<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/NCT02195011</url>
  </required_header>
  <id_info>
    <org_study_id>SCRI GI 189</org_study_id>
    <nct_id>NCT02195011</nct_id>
  </id_info>
  <brief_title>Safety Study of Regorafenib and SIR-Spheres® Microspheres Radioembolization in Patients With Refractory Metastatic Colorectal Cancer With Liver Metastases</brief_title>
  <official_title>A Two Arm Safety Study of Regorafenib Before or After SIR-Spheres Microspheres (90Y) for the Treatment of Patients With Refractory Metastatic Colorectal Cancer With Liver Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>SCRI Development Innovations, LLC</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sirtex Medical</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>SCRI Development Innovations, LLC</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the safety of regorafenib, an antiangiogenic drug,&#xD;
      when combined with radioembolization using SIR-Spheres® microspheres in the treatment of&#xD;
      colorectal cancer (CRC) that has spread to the liver.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Recent targeted therapies and treatment strategies have shown promise in colorectal cancer;&#xD;
      however, elimination of disease remains a challenge once spread to the liver.&#xD;
      Radioembolization using SIR-Spheres® microspheres (SIR-Spheres) to treat liver-only or&#xD;
      liver-dominant metastatic colorectal cancer (mCRC) has been successful in this refractory&#xD;
      setting. In this open-label study we will compare the safety of two treatment cohorts in&#xD;
      which radioembolization will be administered using the device SIR-Spheres microspheres (90Y&#xD;
      resin microspheres) in combination with regorafenib to patients with mCRC with liver&#xD;
      metastases. The two treatment cohorts will be evaluated for safety, overall response (OR),&#xD;
      progression-free survival (PFS), and overall survival (OS).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 2014</start_date>
  <completion_date type="Actual">June 4, 2017</completion_date>
  <primary_completion_date type="Actual">June 4, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The Number of Participants With Treatment-Related Adverse Events and Serious Adverse Events as a Measure of Safety</measure>
    <time_frame>up to 15 months</time_frame>
    <description>A treatment-related adverse event or serious adverse event was any untoward medical occurrence in a participant which was considered to have a relationship with the study drug (suspected to be possibly or probably related to the study drug per the Investigator's assessment). Adverse events and serious adverse events will be assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V4.03.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With an Objective Response (CR or PR)</measure>
    <time_frame>At 6 and 12 weeks after SIR-Spheres, and every 8 weeks thereafter, up to 18 months</time_frame>
    <description>Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST v 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease in of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Progression-Free Survival</measure>
    <time_frame>At 6 and 12 weeks after SIR-Spheres, and every 8 weeks thereafter, up to 18 months.</time_frame>
    <description>Defined as the time (in months) from date of randomization to the date of first observation of progression based on radiological assessment by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or date of death from any cause, in the absence of progressive disease (PD) or censored at the date of last adequate tumor assessment. Progressive Disease is defined by RECIST v1.1 as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum while on study (this includes the baseline sum if that is the smallest on study), or the appearance of one or more new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival</measure>
    <time_frame>up to 18 months</time_frame>
    <description>Defined as the time (in months) from date of randomization to date of death from any cause, or censored at the date last known alive.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Colorectal Neoplasms</condition>
  <arm_group>
    <arm_group_label>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Regorafenib (one cycle) followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.&#xD;
Patients will take regorafenib 160 mg orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres will then be administered to the patient by injection through a trans-femoral catheter into the hepatic artery. Treatment with regorafenib will be re-started 2-4 weeks after SIR-Spheres administration.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2: SIR-Spheres/Regorafenib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>SIR-Spheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.&#xD;
SIR-Spheres microspheres will be administered to the patient by injection through a trans-femoral catheter into the hepatic artery. After SIR-Spheres microspheres have been administered, the treatment with regorafenib will be initiated 2-4 weeks after administration of SIR-Spheres. Patients will take regorafenib 160 mg orally once daily on Days 1-21 of each 28-day treatment cycle.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>SIR-Spheres</intervention_name>
    <description>Radioembolization will be administered once by injection through a trans-femoral catheter into the hepatic artery.</description>
    <arm_group_label>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</arm_group_label>
    <arm_group_label>Cohort 2: SIR-Spheres/Regorafenib</arm_group_label>
    <other_name>90Y-Microspheres</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Regorafenib</intervention_name>
    <description>All patients will take regorafenib 160mg orally once daily on Days 1-21 of each 28-day cycle.</description>
    <arm_group_label>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</arm_group_label>
    <arm_group_label>Cohort 2: SIR-Spheres/Regorafenib</arm_group_label>
    <other_name>Stivarga</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically confirmed metastatic adenocarcinoma of the colon or rectum.&#xD;
&#xD;
          2. Patients who have been previously treated with or are not candidates for fluorouracil,&#xD;
             oxaliplatin, irinotecan, and if Kras wild-type, anti EGFR therapy.&#xD;
&#xD;
          3. Considered an appropriate candidate for regorafenib therapy.&#xD;
&#xD;
          4. Measurable disease or evaluable disease as measured by Response Evaluation Criteria in&#xD;
             Solid Tumors (RECIST) version 1.1.&#xD;
&#xD;
          5. Measurable computed tomography (CT) scan evidence of liver metastases which are not&#xD;
             treatable by surgical resection or local ablation with curative intent at the time of&#xD;
             study entry.&#xD;
&#xD;
          6. ECOG Performance Status score of 0-1.&#xD;
&#xD;
          7. Adequate hematologic, renal and liver function.&#xD;
&#xD;
          8. Male patients with female partners of childbearing potential and women female patients&#xD;
             of childbearing potential are required to use two forms of acceptable contraception,&#xD;
             including one barrier method, during their participation in the study and for 30 days&#xD;
             following last dose.&#xD;
&#xD;
          9. Life expectancy ≥ 3 months.&#xD;
&#xD;
         10. Ability to understand the nature of this study and give written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Most recent chemotherapy ≤14 days and ≥Grade 1 chemotherapy-related side effects, with&#xD;
             the exception of alopecia.&#xD;
&#xD;
          2. Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to&#xD;
             initiation of study treatment. For study drugs for which 5 half-lives is ≤21 days, a&#xD;
             minimum of 10 days between termination of the study drug and administration of study&#xD;
             treatment is required.&#xD;
&#xD;
          3. Wide field radiotherapy (including therapeutic radioisotopes such as strontium-89&#xD;
             administered ≤28 days or limited field radiation for palliation ≤7 days prior to&#xD;
             starting study drug or has not recovered from side effects of such therapy.&#xD;
&#xD;
          4. Previous radiation delivered to the upper abdomen.&#xD;
&#xD;
          5. Major surgical procedures ≤28 days of beginning study drug, or minor surgical&#xD;
             procedures ≤7 days. No waiting required following port-a-cath placement.&#xD;
&#xD;
          6. Previously untreated brain metastases. Patients who have received radiation or surgery&#xD;
             for brain metastases are eligible if therapy was completed at least 2 weeks previously&#xD;
             and there is no evidence of central nervous system disease progression, mild&#xD;
             neurologic symptoms, and no requirement for chronic corticosteroid therapy.&#xD;
&#xD;
          7. Leptomeningeal metastases or spinal cord compression due to disease.&#xD;
&#xD;
          8. Pregnant or lactating.&#xD;
&#xD;
          9. Evidence of ascites, cirrhosis, portal hypertension, or thrombosis as determined by&#xD;
             clinical or radiologic assessment.&#xD;
&#xD;
         10. History of abdominal fistula or gastrointestinal perforation ≤6 months prior to&#xD;
             beginning study treatment.&#xD;
&#xD;
         11. Serious non-healing wound, active ulcer, or untreated bone fracture.&#xD;
&#xD;
         12. Presence of active gastrointestinal disease or other condition that will interfere&#xD;
             significantly with the absorption, distribution, metabolism, or excretion of oral&#xD;
             therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2,&#xD;
             and malabsorption syndrome).&#xD;
&#xD;
         13. Any of the following cardiac diseases currently or within the last 6 months:&#xD;
&#xD;
               -  Unstable angina pectoris&#xD;
&#xD;
               -  Congestive heart failure (NYHA ≥ Grade 2)&#xD;
&#xD;
               -  Conduction abnormality not controlled with pacemaker or medication&#xD;
&#xD;
               -  Significant ventricular or supraventricular arrhythmias (patients with chronic&#xD;
                  rate-controlled atrial fibrillation in the absence of other cardiac abnormalities&#xD;
                  are eligible)&#xD;
&#xD;
               -  Valvular disease with significant compromise in cardiac function&#xD;
&#xD;
         14. Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] &gt;180 mmHg or&#xD;
             diastolic blood pressure (DBP) &gt;100 mmHg) (patients with values above these levels&#xD;
             must have their blood pressure (BP) controlled with medication prior to starting&#xD;
             treatment).&#xD;
&#xD;
         15. Serious active infection at the time of treatment, or another serious underlying&#xD;
             medical condition that would impair the ability of the patient to receive protocol&#xD;
             treatment.&#xD;
&#xD;
         16. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.&#xD;
&#xD;
         17. Presence of other active cancers, or history of treatment for invasive cancer ≤5&#xD;
             years. Patients with Stage I cancer who have received definitive local treatment and&#xD;
             are considered unlikely to recur are eligible. All patients with previously treated in&#xD;
             situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of&#xD;
             non-melanoma skin cancer.&#xD;
&#xD;
         18. Use of strong CYP34A inducers or inhibitors.&#xD;
&#xD;
         19. The herbal medications St. John's wort, kava, ephedra (ma huang), gingko biloba,&#xD;
             dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng will not be allowed&#xD;
             during study treatment. Patients should stop using these herbal medications 7 days&#xD;
             prior to first dose of study drug.&#xD;
&#xD;
         20. Psychological, familial, sociological, or geographical conditions that do not permit&#xD;
             compliance with the protocol.&#xD;
&#xD;
         21. Inability or unwillingness to comply with study and/or follow-up procedures outlined&#xD;
             in the protocol.&#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>Andrew Kennedy, MD</last_name>
    <role>Study Chair</role>
    <affiliation>SCRI Development Innovations, LLC</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Johanna Bendell, MD</last_name>
    <role>Study Chair</role>
    <affiliation>SCRI Development Innovations, LLC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Florida Cancer Specialists - North</name>
      <address>
        <city>Saint Petersburg</city>
        <state>Florida</state>
        <zip>33705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Medical Center</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tennessee Oncology PLLC</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>July 17, 2014</study_first_submitted>
  <study_first_submitted_qc>July 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 21, 2014</study_first_posted>
  <results_first_submitted>June 4, 2018</results_first_submitted>
  <results_first_submitted_qc>July 10, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">July 12, 2018</results_first_posted>
  <last_update_submitted>July 10, 2018</last_update_submitted>
  <last_update_submitted_qc>July 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 12, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Regorafenib</keyword>
  <keyword>90Y</keyword>
  <keyword>Radioembolization</keyword>
  <keyword>SIR-Spheres Microspheres</keyword>
  <keyword>Metastatic Colorectal Cancer</keyword>
  <keyword>Liver Metastases</keyword>
  <keyword>SIRT</keyword>
  <keyword>Refractory</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
  </condition_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>April 15, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/11/NCT02195011/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 22, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/11/NCT02195011/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Between July 2014 and February 2017, 26 patients with metastatic colorectal cancer (mCRC) with liver metastases were enrolled. The study was closed early due to slow enrollment.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</title>
          <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received one cycle (28 days) of regorafenib followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 1 took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres were then be administered to patients by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
        </group>
        <group group_id="P2">
          <title>Cohort 2: SIR-Spheres/Regorafenib</title>
          <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received SIR-Spheres microspheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 2 received SIR-Spheres microspheres administered by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="25"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="25"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Progressive Disease</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All patients who received at least one dose of treatment.</population>
      <group_list>
        <group group_id="B1">
          <title>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</title>
          <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received one cycle (28 days) of regorafenib followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 1 took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres were then be administered to patients by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
        </group>
        <group group_id="B2">
          <title>Cohort 2: SIR-Spheres/Regorafenib</title>
          <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received SIR-Spheres microspheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 2 received SIR-Spheres microspheres administered by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</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="25"/>
            <count group_id="B2" value="1"/>
            <count group_id="B3" value="26"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="56" lower_limit="44" upper_limit="79"/>
                    <measurement group_id="B2" value="64" lower_limit="64" upper_limit="64"/>
                    <measurement group_id="B3" value="56" lower_limit="44" upper_limit="79"/>
                  </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="13"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="13"/>
                  </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="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>The Number of Participants With Treatment-Related Adverse Events and Serious Adverse Events as a Measure of Safety</title>
        <description>A treatment-related adverse event or serious adverse event was any untoward medical occurrence in a participant which was considered to have a relationship with the study drug (suspected to be possibly or probably related to the study drug per the Investigator's assessment). Adverse events and serious adverse events will be assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V4.03.</description>
        <time_frame>up to 15 months</time_frame>
        <population>All patients who receive at least one dose of treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</title>
            <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received one cycle (28 days) of regorafenib followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 1 took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres were then be administered to patients by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2: SIR-Spheres/Regorafenib</title>
            <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received SIR-Spheres microspheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 2 received SIR-Spheres microspheres administered by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
          </group>
        </group_list>
        <measure>
          <title>The Number of Participants With Treatment-Related Adverse Events and Serious Adverse Events as a Measure of Safety</title>
          <description>A treatment-related adverse event or serious adverse event was any untoward medical occurrence in a participant which was considered to have a relationship with the study drug (suspected to be possibly or probably related to the study drug per the Investigator's assessment). Adverse events and serious adverse events will be assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V4.03.</description>
          <population>All patients who receive at least one dose of 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="25"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With an Objective Response (CR or PR)</title>
        <description>Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST v 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease in of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.</description>
        <time_frame>At 6 and 12 weeks after SIR-Spheres, and every 8 weeks thereafter, up to 18 months</time_frame>
        <population>Includes all patients who have received study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</title>
            <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received one cycle (28 days) of regorafenib followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 1 took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres were then be administered to patients by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2: SIR-Spheres/Regorafenib</title>
            <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received SIR-Spheres microspheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 2 received SIR-Spheres microspheres administered by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With an Objective Response (CR or PR)</title>
          <description>Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST v 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease in of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.</description>
          <population>Includes all patients who have received 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="25"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <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>Median Progression-Free Survival</title>
        <description>Defined as the time (in months) from date of randomization to the date of first observation of progression based on radiological assessment by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or date of death from any cause, in the absence of progressive disease (PD) or censored at the date of last adequate tumor assessment. Progressive Disease is defined by RECIST v1.1 as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum while on study (this includes the baseline sum if that is the smallest on study), or the appearance of one or more new lesions.</description>
        <time_frame>At 6 and 12 weeks after SIR-Spheres, and every 8 weeks thereafter, up to 18 months.</time_frame>
        <population>Includes all patients who received treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</title>
            <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received one cycle (28 days) of regorafenib followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 1 took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres were then be administered to patients by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2: SIR-Spheres/Regorafenib</title>
            <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received SIR-Spheres microspheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 2 received SIR-Spheres microspheres administered by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Median Progression-Free Survival</title>
          <description>Defined as the time (in months) from date of randomization to the date of first observation of progression based on radiological assessment by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or date of death from any cause, in the absence of progressive disease (PD) or censored at the date of last adequate tumor assessment. Progressive Disease is defined by RECIST v1.1 as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum while on study (this includes the baseline sum if that is the smallest on study), or the appearance of one or more new lesions.</description>
          <population>Includes all patients who received treatment.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7" lower_limit="2.6" upper_limit="9.7"/>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">Not reached at this time</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Overall Survival</title>
        <description>Defined as the time (in months) from date of randomization to date of death from any cause, or censored at the date last known alive.</description>
        <time_frame>up to 18 months</time_frame>
        <population>Includes all patients who received treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</title>
            <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received one cycle (28 days) of regorafenib followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 1 took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres were then be administered to patients by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2: SIR-Spheres/Regorafenib</title>
            <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received SIR-Spheres microspheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 2 received SIR-Spheres microspheres administered by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Median Overall Survival</title>
          <description>Defined as the time (in months) from date of randomization to date of death from any cause, or censored at the date last known alive.</description>
          <population>Includes all patients who received treatment.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.1" lower_limit="6.0" upper_limit="16.4"/>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">Not reached at this time.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 15 months.</time_frame>
      <desc>All patients who received at least one dose of protocol treatment were followed for safety. Adverse events and serious adverse events were collected from day of first dose to 30 days after last protocol treatment and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.</desc>
      <group_list>
        <group group_id="E1">
          <title>Cohort 1: Regorafenib/SIR-Spheres/Regorafenib</title>
          <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received one cycle (28 days) of regorafenib followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 1 took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres were then be administered to patients by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
        </group>
        <group group_id="E2">
          <title>Cohort 2: SIR-Spheres/Regorafenib</title>
          <description>Patients with metastatic colorectal cancer (mCRC) with liver metastases received SIR-Spheres microspheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.&#xD;
Patients in Cohort 2 received SIR-Spheres microspheres administered by injection via trans-femoral catheter into the hepatic artery. Following treatment with SIR-Spheres, patients took 160 mg regorafenib orally once daily on Days 1-21 of each 28-day treatment cycle</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (Unspecified)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Intestinal perforation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Portal hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </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="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Muscle haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Mental status changes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertensive crisis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (Unspecified)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </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="6" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>NEUTROPENIA</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>THROMBOCYTOPENIA</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>MYOCARDIAL INFARCTION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PERICARDIAL EFFUSION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>MOTION SICKNESS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>VISION BLURRED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>ABDOMINAL DISTENSION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>ABDOMINAL PAIN</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>ASCITES</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>CONSTIPATION</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DIARRHOEA</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DRY MOUTH</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DUODENAL ULCER</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DYSPEPSIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DYSPHAGIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>EPIGASTRIC DISCOMFORT</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>FAECES DISCOLOURED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>GASTROINTESTINAL PAIN</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>GASTROOESOPHAGEAL REFLUX DISEASE</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>GINGIVAL BLEEDING</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HAEMORRHOIDS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HIATUS HERNIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>IMPAIRED GASTRIC EMPTYING</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>INTESTINAL PERFORATION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>NAUSEA</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>OESOPHAGITIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>ORAL PAIN</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SENSITIVITY OF TEETH</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>STOMATITIS</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>VOMITING</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>ASTHENIA</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>CHILLS</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>FATIGUE</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HERNIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HERNIA PAIN</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>INFLUENZA LIKE ILLNESS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MALAISE</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MUCOSAL INFLAMMATION</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>OEDEMA PERIPHERAL</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PAIN</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PYREXIA</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SWELLING</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>CHOLANGITIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>CHOLECYSTITIS ACUTE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HEPATIC CIRRHOSIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HEPATIC FAILURE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HEPATOTOXICITY</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPERBILIRUBINAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>NON-ALCOHOLIC STEATOHEPATITIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PORTAL HYPERTENSION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>HYPERSENSITIVITY</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SEASONAL ALLERGY</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>CANDIDA INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HERPES ZOSTER</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>ORAL CANDIDIASIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PHARYNGITIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>POSTOPERATIVE WOUND INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SEPSIS</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SKIN CANDIDA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>URINARY TRACT INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>PROCEDURAL PAIN</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>STOMA SITE IRRITATION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>ALANINE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>ASPARTATE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD ALBUMIN DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD ALKALINE PHOSPHATASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD BILIRUBIN DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD BILIRUBIN INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD CALCIUM DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD CHLORIDE DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD CREATININE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD GLUCOSE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD LACTATE DEHYDROGENASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD PHOSPHORUS DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD PRESSURE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BLOOD SODIUM DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>CARCINOEMBRYONIC ANTIGEN INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HAEMOGLOBIN DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>LYMPHOCYTE COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PARACENTESIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PLATELET COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PLATELET COUNT INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PROTEIN TOTAL DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>WEIGHT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </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="12" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DEHYDRATION</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>FAILURE TO THRIVE</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPERKALAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPOALBUMINAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPOGLYCAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPOKALAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPONATRAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>ARTHRALGIA</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>BACK PAIN</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>FLANK PAIN</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>GROIN PAIN</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>JOINT SWELLING</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MUSCLE HAEMORRHAGE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MUSCLE SPASMS</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MUSCULAR WEAKNESS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MUSCULOSKELETAL DISCOMFORT</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MYALGIA</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>NECK PAIN</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PAIN IN EXTREMITY</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>RHEUMATOID ARTHRITIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>BALANCE DISORDER</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DYSGEUSIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HEADACHE</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPOAESTHESIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MIGRAINE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>NEUROPATHY PERIPHERAL</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SEIZURE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>TREMOR</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>ABNORMAL DREAMS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>ANXIETY</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>CONFUSIONAL STATE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DEPRESSION</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>INSOMNIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MENTAL STATUS CHANGES</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>ACUTE KIDNEY INJURY</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DYSURIA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>MICTURITION URGENCY</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>BREAST TENDERNESS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PELVIC PAIN</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>VAGINAL HAEMORRHAGE</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>VULVA CYST</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>ATELECTASIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>COUGH</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DYSPHONIA</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DYSPNOEA</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DYSPNOEA EXERTIONAL</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HICCUPS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PARANASAL SINUS HYPERSECRETION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PLEURAL EFFUSION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PULMONARY EMBOLISM</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SINUS CONGESTION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>BLISTER</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DERMATITIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>DERMATITIS ACNEIFORM</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>ERYTHEMA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPERKERATOSIS</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>NIGHT SWEATS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PRURITUS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>RASH</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>RASH GENERALISED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>RASH MACULAR</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>RASH MACULO-PAPULAR</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>RASH PAPULAR</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SKIN HYPERPIGMENTATION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>SKIN DISORDER NOT OTHERWISE SPECIFIED</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>CHEST TUBE INSERTION</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HERNIA REPAIR</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>HOT FLUSH</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPERTENSION</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>HYPERTENSIVE CRISIS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>PERIPHERAL COLDNESS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
              </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>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Senior Director, Regulatory Science</name_or_title>
      <organization>Sarah Cannon Development Innovations</organization>
      <phone>844-710-6157</phone>
      <email>CANN.InnovationsMedical@sarahcannon.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/NCT02195011
org study id: SCRI GI 189
nct id: NCT02195011
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: Yes
The purpose of this study is to determine the safety of regorafenib, an antiangiogenic drug,
      when combined with radioembolization using SIR-Spheres® microspheres in the treatment of
      colorectal cancer (CRC) that has spread to the liver.
Recent targeted therapies and treatment strategies have shown promise in colorectal cancer;
      however, elimination of disease remains a challenge once spread to the liver.
      Radioembolization using SIR-Spheres® microspheres (SIR-Spheres) to treat liver-only or
      liver-dominant metastatic colorectal cancer (mCRC) has been successful in this refractory
      setting. In this open-label study we will compare the safety of two treatment cohorts in
      which radioembolization will be administered using the device SIR-Spheres microspheres (90Y
      resin microspheres) in combination with regorafenib to patients with mCRC with liver
      metastases. The two treatment cohorts will be evaluated for safety, overall response (OR),
      progression-free survival (PFS), and overall survival (OS).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The Number of Participants With Treatment-Related Adverse Events and Serious Adverse Events as a Measure of Safety
time frame: up to 15 months
description: A treatment-related adverse event or serious adverse event was any untoward medical occurrence in a participant which was considered to have a relationship with the study drug (suspected to be possibly or probably related to the study drug per the Investigator's assessment). Adverse events and serious adverse events will be assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V4.03.
measure: Number of Patients With an Objective Response (CR or PR)
time frame: At 6 and 12 weeks after SIR-Spheres, and every 8 weeks thereafter, up to 18 months
description: Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST v 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease in of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters.
measure: Median Progression-Free Survival
time frame: At 6 and 12 weeks after SIR-Spheres, and every 8 weeks thereafter, up to 18 months.
description: Defined as the time (in months) from date of randomization to the date of first observation of progression based on radiological assessment by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or date of death from any cause, in the absence of progressive disease (PD) or censored at the date of last adequate tumor assessment. Progressive Disease is defined by RECIST v1.1 as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum while on study (this includes the baseline sum if that is the smallest on study), or the appearance of one or more new lesions.
measure: Median Overall Survival
time frame: up to 18 months
description: Defined as the time (in months) from date of randomization to date of death from any cause, or censored at the date last known alive.
arm group label: Cohort 1: Regorafenib/SIR-Spheres/Regorafenib
arm group type: Experimental
description: Regorafenib (one cycle) followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.
Patients will take regorafenib 160 mg orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres will then be administered to the patient by injection through a trans-femoral catheter into the hepatic artery. Treatment with regorafenib will be re-started 2-4 weeks after SIR-Spheres administration.
arm group label: Cohort 2: SIR-Spheres/Regorafenib
arm group type: Experimental
description: SIR-Spheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.
SIR-Spheres microspheres will be administered to the patient by injection through a trans-femoral catheter into the hepatic artery. After SIR-Spheres microspheres have been administered, the treatment with regorafenib will be initiated 2-4 weeks after administration of SIR-Spheres. Patients will take regorafenib 160 mg orally once daily on Days 1-21 of each 28-day treatment cycle.
intervention type: Device
intervention name: SIR-Spheres
description: Radioembolization will be administered once by injection through a trans-femoral catheter into the hepatic artery.
arm group label: Cohort 1: Regorafenib/SIR-Spheres/Regorafenib
arm group label: Cohort 2: SIR-Spheres/Regorafenib
other name: 90Y-Microspheres
intervention type: Drug
intervention name: Regorafenib
description: All patients will take regorafenib 160mg orally once daily on Days 1-21 of each 28-day cycle.
arm group label: Cohort 1: Regorafenib/SIR-Spheres/Regorafenib
arm group label: Cohort 2: SIR-Spheres/Regorafenib
other name: Stivarga
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrew Kennedy, MD
role: Study Chair
affiliation: SCRI Development Innovations, LLC
last name: Johanna Bendell, MD
role: Study Chair
affiliation: SCRI Development Innovations, LLC
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Neoplasm Metastasis
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 