<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/NCT02979899</url>
  </required_header>
  <id_info>
    <org_study_id>105SAR301</org_study_id>
    <nct_id>NCT02979899</nct_id>
  </id_info>
  <brief_title>Trial of TRC105 and Pazopanib Versus Pazopanib Alone in Patients With Advanced Angiosarcoma</brief_title>
  <acronym>TAPPAS</acronym>
  <official_title>A Randomized Phase 3 Trial of TRC105 and Pazopanib Versus Pazopanib Alone in Patients With Advanced Angiosarcoma (TAPPAS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tracon Pharmaceuticals Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tracon Pharmaceuticals Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a study of TRC105 in combination with standard dose pazopanib compared to single&#xD;
      agent pazopanib in patients with angiosarcoma not amenable to curative intent surgery (e.g.,&#xD;
      metastatic or bulky disease, and disease for which surgical resection would carry an&#xD;
      unacceptable risk to the patient) who have not received pazopanib or TRC105 previously.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      TRC105 (carotuximab) is a monoclonal antibody to endoglin (CD105), an essential angiogenic&#xD;
      target highly expressed on tumor vessels that is distinct from VEGFR. Endoglin is also&#xD;
      expressed directly on tumor cells in angiosarcoma and is upregulated following VEGF&#xD;
      inhibition. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models&#xD;
      and complements the activity of bevacizumab and multi-kinase inhibitors that target the&#xD;
      VEGFR.&#xD;
&#xD;
      Pazopanib is an oral inhibitor of multiple receptor tyrosine kinases, including vascular&#xD;
      endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma&#xD;
      concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and&#xD;
      cancer progression.&#xD;
&#xD;
      By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the&#xD;
      potential to complement VEGFR tyrosine kinase inhibitors (TKIs) and could represent a major&#xD;
      advance in the treatment of angiosarcoma. Together, the use of TRC105 with pazopanib may&#xD;
      result in more effective angiogenesis inhibition and improved clinical efficacy over that&#xD;
      seen with pazopanib alone.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 13, 2017</start_date>
  <completion_date type="Actual">August 31, 2019</completion_date>
  <primary_completion_date type="Actual">April 11, 2019</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival of Patients With Unresectable Angiosarcoma</measure>
    <time_frame>from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut off date of interim analysis (25 months)</time_frame>
    <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Progression free survival is defined as time from randomization to either first disease progression (per independent radiology review of images by RECIST 1.1) or death from any cause.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate of Patients With Unresectable Angiosarcoma</measure>
    <time_frame>from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut off date of interim analysis (25 months)</time_frame>
    <description>Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR) is disappearance of all target lesions; Partial Response (PR) is &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Overall response rate is defined as the number of patients with a best response designation of complete response or partial response recorded between the date of randomization and the date of documented progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival of Patients With Unresectable Angiosarcoma</measure>
    <time_frame>from beginning of study to cut off date of interim analysis (25 months)</time_frame>
    <description>Overall survival is the number of death events at 25 months, including all on-study and off-study deaths (past post-treatment 28-day follow up visit)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To Characterize Patient Reported Outcomes Between the Two Arms of the Study</measure>
    <time_frame>Screening and 9 weeks (Cycle 3 Day 1)</time_frame>
    <description>Patient reported outcomes as measured by the EuroQol five dimensions questionnaire (EQ-5D-5L) and the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 health scale is on a scale of 1 to 7, with 1 being poor health and 7 being excellent health. The EQ-5D-5L scale is on a scale of 0 to 100, with 0 being the worst health one can imagine, and 100 being the best health one can imagine.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">128</enrollment>
  <condition>Advanced Angiosarcoma</condition>
  <arm_group>
    <arm_group_label>TRC105 plus votrient</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>votrient</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>standard dose votrient by mouth, once daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>TRC105</intervention_name>
    <description>TRC105 antibody</description>
    <arm_group_label>TRC105 plus votrient</arm_group_label>
    <other_name>anti-endoglin antibody</other_name>
    <other_name>carotuximab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Votrient</intervention_name>
    <description>pazopanib</description>
    <arm_group_label>TRC105 plus votrient</arm_group_label>
    <arm_group_label>votrient</arm_group_label>
    <other_name>pazopanib</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically-confirmed angiosarcoma that is not amenable to curative intent surgery&#xD;
             (e.g., metastatic or bulky disease and disease for which surgical resection would&#xD;
             carry an unacceptable risk to the patient). Pathology report will be reviewed by&#xD;
             sponsor prior to randomization.&#xD;
&#xD;
          2. Documented progression on or following most recent systemic chemotherapy regimen (not&#xD;
             required for chemotherapy-naïve patients), within 4 months prior to screening&#xD;
&#xD;
          3. Measurable disease by RECIST v1.1&#xD;
&#xD;
          4. Age of 18 years or older; in addition, patients age 12 to 17 years may enroll&#xD;
             beginning in Cohort 2 if weight ≥ 40 kg&#xD;
&#xD;
          5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1&#xD;
&#xD;
          6. Resolution of all acute AEs resulting from prior cancer therapies to National Cancer&#xD;
             Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE&#xD;
             v4.03) grade ≤ 1 or to that patient's pre-study baseline (except alopecia or&#xD;
             neuropathy)&#xD;
&#xD;
          7. Adequate organ function&#xD;
&#xD;
          8. Willingness and ability to consent (and assent if under age 18) for self to&#xD;
             participate in study&#xD;
&#xD;
          9. Willingness and ability to comply with scheduled visits, treatment plan, laboratory&#xD;
             tests, and other study procedures&#xD;
&#xD;
         10. Angiosarcoma tumor specimen, if available&#xD;
&#xD;
         11. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis)&#xD;
             OR agree to use a condom with spermicide (refer to Section 2.6.1.3) and to not donate&#xD;
             sperm during the study and for at least 180 days following last dose of TRC105 or&#xD;
             pazopanib&#xD;
&#xD;
         12. Woman of non-child bearing potential due to surgical sterilization (at least 6 weeks&#xD;
             following surgical bilateral oophorectomy with or without hysterectomy or tubal&#xD;
             ligation) confirmed by medical history or menopause (i.e., no menstrual bleeding for&#xD;
             more than 12 months in a women aged 45 years or more), OR woman of child bearing&#xD;
             potential who test negative for pregnancy at time of enrollment based on serum&#xD;
             pregnancy test and agree to use at least 2 acceptable methods of birth control, one of&#xD;
             which must be highly effective, during the study and for at least 180 days after&#xD;
             stopping TRC105 or pazopanib&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior treatment with TRC105&#xD;
&#xD;
          2. Prior treatment with any VEGF inhibitor&#xD;
&#xD;
          3. More than two prior lines (may be combination regimens) of chemotherapy for&#xD;
             angiosarcoma (neoadjuvant/adjuvant treatment does not count as a line of treatment)&#xD;
&#xD;
          4. Current treatment or participation on another therapeutic clinical trial&#xD;
&#xD;
          5. Women who are pregnant or breastfeeding&#xD;
&#xD;
          6. Receipt of systemic anticancer therapy, including investigational agents, within 5&#xD;
             times the agent's elimination half-life of starting study treatment&#xD;
&#xD;
          7. Major surgical procedure or significant traumatic injury within 4 weeks prior to&#xD;
             randomization and must have fully recovered from any such procedure or injury; planned&#xD;
             surgery (if applicable) or the anticipated need for a major surgical procedure within&#xD;
             the next six months. Note: the following are not considered to be major procedures and&#xD;
             are permitted up to 7 days before randomization: Thoracentesis, paracentesis, port&#xD;
             placement, laparoscopy, thoracoscopy, tube thoracostomy, bronchoscopy, endoscopic&#xD;
             ultrasonographic procedures, mediastinoscopy, skin biopsies, and imaging-guided biopsy&#xD;
             for diagnostic purposes&#xD;
&#xD;
          8. Patients who have received wide field radiotherapy ≤ 28 days (defined as &gt; 50% of&#xD;
             volume of pelvic bones or equivalent) or limited field radiation for palliation &lt; 14&#xD;
             days prior to randomization&#xD;
&#xD;
          9. Uncontrolled hypertension defined as systolic &gt; 150 or diastolic &gt; 100 mm Hg on the&#xD;
             average of the 3 most recent BP readings. Anti-hypertensives may be started prior to&#xD;
             randomization.&#xD;
&#xD;
         10. Ascites or pleural effusion requiring intervention or that required intervention or&#xD;
             recurred within three months prior to randomization&#xD;
&#xD;
         11. Pericardial effusion (except trace effusion identified by echocardiogram) within three&#xD;
             months prior to randomization&#xD;
&#xD;
         12. History of brain involvement with cancer, spinal cord compression, or carcinomatous&#xD;
             meningitis, or new evidence of brain or leptomeningeal disease. Patients with radiated&#xD;
             or resected lesions are permitted, provided the lesions are fully treated and&#xD;
             inactive, patients are asymptomatic, and no steroids have been administered for at&#xD;
             least 28 days prior to randomization&#xD;
&#xD;
         13. Angina, myocardial infarction, symptomatic congestive heart failure, cerebrovascular&#xD;
             accident, transient ischemic attack, arterial embolism , pulmonary embolism,&#xD;
             percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft&#xD;
             (CABG) within 6 months prior to randomization. Deep venous thrombosis within 3 months&#xD;
             prior to randomization unrelated to a central venous catheter, unless the patient is&#xD;
             anti-coagulated without the use of warfarin for at least 2 weeks prior to&#xD;
             randomization. In this situation, low molecular weight heparin is preferred&#xD;
&#xD;
         14. Active bleeding or pathologic condition that carries a high risk of bleeding (e.g.,&#xD;
             hereditary hemorrhagic telangiectasia). Patients with bleeding cutaneous lesions not&#xD;
             actively requiring transfusions are eligible. Patients who have been uneventfully&#xD;
             anti-coagulated with low molecular weight heparin are eligible&#xD;
&#xD;
         15. Hemoptysis (&gt; ½ teaspoon [2.5 mL] of bright red blood) within 6 months prior to&#xD;
             randomization&#xD;
&#xD;
         16. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to&#xD;
             randomization&#xD;
&#xD;
         17. Known active viral or nonviral hepatitis or cirrhosis&#xD;
&#xD;
         18. Peptic ulcer within the past 3 months prior to randomization, unless treated for the&#xD;
             condition and complete resolution has been documented by esophagogastroduodenoscopy&#xD;
             (EGD)&#xD;
&#xD;
         19. Presence of tumor(s) invading into the heart or great vessels (including carotid&#xD;
             artery) or another location where bleeding is associated with high morbidity including&#xD;
             patients with primary cardiac or great vessel angiosarcoma&#xD;
&#xD;
         20. Gastrointestinal perforation or fistula in the 6 months prior to randomization unless&#xD;
             underlying risk has been resolved (e.g., through surgical resection or repair)&#xD;
&#xD;
         21. Presence of a malabsorption syndrome, gastrointestinal disorder, or gastrointestinal&#xD;
             surgery that could affect the absorption of pazopanib&#xD;
&#xD;
         22. History of prior malignancy except adequately treated basal cell or squamous cell skin&#xD;
             cancer or adequately treated, with curative intent, cancer from which the patient is&#xD;
             currently in complete remission per Investigator's judgment; patients with history of&#xD;
             breast cancer and no evidence of disease on hormonal therapy to prevent recurrence and&#xD;
             patients with prostate cancer on adjuvant hormonal therapy with undetectable PSA are&#xD;
             eligible&#xD;
&#xD;
         23. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)&#xD;
             related illness&#xD;
&#xD;
         24. Active infection that requires systemic treatment&#xD;
&#xD;
         25. Concurrent use or receipt of a strong CYP3A4 inducer within 12 days prior to&#xD;
             randomization or a strong CYP3A4 inhibitor within 7 days prior to randomization (see&#xD;
             Table 10)&#xD;
&#xD;
         26. History of severe hypersensitivity reaction to any monoclonal antibody&#xD;
&#xD;
         27. Other severe acute or chronic medical (including bone marrow suppressive diseases) or&#xD;
             psychiatric condition or laboratory abnormality that may increase the risk associated&#xD;
             with study participation, impede the ability of the patient to complete all&#xD;
             protocol-specified activities, or may interfere with the interpretation of study&#xD;
             results and, in the judgment of the Investigator, would make the patient inappropriate&#xD;
             for this study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Charles Theuer, MD</last_name>
    <role>Study Director</role>
    <affiliation>TRACON Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Arizona Cancer Center</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85724</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sarcoma Oncology Center</name>
      <address>
        <city>Santa Monica</city>
        <state>California</state>
        <zip>90403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Colorado Denver</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Jacksonville</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northside Hospital</name>
      <address>
        <city>Sandy Springs</city>
        <state>Georgia</state>
        <zip>30342</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University St. Louis</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Roswell Park Cancer Institute</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14263</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwell Health</name>
      <address>
        <city>Lake Success</city>
        <state>New York</state>
        <zip>11042</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MSKCC</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10017</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Thomas Jefferson University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt University</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37212</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD Anderson</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah, Huntsman Cancer Institute</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Washinton</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical University,Vienna</name>
      <address>
        <city>Wien</city>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Bergonié</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Oscar Lambret</name>
      <address>
        <city>Lille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Léon Bérard</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helios Klinikum</name>
      <address>
        <city>Bad Saarow</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mannheim University Medical Center</name>
      <address>
        <city>Mannheim</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum derUniversitat Munchen</name>
      <address>
        <city>Munich</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondazione IRCCS Istituto Nazionale dei Tumori</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Cancer Center and Institute of Oncology</name>
      <address>
        <city>Warszawa</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Català d'Oncologia (ICO)</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>12 de Octubre University Hospital</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Marsden NHS</name>
      <address>
        <city>Chelsea</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>France</country>
    <country>Germany</country>
    <country>Italy</country>
    <country>Poland</country>
    <country>Spain</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Belgium</country>
  </removed_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>November 29, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <results_first_submitted>February 27, 2020</results_first_submitted>
  <results_first_submitted_qc>May 11, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">May 12, 2020</results_first_posted>
  <last_update_submitted>May 11, 2020</last_update_submitted>
  <last_update_submitted_qc>May 11, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 12, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>angiosarcoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemangiosarcoma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 23, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/99/NCT02979899/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>TRC105 + Votrient</title>
          <description>Weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily&#xD;
TRC105: TRC105 antibody&#xD;
Votrient: pazopanib</description>
        </group>
        <group group_id="P2">
          <title>Votrient</title>
          <description>Standard dose votrient by mouth, once daily&#xD;
Votrient: pazopanib</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="64"/>
                <participants group_id="P2" count="64"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="64"/>
                <participants group_id="P2" count="64"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>TRC105 + Votrient</title>
          <description>Weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily&#xD;
TRC105: TRC105 antibody&#xD;
Votrient: pazopanib</description>
        </group>
        <group group_id="B2">
          <title>Votrient</title>
          <description>Standard dose votrient by mouth, once daily&#xD;
Votrient: pazopanib</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="64"/>
            <count group_id="B2" value="64"/>
            <count group_id="B3" value="128"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="69" lower_limit="32" upper_limit="82"/>
                    <measurement group_id="B2" value="67" lower_limit="25" upper_limit="84"/>
                    <measurement group_id="B3" value="68" lower_limit="25" upper_limit="84"/>
                  </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="35"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="77"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="51"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55"/>
                    <measurement group_id="B2" value="56"/>
                    <measurement group_id="B3" value="111"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Reported</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50"/>
                    <measurement group_id="B2" value="46"/>
                    <measurement group_id="B3" value="96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Poland</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>France</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG Performance Status</title>
          <description>0 = Fully active, able to carry on all pre-disease performance without restriction&#xD;
= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work&#xD;
= Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours&#xD;
= Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours&#xD;
= Completely disabled; cannot carry on any selfcare; totally confined to bed or chair&#xD;
= Dead</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>ECOG Grade 0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="57"/>
                  </measurement_list>
                </category>
                <category>
                  <title>ECOG Grade 1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="32"/>
                    <measurement group_id="B2" value="36"/>
                    <measurement group_id="B3" value="68"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Available</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression Free Survival of Patients With Unresectable Angiosarcoma</title>
        <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Progression free survival is defined as time from randomization to either first disease progression (per independent radiology review of images by RECIST 1.1) or death from any cause.</description>
        <time_frame>from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut off date of interim analysis (25 months)</time_frame>
        <population>All patients randomized onto study by cut off date of interim analysis</population>
        <group_list>
          <group group_id="O1">
            <title>TRC105 + Votrient</title>
            <description>Weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily&#xD;
TRC105: TRC105 antibody&#xD;
Votrient: pazopanib</description>
          </group>
          <group group_id="O2">
            <title>Votrient</title>
            <description>Standard dose votrient by mouth, once daily&#xD;
Votrient: pazopanib</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival of Patients With Unresectable Angiosarcoma</title>
          <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Progression free survival is defined as time from randomization to either first disease progression (per independent radiology review of images by RECIST 1.1) or death from any cause.</description>
          <population>All patients randomized onto study by cut off date of interim analysis</population>
          <units>months</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
                <count group_id="O2" value="61"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>PFS by RECIST 1.1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.2" lower_limit="2.8" upper_limit="8.3"/>
                    <measurement group_id="O2" value="4.3" lower_limit="2.9" upper_limit="NA">Confidence interval not estimable because not enough events to estimate a standard error</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PFS by Investigator Assessment</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.5" lower_limit="2.6" upper_limit="5.5"/>
                    <measurement group_id="O2" value="2.9" lower_limit="2.6" upper_limit="4.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rate of Patients With Unresectable Angiosarcoma</title>
        <description>Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR) is disappearance of all target lesions; Partial Response (PR) is &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Overall response rate is defined as the number of patients with a best response designation of complete response or partial response recorded between the date of randomization and the date of documented progression.</description>
        <time_frame>from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut off date of interim analysis (25 months)</time_frame>
        <population>All patients randomized onto study by cut off date of interim analysis</population>
        <group_list>
          <group group_id="O1">
            <title>TRC105 + Votrient</title>
            <description>Weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily&#xD;
TRC105: TRC105 antibody&#xD;
Votrient: pazopanib</description>
          </group>
          <group group_id="O2">
            <title>Votrient</title>
            <description>Standard dose votrient by mouth, once daily&#xD;
Votrient: pazopanib</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate of Patients With Unresectable Angiosarcoma</title>
          <description>Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR) is disappearance of all target lesions; Partial Response (PR) is &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Overall response rate is defined as the number of patients with a best response designation of complete response or partial response recorded between the date of randomization and the date of documented progression.</description>
          <population>All patients randomized onto study by cut off date of interim analysis</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="62"/>
                <count group_id="O2" value="61"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival of Patients With Unresectable Angiosarcoma</title>
        <description>Overall survival is the number of death events at 25 months, including all on-study and off-study deaths (past post-treatment 28-day follow up visit)</description>
        <time_frame>from beginning of study to cut off date of interim analysis (25 months)</time_frame>
        <population>All patients randomized onto study by cut off date of interim analysis</population>
        <group_list>
          <group group_id="O1">
            <title>TRC105 + Votrient</title>
            <description>Weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily&#xD;
TRC105: TRC105 antibody&#xD;
Votrient: pazopanib</description>
          </group>
          <group group_id="O2">
            <title>Votrient</title>
            <description>Standard dose votrient by mouth, once daily&#xD;
Votrient: pazopanib</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival of Patients With Unresectable Angiosarcoma</title>
          <description>Overall survival is the number of death events at 25 months, including all on-study and off-study deaths (past post-treatment 28-day follow up visit)</description>
          <population>All patients randomized onto study by cut off date of interim analysis</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="62"/>
                <count group_id="O2" value="61"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>To Characterize Patient Reported Outcomes Between the Two Arms of the Study</title>
        <description>Patient reported outcomes as measured by the EuroQol five dimensions questionnaire (EQ-5D-5L) and the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 health scale is on a scale of 1 to 7, with 1 being poor health and 7 being excellent health. The EQ-5D-5L scale is on a scale of 0 to 100, with 0 being the worst health one can imagine, and 100 being the best health one can imagine.</description>
        <time_frame>Screening and 9 weeks (Cycle 3 Day 1)</time_frame>
        <population>All patients who completed the questionnaire during specified intervals listed below</population>
        <group_list>
          <group group_id="O1">
            <title>TRC105 + Votrient</title>
            <description>Weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily&#xD;
TRC105: TRC105 antibody&#xD;
Votrient: pazopanib</description>
          </group>
          <group group_id="O2">
            <title>Votrient</title>
            <description>Standard dose votrient by mouth, once daily&#xD;
Votrient: pazopanib</description>
          </group>
        </group_list>
        <measure>
          <title>To Characterize Patient Reported Outcomes Between the Two Arms of the Study</title>
          <description>Patient reported outcomes as measured by the EuroQol five dimensions questionnaire (EQ-5D-5L) and the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 health scale is on a scale of 1 to 7, with 1 being poor health and 7 being excellent health. The EQ-5D-5L scale is on a scale of 0 to 100, with 0 being the worst health one can imagine, and 100 being the best health one can imagine.</description>
          <population>All patients who completed the questionnaire during specified intervals listed below</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="64"/>
                <count group_id="O2" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>EORTC QLQ-C30 Health Score at Screening</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="64"/>
                    <count group_id="O2" value="62"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" lower_limit="1" upper_limit="7"/>
                    <measurement group_id="O2" value="5" lower_limit="1" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>EQ-5D-5L Health Score at Screening</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="59"/>
                    <count group_id="O2" value="54"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75" lower_limit="5" upper_limit="100"/>
                    <measurement group_id="O2" value="75" lower_limit="20" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>EORTC QLQ-C30 Health Score at Cycle 3 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="39"/>
                    <count group_id="O2" value="38"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4" lower_limit="1" upper_limit="6"/>
                    <measurement group_id="O2" value="5" lower_limit="1" upper_limit="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>EQ-5D-5L Health Score at Cycle 3 Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="38"/>
                    <count group_id="O2" value="38"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="70" lower_limit="20" upper_limit="100"/>
                    <measurement group_id="O2" value="70" lower_limit="20" upper_limit="97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected over the entire duration of the study (a period of 26 months).</time_frame>
      <desc>AEs were collected for each patient that received at least 1 dose of study drug from informed consent through 28 days following the last dose of study drug. Related AEs were followed until they resolved or became stable. All-Cause Mortality was monitored in all randomized participants as overall survival (OS) was a secondary endpoint of the study. OS was followed until death regardless of subsequent treatment. Patients were eligible for participation in the trial until they progressed.</desc>
      <group_list>
        <group group_id="E1">
          <title>TRC105 + Votrient</title>
          <description>All patients that received at least one dose of TRC105 in combination with pazopanib</description>
        </group>
        <group group_id="E2">
          <title>Votrient</title>
          <description>All patients that received at least one dose of pazopanib alone.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="64"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="64"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="27" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Platelet Disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </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="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Cardiac Failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Retinal Detachment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Upper Gastrointestinal Hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Proctalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hematemesis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Gastrointestinal Hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Disease Progression</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Multi-Organ Failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute Hepatic Failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Osteomyelitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Meningitis Aseptic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Bacteremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Subdural Hematoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Rib Fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Infusion Related Reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Clavicle Fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Aspartate Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Alanine Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Tumor Lysis Syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Failure To Thrive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Musculoskeletal Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Haemorrhage Intracranial</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Tumor Hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Mental Status Change</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory Failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Respiratory Distress</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pleural Effusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hydropneumothorax</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Embolism</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="63" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="57" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="33" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision Blurred</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Lacrimation Increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="38" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="34" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Gingival Bleeding</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Abdominal Pain Upper</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dry Mouth</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Mouth Hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Oral Pain</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal Reflux Disease</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Abdominal Distension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Gingival Pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hematemesis</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Oral Dysesthesia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="42" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Edema Peripheral</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Mucosal Inflammation</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Disease Progression</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Non-Cardiac Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Facial Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperbilirubinemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Infusion Related Reaction</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Weight Decreased</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Aspartate Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Alanine Aminotransferase Increased</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Platelet Count Decreased</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Lipase Increased</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Blood Bilirubin Increased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Blood Thyroid Stimulating Hormone Increased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Neutrophil Count Decreased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Blood Alkaline Phosphatase Increased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Lymphocyte Count Decreased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Blood Creatinine Increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>White Blood Cell Count Decreased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Blood Amylase Increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </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="26" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </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="13" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Muscular Weakness</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Musculoskeletal Pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Muscle Spasms</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pain In Extremity</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Musculoskeletal Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pain In Jaw</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumor Pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="42" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="44" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Oropharyngeal Pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dysphonia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Nasal Congestion</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Palmar-Plantar Erythrodysaesthesia Syndrome</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Dry Skin</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Rash Maculo-Papular</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Telangiectasia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Skin Lesion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Pain Of Skin</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="32" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="57"/>
              </event>
              <event>
                <sub_title>Embolism</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="63"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="57"/>
              </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>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Charles Theuer, Medical Monitor</name_or_title>
      <organization>TRACON Pharmaceuticals Inc</organization>
      <phone>8585500780</phone>
      <email>ctheuer@traconpharma.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/NCT02979899
org study id: 105SAR301
nct id: NCT02979899
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a study of TRC105 in combination with standard dose pazopanib compared to single
      agent pazopanib in patients with angiosarcoma not amenable to curative intent surgery (e.g.,
      metastatic or bulky disease, and disease for which surgical resection would carry an
      unacceptable risk to the patient) who have not received pazopanib or TRC105 previously.
TRC105 (carotuximab) is a monoclonal antibody to endoglin (CD105), an essential angiogenic
      target highly expressed on tumor vessels that is distinct from VEGFR. Endoglin is also
      expressed directly on tumor cells in angiosarcoma and is upregulated following VEGF
      inhibition. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models
      and complements the activity of bevacizumab and multi-kinase inhibitors that target the
      VEGFR.

      Pazopanib is an oral inhibitor of multiple receptor tyrosine kinases, including vascular
      endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma
      concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and
      cancer progression.

      By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the
      potential to complement VEGFR tyrosine kinase inhibitors (TKIs) and could represent a major
      advance in the treatment of angiosarcoma. Together, the use of TRC105 with pazopanib may
      result in more effective angiogenesis inhibition and improved clinical efficacy over that
      seen with pazopanib alone.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival of Patients With Unresectable Angiosarcoma
time frame: from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut off date of interim analysis (25 months)
description: Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Progression free survival is defined as time from randomization to either first disease progression (per independent radiology review of images by RECIST 1.1) or death from any cause.
measure: Objective Response Rate of Patients With Unresectable Angiosarcoma
time frame: from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to cut off date of interim analysis (25 months)
description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR) is disappearance of all target lesions; Partial Response (PR) is >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Overall response rate is defined as the number of patients with a best response designation of complete response or partial response recorded between the date of randomization and the date of documented progression.
measure: Overall Survival of Patients With Unresectable Angiosarcoma
time frame: from beginning of study to cut off date of interim analysis (25 months)
description: Overall survival is the number of death events at 25 months, including all on-study and off-study deaths (past post-treatment 28-day follow up visit)
measure: To Characterize Patient Reported Outcomes Between the Two Arms of the Study
time frame: Screening and 9 weeks (Cycle 3 Day 1)
description: Patient reported outcomes as measured by the EuroQol five dimensions questionnaire (EQ-5D-5L) and the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 health scale is on a scale of 1 to 7, with 1 being poor health and 7 being excellent health. The EQ-5D-5L scale is on a scale of 0 to 100, with 0 being the worst health one can imagine, and 100 being the best health one can imagine.
arm group label: TRC105 plus votrient
arm group type: Experimental
description: weekly TRC105 i.v. in combination with standard dose votrient by mouth, once daily
arm group label: votrient
arm group type: Active Comparator
description: standard dose votrient by mouth, once daily
intervention type: Biological
intervention name: TRC105
description: TRC105 antibody
arm group label: TRC105 plus votrient
other name: anti-endoglin antibody
other name: carotuximab
intervention type: Drug
intervention name: Votrient
description: pazopanib
arm group label: TRC105 plus votrient
arm group label: votrient
other name: pazopanib
criteria: 
gender: All
minimum age: 12 Years
maximum age: N/A
healthy volunteers: No
last name: Charles Theuer, MD
role: Study Director
affiliation: TRACON Pharmaceuticals
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
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country: Austria
country: France
country: Germany
country: Italy
country: Poland
country: Spain
country: United Kingdom
country: United States
country: Belgium
responsible party type: Sponsor
mesh term: Hemangiosarcoma
sharing ipd: No
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certain agreements: 
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