immune response against the tumor-associated antigen mesothelin,
      which has been shown to be present at higher levels on certain tumor cells (such as
      mesothelioma) than on normal cells. Pemetrexed and cisplatin are the standard chemotherapy
      regimen to treat malignant pleural mesothelioma. This trial will evaluate whether giving
      CRS-207 cancer vaccine with chemotherapy will induce anti-tumor immune responses and/or
      objective tumor response.
Up to 60 subjects will be enrolled in this study. Eligible subjects will receive 2 prime
      vaccinations of CRS-207 (1×10^9 colony-forming units [CFU] given intravenously [i.v.] over 2
      hours) (with or without cyclophosphamide) 2 weeks apart followed 2 weeks later by up to 6
      cycles of pemetrexed and cisplatin 21 days apart. Three weeks after completion of
      chemotherapy, subjects will receive an additional 2 infusions (boost vaccinations) of CRS-207
      3 weeks apart. Subjects will be followed every 8 weeks until disease progression by
      immune-related response criteria. Subjects who continue to meet dosing eligibility may
      receive additional CRS-207 (with or without cyclophosphamide) infusions (maintenance
      vaccinations) at each follow-up visit.

      Study assessments include blood draws for safety and immune response monitoring and CT scans
      [with optional fluorodeoxyglucose positron emission tomography (FDG-PET)] or magnetic
      resonance imaging (MRI) to monitor disease status. In addition, optional tumor biopsies may
      be performed before, during and after treatment.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Subjects Reporting Adverse Events
time frame: From first study dose until 28 days after the final dose (an average of 44 weeks)
description: Count of subjects with incidences of adverse events.
measure: Induction of Immune Response to Mesothelin by Enzyme-linked Immunosorbent Spot (ELISPOT) Assay
time frame: Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)
measure: Objective Tumor Response
time frame: Baseline to measured disease progression or death (up to 12 months or longer)
description: Objective tumor response was measured using modified Response Evaluation Criteria in Solid Tumors (mRECIST) for assessment of response in malignant pleural mesothelioma (MPM). Per mRECIST for target lesions and assessed by CT: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease, those who fulfilled the criteria for neither PR nor PD; Progressive Disease (PD), >=20% increase in the sum of the longest diameter of target lesions.
measure: Time to Progression
time frame: From date of randomization until date of documented progression (by modified RECIST or immune-related response criteria) or death, assessed up to 12 months or longer
measure: Serum Mesothelin as Correlate of Therapeutic Response
time frame: Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)
arm group label: Immunotherapy plus chemotherapy
arm group type: Experimental
description: Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)
Weeks 23 and 26: CRS-207
Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression
arm group label: Immunotherapy with cyclophosphamide plus chemotherapy
arm group type: Experimental
description: Weeks 1 and 3: cyclophosphamide (200 mg/m^2), CRS-207 (1 × 10^9 CFU)
Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m^2) and cisplatin (75 mg/m^2)
Weeks 23 and 26: cyclophosphamide one day before CRS-207
Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression
intervention type: Biological
intervention name: Immunotherapy plus chemotherapy
description: live attenuated double deleted Lm
arm group label: Immunotherapy plus chemotherapy
other name: CRS-207
other name: Listeria
other name: pemetrexed
other name: cisplatin
other name: ALIMTA
other name: Platinol
intervention type: Biological
intervention name: Immunotherapy with cyclophosphamide plus chemotherapy
description: live attenuated double deleted Lm
arm group label: Immunotherapy with cyclophosphamide plus chemotherapy
other name: CRS-207
other name: Cytoxan
other name: pemetrexed
other name: cisplatin
other name: ALIMTA
other name: Platinol
other name: Listeria
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Raffit Hassan, MD
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
citation: Le DT, Dubenksy TW Jr, Brockstedt DG. Clinical development of Listeria monocytogenes-based immunotherapies. Semin Oncol. 2012 Jun;39(3):311-22. doi: 10.1053/j.seminoncol.2012.02.008.
PMID: 22595054
responsible party type: Sponsor
mesh term: Mesothelioma
mesh term: Mesothelioma, Malignant
mesh term: Cyclophosphamide
mesh term: Cisplatin
mesh term: Pemetrexed
mesh term: Immunologic Factors
mesh term: Immunomodulating Agents
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 