<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/NCT01664182</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2012-01289</org_study_id>
    <secondary_id>NCI-2012-01289</secondary_id>
    <secondary_id>PHII-122</secondary_id>
    <secondary_id>P9048_A12PAMDREVW01</secondary_id>
    <secondary_id>CDR0000738785</secondary_id>
    <secondary_id>9048</secondary_id>
    <secondary_id>9048</secondary_id>
    <secondary_id>N01CM00038</secondary_id>
    <secondary_id>P30CA033572</secondary_id>
    <nct_id>NCT01664182</nct_id>
  </id_info>
  <brief_title>Trebananib With or Without Bevacizumab, Pazopanib Hydrochloride, Sorafenib Tosylate, or Sunitinib Malate in Treating Patients With Advanced Kidney Cancer</brief_title>
  <official_title>A Randomized Phase 2 Study of AMG 386 With or Without Continued Anti-Vascular Endothelial Growth Factor (VEGF) Therapy in Patients With Renal Cell Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <brief_summary>
    <textblock>
      This randomized phase II trial studies how well trebananib with or without bevacizumab,&#xD;
      pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate works in treating patients&#xD;
      with kidney cancer that has spread to other places in the body and usually cannot be cured or&#xD;
      controlled with treatment (advanced). Trebananib may stop the growth of tumor cells by&#xD;
      blocking blood flow to the tumor. Immunotherapy with monoclonal, such as bevacizumab, may&#xD;
      help the body's immune system attack the cancer, and may interfere with the ability of tumor&#xD;
      cells to grow and spread. Pazopanib hydrochloride, sorafenib tosylate, and sunitinib malate&#xD;
      may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or&#xD;
      by blocking blood flow to the tumor. It is not yet known whether giving trebananib with or&#xD;
      without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate is more&#xD;
      effective in treating kidney cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To evaluate the overall response rate (complete response [CR] + partial response [PR]) of&#xD;
      trebananib (AMG 386) alone and in combination with continuation of previously administered&#xD;
      bevacizumab, pazopanib hydrochloride (pazopanib), sorafenib tosylate (sorafenib), or&#xD;
      sunitinib malate (sunitinib) in advanced renal cell carcinoma.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate progression free survival in each arm. II. To evaluate the tolerance and&#xD;
      toxicity of AMG 386 alone and in combination with continuation of the prior VEGF targeted&#xD;
      agent.&#xD;
&#xD;
      CORRELATIVE OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the association between pretreatment tumor gene expression levels and response&#xD;
      to AMG 386 in combination with continuation of the prior VEGF targeted agent.&#xD;
&#xD;
      II. To evaluate the association between single nucleotide polymorphisms (SNPs) in angiogenic&#xD;
      genes and response to AMG 386 in combination with continuation of the prior VEGF targeted&#xD;
      agent.&#xD;
&#xD;
      III. To compare changes in circulating angiogenic factors in patients treated with AMG 386&#xD;
      monotherapy to those treated with AMG 386 in combination with VEGF-targeted therapy.&#xD;
&#xD;
      IV. To compare expression of angiogenic genes from archival tumor specimens to the expression&#xD;
      in biopsy specimens obtained after progression on anti-VEGF therapy.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 treatment arms.&#xD;
&#xD;
      ARM I: Patients receive trebananib intravenously (IV) over 30-60 minutes on days 1, 8, 15,&#xD;
      22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      ARM II: Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes&#xD;
      on days 1, 15, and 29, pazopanib hydrochloride orally (PO) once daily (QD) on days 1-42,&#xD;
      sorafenib tosylate PO twice daily (BID) on days 1-42, or sunitinib malate PO QD on days 1-28.&#xD;
      Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 4-8 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 1, 2012</start_date>
  <completion_date type="Actual">December 7, 2020</completion_date>
  <primary_completion_date type="Actual">December 7, 2020</primary_completion_date>
  <phase>Phase 2</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>Observed Response Rate</measure>
    <time_frame>Up to 8 weeks</time_frame>
    <description>Defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by RECIST version 1.1 criteria, assessed by MRI: Complete Response (CR), Disappearance of all target lesions:&#xD;
any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm; Partial Response (PR), &gt;= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Best response will be listed for each patient and summarized using standard descriptive methods-point estimate and associated confidence intervals.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tumor Response</measure>
    <time_frame>at 8 weeks</time_frame>
    <description>Tumor Response Classification</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>From start of treatment to time of progression or death, whichever occurs first, assessed up to 8 weeks</time_frame>
    <description>Time to reach Kaplan-Meier median survival (outcome being death or progression) (95% Confidence Interval) is reported. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered a progression.)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs</measure>
    <time_frame>8 weeks for adverse events. Until removal from the study or to death for late adverse events, up to 12 weeks</time_frame>
    <description>Adverse events were graded using CTCAE version 5.0. Grades 3, 4, 5 (on a scale of 1 to 5, 5 being the worst grade - death) toxicities related ('Possibly', 'Probably', or 'Definitely') to the treatment drugs (AMG 386 alone or in combination with prior VEGF targeted agent).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Changes in Circulating Angiogenic Factors</measure>
    <time_frame>Baseline to up to 8 weeks</time_frame>
    <description>Analyzed as continuous variables (most likely after transformation). The gene expression results from the pretreatment tumor biopsies are expressed as ratios between that of the gene of interest and the internal reference gene beta-actin and can be analyzed as continuous variables - generally after log transformation.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Advanced Renal Cell Carcinoma</condition>
  <condition>Advanced Sarcomatoid Renal Cell Carcinoma</condition>
  <condition>Stage III Renal Cell Cancer AJCC v7</condition>
  <condition>Stage IV Renal Cell Cancer AJCC v7</condition>
  <arm_group>
    <arm_group_label>Arm I (trebananib monotherapy)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (trebananib and anti-VEGF therapy)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm II (trebananib and anti-VEGF therapy)</arm_group_label>
    <other_name>Anti-VEGF</other_name>
    <other_name>Anti-VEGF Humanized Monoclonal Antibody</other_name>
    <other_name>Anti-VEGF rhuMAb</other_name>
    <other_name>Avastin</other_name>
    <other_name>Bevacizumab awwb</other_name>
    <other_name>Bevacizumab Biosimilar BEVZ92</other_name>
    <other_name>Bevacizumab Biosimilar BI 695502</other_name>
    <other_name>Bevacizumab Biosimilar CBT 124</other_name>
    <other_name>Bevacizumab Biosimilar CT-P16</other_name>
    <other_name>Bevacizumab Biosimilar FKB238</other_name>
    <other_name>Bevacizumab Biosimilar GB-222</other_name>
    <other_name>Bevacizumab Biosimilar HD204</other_name>
    <other_name>Bevacizumab Biosimilar HLX04</other_name>
    <other_name>Bevacizumab Biosimilar IBI305</other_name>
    <other_name>Bevacizumab Biosimilar LY01008</other_name>
    <other_name>Bevacizumab Biosimilar MIL60</other_name>
    <other_name>Bevacizumab Biosimilar QL 1101</other_name>
    <other_name>Bevacizumab Biosimilar RPH-001</other_name>
    <other_name>Bevacizumab Biosimilar SCT501</other_name>
    <other_name>BP102</other_name>
    <other_name>BP102 Biosimilar</other_name>
    <other_name>HD204</other_name>
    <other_name>Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer</other_name>
    <other_name>Recombinant Humanized Anti-VEGF Monoclonal Antibody</other_name>
    <other_name>rhuMab-VEGF</other_name>
    <other_name>SCT501</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pazopanib Hydrochloride</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm II (trebananib and anti-VEGF therapy)</arm_group_label>
    <other_name>GW786034B</other_name>
    <other_name>Votrient</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sorafenib Tosylate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm II (trebananib and anti-VEGF therapy)</arm_group_label>
    <other_name>BAY 43-9006 Tosylate</other_name>
    <other_name>BAY 54-9085</other_name>
    <other_name>Nexavar</other_name>
    <other_name>sorafenib</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sunitinib Malate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm II (trebananib and anti-VEGF therapy)</arm_group_label>
    <other_name>SU011248</other_name>
    <other_name>SU11248</other_name>
    <other_name>sunitinib</other_name>
    <other_name>Sutent</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Trebananib</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm I (trebananib monotherapy)</arm_group_label>
    <arm_group_label>Arm II (trebananib and anti-VEGF therapy)</arm_group_label>
    <other_name>AMG 386</other_name>
    <other_name>AMG386</other_name>
    <other_name>Angiopoietin 1/2-Neutralizing Peptibody AMG 386</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed renal cell carcinoma&#xD;
             except medullary or collecting duct subtypes; sarcomatoid differentiation will be&#xD;
             allowed&#xD;
&#xD;
          -  Patients must have measurable disease, defined as at least one lesion that can be&#xD;
             accurately measured in at least one dimension (longest diameter to be recorded for&#xD;
             non-nodal lesions and short axis for nodal lesions) as &gt;= 20 mm with conventional&#xD;
             techniques or as &gt;= 10 mm with spiral computed tomography (CT) scan, magnetic&#xD;
             resonance imaging (MRI), or calipers by clinical exam&#xD;
&#xD;
          -  Patients must have documented radiologic or clinical progressive disease following at&#xD;
             least one prior anti-VEGF regimen administered either as a single agent or in&#xD;
             combination with other agents for at least 8 weeks; the prior anti-VEGF treatment&#xD;
             regimen must have included bevacizumab, pazopanib, sorafenib or sunitinib administered&#xD;
             not more than 12 weeks before study entry; Note: enrollment not more than 8 weeks&#xD;
             after the last dose of anti-VEGF therapy is encouraged; nevertheless, intercurrent&#xD;
             therapy with an mTOR inhibitor (everolimus or temsirolimus) will be allowed if&#xD;
             progression on that treatment is observed within 12 weeks of the prior anti-VEGF&#xD;
             therapy&#xD;
&#xD;
          -  Any number of prior regimens is allowed; prior investigational therapy is allowed&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 1 (Karnofsky &gt;= 70%)&#xD;
&#xD;
          -  Life expectancy of greater than 3 months&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Total bilirubin =&lt; institutional upper limits of normal&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 2.5 x institutional upper limit of normal&#xD;
&#xD;
          -  Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =&lt;&#xD;
             upper limit of normal (ULN) per institutional laboratory range&#xD;
&#xD;
          -  International normalized ratio (INR) =&lt; 1.5&#xD;
&#xD;
          -  Creatinine within normal institutional limits OR creatinine clearance &gt; 40 mL/min per&#xD;
             24 hour (h) urine collection or calculated according to the Cockcroft-Gault formula&#xD;
&#xD;
          -  Urinary protein =&lt; 100 mg/dL in urinalysis or =&lt; 1+ on dipstick, unless quantitative&#xD;
             protein is &lt; 1000 mg in a 24 h urine sample&#xD;
&#xD;
          -  Generally well-controlled blood pressure with systolic blood pressure =&lt; 140 mmHg AND&#xD;
             diastolic blood pressure =&lt; 90 mmHg prior to enrollment; the use of anti-hypertensive&#xD;
             medications to control hypertension is permitted&#xD;
&#xD;
          -  Patients must have a tumor site amenable to biopsy as determined by the treating&#xD;
             investigator; any questions regarding suitability of a site for biopsy will be&#xD;
             adjudicated by the principal investigator&#xD;
&#xD;
          -  Patients must be willing to consent to tumor biopsy for research purposes&#xD;
&#xD;
          -  Patients should have archival tumor tissue (either unstained slides or tumor blocks)&#xD;
             available for retrieval&#xD;
&#xD;
          -  The effects of AMG 386 are known to be detrimental to fetal development; for this&#xD;
             reason and because inhibitors of angiogenesis as well as other therapeutic agents used&#xD;
             in this trial are known to be teratogenic, women of child-bearing potential and men&#xD;
             must agree to use adequate contraception (hormonal or barrier method of birth control;&#xD;
             abstinence) prior to study entry, for the duration of study participation, and 6&#xD;
             months after completion of AMG 386; should a woman become pregnant or suspect she is&#xD;
             pregnant while she or her partner is participating in this study, she should inform&#xD;
             her treating physician immediately; men treated or enrolled on this protocol must also&#xD;
             agree to use adequate contraception prior to the study, for the duration of study&#xD;
             participation, and 6 months after completion of AMG 386 and bevacizumab, pazopanib,&#xD;
             sunitinib, or sorafenib administration&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Intolerance of prior treatment with bevacizumab, pazopanib, sorafenib, or sunitinib;&#xD;
             Note: subjects who required a dose reduction of pazopanib, sorafenib, or sunitinib&#xD;
             during prior therapy MAY be eligible if they tolerated the agent after dose level&#xD;
             reduction (to a minimum of dose level -2 as defined in this protocol)&#xD;
&#xD;
          -  Central nervous system metastases unless: (1) metastases have been treated and have&#xD;
             remained controlled for at least two weeks following treatment, AND (2) patient has no&#xD;
             residual neurological dysfunction off corticosteroids for at least one week; a CT or&#xD;
             MRI to evaluate for central nervous system (CNS) disease is required for symptomatic&#xD;
             patients only&#xD;
&#xD;
          -  History of venous or arterial thromboembolism within 12 months prior to&#xD;
             enrollment/randomization&#xD;
&#xD;
          -  History of clinically significant bleeding within 6 months of enrollment/randomization&#xD;
&#xD;
          -  Unresolved toxicities from prior systemic therapy that are Common Terminology Criteria&#xD;
             in Adverse Events (CTCAE) version 3.0 or 4.0 &gt;= grade 2 in severity except alopecia&#xD;
&#xD;
          -  Currently or previously treated with AMG 386, or other molecules that inhibit the&#xD;
             angiopoietins or Tie2 receptor&#xD;
&#xD;
          -  Clinically significant cardiovascular disease within 12 months prior to&#xD;
             enrollment/randomization, including myocardial infarction, unstable angina, grade 2 or&#xD;
             greater peripheral vascular disease, cerebrovascular accident, transient ischemic&#xD;
             attack, congestive heart failure, or arrhythmias not controlled by outpatient&#xD;
             medication or placement of percutaneous transluminal coronary angioplasty/stent&#xD;
&#xD;
          -  Major surgery within 28 days prior to enrollment or still recovering from prior&#xD;
             surgery&#xD;
&#xD;
          -  Minor surgical procedures except placement of tunneled central venous access device&#xD;
             within 3 days prior to enrollment&#xD;
&#xD;
          -  Non-healing wound, ulcer (including gastrointestinal), or fracture&#xD;
&#xD;
          -  Subject not consenting to the use of highly effective contraceptive precautions (e.g.,&#xD;
             double barrier method [i.e., condom plus diaphragm]) during the course of the study&#xD;
             and for 6 months after administration of the last study medication&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to AMG 386 or the anti-VEGF agent used in study&#xD;
&#xD;
          -  History of allergic reactions to bacterially-produced proteins&#xD;
&#xD;
          -  Patients who have had anti-VEGFR tyrosine kinase inhibitor within 1 week, mTOR&#xD;
             inhibitor within 1 week or anti-VEGF antibody therapy within 3 weeks prior to entering&#xD;
             the study; patients who have had other forms of chemotherapy or radiotherapy within 4&#xD;
             weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those&#xD;
             who have not recovered from adverse events due to agents administered more than 4&#xD;
             weeks earlier&#xD;
&#xD;
          -  Patients who have not yet completed at least 21 days (30 days for prior monoclonal&#xD;
             antibody therapy) since ending other investigational device or drug trials, or who are&#xD;
             currently receiving other investigational treatments&#xD;
&#xD;
          -  Patients receiving any medications or substances that are strong inhibitors or&#xD;
             inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP450 3A4) are&#xD;
             ineligible; caution is advised for patients requiring weak or moderate CYP450 3A4&#xD;
             inhibitors or inducers; specifically prohibited medicines include indinavir,&#xD;
             nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone,&#xD;
             carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's&#xD;
             wort, and troglitazone&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Pregnant women are excluded from this study because AMG 386, bevacizumab, pazopanib,&#xD;
             sorafenib, and sunitinib are inhibitors of angiogenesis with the potential for&#xD;
             teratogenic or abortifacient effects; because there is an unknown but potential risk&#xD;
             for adverse events in nursing infants secondary to treatment of the mother with AMG&#xD;
             386, breastfeeding must be discontinued if the mother is treated with AMG 386&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             pazopanib, sorafenib, or sunitinib; in addition, these patients are at increased risk&#xD;
             of lethal infections when treated with marrow-suppressive therapy; appropriate studies&#xD;
             will be undertaken in patients receiving combination antiretroviral therapy when&#xD;
             indicated&#xD;
&#xD;
          -  Inability to take oral medications on a continuous basis; patients who are to take&#xD;
             pazopanib, sorafenib, or sunitinib and are unable to swallow pills whole are&#xD;
             ineligible (the pills cannot be crushed or broken)&#xD;
&#xD;
          -  Any condition which in the investigator's opinion makes the subject unsuitable for&#xD;
             study participation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas J Semrad</last_name>
    <role>Principal Investigator</role>
    <affiliation>City of Hope Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>City of Hope Comprehensive Cancer Center</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC / Norris Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California Davis Comprehensive Cancer Center</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City of Hope South Pasadena</name>
      <address>
        <city>South Pasadena</city>
        <state>California</state>
        <zip>91030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wayne State University/Karmanos Cancer Institute</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Metro Minnesota Community Oncology Research Consortium</name>
      <address>
        <city>Saint Louis Park</city>
        <state>Minnesota</state>
        <zip>55416</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UNC Lineberger Comprehensive Cancer Center</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Penn State Milton S Hershey Medical Center</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033-0850</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Cancer Institute (UPCI)</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VCU Massey Cancer Center at Hanover Medical Park</name>
      <address>
        <city>Mechanicsville</city>
        <state>Virginia</state>
        <zip>23116</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Singapore</country>
  </removed_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>August 10, 2012</study_first_submitted>
  <study_first_submitted_qc>August 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 14, 2012</study_first_posted>
  <results_first_submitted>January 7, 2022</results_first_submitted>
  <results_first_submitted_qc>May 17, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">June 7, 2022</results_first_posted>
  <last_update_submitted>May 17, 2022</last_update_submitted>
  <last_update_submitted_qc>May 17, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Renal Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Antineoplastic Agents, Immunological</mesh_term>
    <mesh_term>Sunitinib</mesh_term>
    <mesh_term>Trebananib</mesh_term>
    <mesh_term>Sorafenib</mesh_term>
    <mesh_term>Endothelial Growth Factors</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
    <mesh_term>Immunoglobulin G</mesh_term>
  </intervention_browse>
  <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>August 26, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/82/NCT01664182/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Arm I (Trebananib Monotherapy)</title>
          <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Trebananib: Given IV</description>
        </group>
        <group group_id="P2">
          <title>Arm II (Trebananib and Anti-VEGF Therapy)</title>
          <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Bevacizumab: Given IV&#xD;
Pazopanib Hydrochloride: Given PO&#xD;
Sorafenib Tosylate: Given PO&#xD;
Sunitinib Malate: Given PO&#xD;
Trebananib: Given IV</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Arm I (Trebananib Monotherapy)</title>
          <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Trebananib: Given IV</description>
        </group>
        <group group_id="B2">
          <title>Arm II (Trebananib and Anti-VEGF Therapy)</title>
          <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Bevacizumab: Given IV&#xD;
Pazopanib Hydrochloride: Given PO&#xD;
Sorafenib Tosylate: Given PO&#xD;
Sunitinib Malate: Given PO&#xD;
Trebananib: Given IV</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="17"/>
            <count group_id="B2" value="18"/>
            <count group_id="B3" value="35"/>
          </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="64" lower_limit="49" upper_limit="76"/>
                    <measurement group_id="B2" value="59" lower_limit="46" upper_limit="74"/>
                    <measurement group_id="B3" value="60" lower_limit="46" upper_limit="76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="27"/>
                  </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>American Indian/Alaska Native</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian/Pacific Islander</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black</title>
              <category_list>
                <category>
                  <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>
              <title>Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="21"/>
                  </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="17"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG Performance Score</title>
          <description>ECOG (Eastern Cooperative Oncology Group) Performance Score is a measure of patients' ability to tolerate therapies in serious illness, e.g. chemotherapy.&#xD;
0 = Asymptomatic: Fully active, able to carry on all pre-disease activities without restriction&#xD;
= Restricted in strenuous activity, ambulatory and able to do light work&#xD;
= Capable of all self care, but no work activities; out of bed &gt; 50% of day&#xD;
= Capable of limited self-care; confined to bed or chair &gt; 50% of day&#xD;
= Completely disabled; no self-care; confined to bed or chair&#xD;
= Dead</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior Anti-VEGF Agent</title>
          <description>anti-VEGF agent: anti-Vascular Endothelial Growth Factor receptor agent.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Bevacizumab</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Pazopanib</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Sorafenib</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Sunitinib</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Observed Response Rate</title>
        <description>Defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by RECIST version 1.1 criteria, assessed by MRI: Complete Response (CR), Disappearance of all target lesions:&#xD;
any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm; Partial Response (PR), &gt;= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Best response will be listed for each patient and summarized using standard descriptive methods-point estimate and associated confidence intervals.</description>
        <time_frame>Up to 8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm I (Trebananib Monotherapy)</title>
            <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Trebananib: Given IV</description>
          </group>
          <group group_id="O2">
            <title>Arm II (Trebananib and Anti-VEGF Therapy)</title>
            <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Bevacizumab: Given IV&#xD;
Pazopanib Hydrochloride: Given PO&#xD;
Sorafenib Tosylate: Given PO&#xD;
Sunitinib Malate: Given PO&#xD;
Trebananib: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Observed Response Rate</title>
          <description>Defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by RECIST version 1.1 criteria, assessed by MRI: Complete Response (CR), Disappearance of all target lesions:&#xD;
any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm; Partial Response (PR), &gt;= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Best response will be listed for each patient and summarized using standard descriptive methods-point estimate and associated confidence intervals.</description>
          <units>percentage of patients responding</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="0" upper_limit="20"/>
                    <measurement group_id="O2" value="11" lower_limit="1" upper_limit="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Tumor Response</title>
        <description>Tumor Response Classification</description>
        <time_frame>at 8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm I (Trebananib Monotherapy)</title>
            <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Trebananib: Given IV</description>
          </group>
          <group group_id="O2">
            <title>Arm II (Trebananib and Anti-VEGF Therapy)</title>
            <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Bevacizumab: Given IV&#xD;
Pazopanib Hydrochloride: Given PO&#xD;
Sorafenib Tosylate: Given PO&#xD;
Sunitinib Malate: Given PO&#xD;
Trebananib: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Tumor Response</title>
          <description>Tumor Response Classification</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Evaluable</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS)</title>
        <description>Time to reach Kaplan-Meier median survival (outcome being death or progression) (95% Confidence Interval) is reported. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered a progression.)</description>
        <time_frame>From start of treatment to time of progression or death, whichever occurs first, assessed up to 8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm I (Trebananib Monotherapy)</title>
            <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Trebananib: Given IV</description>
          </group>
          <group group_id="O2">
            <title>Arm II (Trebananib and Anti-VEGF Therapy)</title>
            <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Bevacizumab: Given IV&#xD;
Pazopanib Hydrochloride: Given PO&#xD;
Sorafenib Tosylate: Given PO&#xD;
Sunitinib Malate: Given PO&#xD;
Trebananib: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS)</title>
          <description>Time to reach Kaplan-Meier median survival (outcome being death or progression) (95% Confidence Interval) is reported. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered a progression.)</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.7" lower_limit="2.3" upper_limit="4.7"/>
                    <measurement group_id="O2" value="5.2" lower_limit="2.7" upper_limit="10.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs</title>
        <description>Adverse events were graded using CTCAE version 5.0. Grades 3, 4, 5 (on a scale of 1 to 5, 5 being the worst grade - death) toxicities related ('Possibly', 'Probably', or 'Definitely') to the treatment drugs (AMG 386 alone or in combination with prior VEGF targeted agent).</description>
        <time_frame>8 weeks for adverse events. Until removal from the study or to death for late adverse events, up to 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm I (Trebananib Monotherapy)</title>
            <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Trebananib: Given IV</description>
          </group>
          <group group_id="O2">
            <title>Arm II (Trebananib and Anti-VEGF Therapy)</title>
            <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Bevacizumab: Given IV&#xD;
Pazopanib Hydrochloride: Given PO&#xD;
Sorafenib Tosylate: Given PO&#xD;
Sunitinib Malate: Given PO&#xD;
Trebananib: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs</title>
          <description>Adverse events were graded using CTCAE version 5.0. Grades 3, 4, 5 (on a scale of 1 to 5, 5 being the worst grade - death) toxicities related ('Possibly', 'Probably', or 'Definitely') to the treatment drugs (AMG 386 alone or in combination with prior VEGF targeted agent).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>SAE Cardiac disorders: Cardiac arrest</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE Metabolism and nutrition disorders: Hypokalemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE Respiratory, thoracic and mediastinal disorders: Dyspnea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE Respiratory, thoracic and mediastinal disorders: Pleural effusion</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Blood and lymphatic system disorders: Anemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>General disorders and administrative site conditions: Fatigue</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Investigations: Lymphocyte count decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Investigations: Weight gain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Metabolism and nutrition disorders: Acidosis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Metabolism and nutrition disorders: Hyperglycemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Metabolism and nutrition disorders: Hyponatremia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Musculoskeletal and connective tissue disorders: Back pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Vascular disorders: Hypertension</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Changes in Circulating Angiogenic Factors</title>
        <description>Analyzed as continuous variables (most likely after transformation). The gene expression results from the pretreatment tumor biopsies are expressed as ratios between that of the gene of interest and the internal reference gene beta-actin and can be analyzed as continuous variables - generally after log transformation.</description>
        <time_frame>Baseline to up to 8 weeks</time_frame>
        <population>availability of samples. attrition from the study.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm I (Trebananib Monotherapy)</title>
            <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Trebananib: Given IV</description>
          </group>
          <group group_id="O2">
            <title>Arm II (Trebananib and Anti-VEGF Therapy)</title>
            <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Bevacizumab: Given IV&#xD;
Pazopanib Hydrochloride: Given PO&#xD;
Sorafenib Tosylate: Given PO&#xD;
Sunitinib Malate: Given PO&#xD;
Trebananib: Given IV</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Circulating Angiogenic Factors</title>
          <description>Analyzed as continuous variables (most likely after transformation). The gene expression results from the pretreatment tumor biopsies are expressed as ratios between that of the gene of interest and the internal reference gene beta-actin and can be analyzed as continuous variables - generally after log transformation.</description>
          <population>availability of samples. attrition from the study.</population>
          <units>pg/ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Angiopoietin--2 at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3909" lower_limit="3246" upper_limit="4863"/>
                    <measurement group_id="O2" value="3237" lower_limit="2424" upper_limit="4813"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Angiopoietin--2 prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="132156" lower_limit="110775" upper_limit="160316"/>
                    <measurement group_id="O2" value="120956" lower_limit="84474" upper_limit="131643"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Angiopoietin--2 prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="125928" lower_limit="114871" upper_limit="141528"/>
                    <measurement group_id="O2" value="96075" lower_limit="84200" upper_limit="150486"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tie--2 at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="803" lower_limit="510" upper_limit="1035"/>
                    <measurement group_id="O2" value="835" lower_limit="650" upper_limit="1094"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tie--2 prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="783" lower_limit="535" upper_limit="1041"/>
                    <measurement group_id="O2" value="671" lower_limit="571" upper_limit="856"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tie--2 prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="912" lower_limit="263" upper_limit="1232"/>
                    <measurement group_id="O2" value="753" lower_limit="424" upper_limit="912"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGF--A at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.3" lower_limit="10.5" upper_limit="48.4"/>
                    <measurement group_id="O2" value="26.1" lower_limit="19.6" upper_limit="38.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGF--A prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.3" lower_limit="10.5" upper_limit="29.0"/>
                    <measurement group_id="O2" value="33.4" lower_limit="13.6" upper_limit="48.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGF--A prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.7" lower_limit="0.3" upper_limit="34.2"/>
                    <measurement group_id="O2" value="41.2" lower_limit="26.1" upper_limit="56.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PIGF at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.1" lower_limit="26.1" upper_limit="35.2"/>
                    <measurement group_id="O2" value="30.7" lower_limit="28.3" upper_limit="46.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PIGF prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.5" lower_limit="21.8" upper_limit="36.0"/>
                    <measurement group_id="O2" value="33.6" lower_limit="29.9" upper_limit="39.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PIGF prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.4" lower_limit="30.5" upper_limit="34.3"/>
                    <measurement group_id="O2" value="31.5" lower_limit="26.3" upper_limit="41.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGFR--3 at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="873" lower_limit="157" upper_limit="1073"/>
                    <measurement group_id="O2" value="489" lower_limit="50" upper_limit="898"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGFR--3 prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="722" lower_limit="117" upper_limit="869"/>
                    <measurement group_id="O2" value="50" lower_limit="50" upper_limit="321"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGFR--3 prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="489" lower_limit="362" upper_limit="954"/>
                    <measurement group_id="O2" value="50" lower_limit="50" upper_limit="416"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGF--C at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="255" lower_limit="72" upper_limit="425"/>
                    <measurement group_id="O2" value="283" lower_limit="251" upper_limit="380"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGF--C prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="209" lower_limit="67" upper_limit="340"/>
                    <measurement group_id="O2" value="311" lower_limit="247" upper_limit="357"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VEGF--C prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="230" lower_limit="45" upper_limit="358"/>
                    <measurement group_id="O2" value="311" lower_limit="154" upper_limit="503"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IL--8 at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.1" lower_limit="0.1" upper_limit="12.6"/>
                    <measurement group_id="O2" value="0.1" lower_limit="0.1" upper_limit="4.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IL--8 prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.6" lower_limit="0.1" upper_limit="17.5"/>
                    <measurement group_id="O2" value="5.9" lower_limit="0.1" upper_limit="13.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IL--8 prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.5" lower_limit="0.1" upper_limit="8.1"/>
                    <measurement group_id="O2" value="0.4" lower_limit="0.1" upper_limit="17.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ICAM--1 at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="161879" lower_limit="103645" upper_limit="240620"/>
                    <measurement group_id="O2" value="243594" lower_limit="185653" upper_limit="601003"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ICAM--1 prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="193335" lower_limit="117584" upper_limit="247434"/>
                    <measurement group_id="O2" value="239027" lower_limit="160295" upper_limit="318968"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ICAM--1 prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="262636" lower_limit="221161" upper_limit="266594"/>
                    <measurement group_id="O2" value="200959" lower_limit="150610" upper_limit="276615"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VCAM--1 at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="965554" lower_limit="738499" upper_limit="1421550"/>
                    <measurement group_id="O2" value="1307900" lower_limit="982643" upper_limit="1946700"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VCAM--1 prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1336300" lower_limit="955663" upper_limit="1903550"/>
                    <measurement group_id="O2" value="1850000" lower_limit="1327000" upper_limit="2555600"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>VCAM--1 prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="982488" lower_limit="969237" upper_limit="1581000"/>
                    <measurement group_id="O2" value="1666200" lower_limit="1351500" upper_limit="2091050"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>FGF2 at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="124" lower_limit="105" upper_limit="136"/>
                    <measurement group_id="O2" value="120" lower_limit="105" upper_limit="136"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>FGF2 prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="112" lower_limit="89" upper_limit="131"/>
                    <measurement group_id="O2" value="110" lower_limit="95" upper_limit="132"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>FGF2 prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="131" lower_limit="104" upper_limit="136"/>
                    <measurement group_id="O2" value="120" lower_limit="97" upper_limit="133"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PDGF -- AA at baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="351" lower_limit="237" upper_limit="788"/>
                    <measurement group_id="O2" value="478" lower_limit="112" upper_limit="647"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PDGF -- AA prior to cycle 2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="291" lower_limit="190" upper_limit="394"/>
                    <measurement group_id="O2" value="262" lower_limit="213" upper_limit="829"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PDGF -- AA prior to cycle 3</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="264" lower_limit="119" upper_limit="710"/>
                    <measurement group_id="O2" value="173" lower_limit="105" upper_limit="777"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Arm A vs Arm B shift test on Angiopoietin -- 2 prior to cycle 2. Wilcoxon rank-sum test p-value.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.86</p_value>
            <p_value_desc>No adjustment for multiple comparisons. A-priori threshold for statistical significance is 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Angiopoietin -- 2 prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.76</p_value>
            <p_value_desc>Angiopoietin -- 2 prior to cycle 3.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Tie--2 Prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.14</p_value>
            <p_value_desc>No adjustment for multiple comparison. A-priori threshold for statistical significance is 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Tie -- 2 prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.069</p_value>
            <p_value_desc>No adjustment for multiple comparisons. A-priori threshold for statistical significance is 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>VEGF -- A prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.19</p_value>
            <p_value_desc>P-value is not adjusted for multiple comparisons. A-priori threshold for statistical significance is 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>VEGF--A prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.046</p_value>
            <p_value_desc>P-value is not adjusted for multiple comparisons. The a-priori threshold for statistical significance is 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>PIGF Prior to Cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.029</p_value>
            <p_value_desc>Not adjusted for multiple comparisons. A-priori threshold for statistical significance is 0.05</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>PIGF prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.20</p_value>
            <p_value_desc>P-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is 0.05</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>VEGFR--3 prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.11</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a-priori threshold for statistical significance is 0.05</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>VEGFR--3 prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.068</p_value>
            <p_value_desc>P-value was not adjusted for multiple comparisons. The a-priori threshold for statistical significance was 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>VEGF--C prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.61</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a-priori threshold for statistical significance was 0.05</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>VEGF--C prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.27</p_value>
            <p_value_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>IL--8 prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.61</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a-priori threshold for statistical significance was 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>IL--8 prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.49</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons, and the a-priori threshold for statistical significance was 0.05</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>ICAM--1 prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.82</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a-priori threshold for statistical significance was 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>ICAM--1 prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.069</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>VCAM--1 prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.34</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>VCAM--1 prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.046</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was set to 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>FGF2 prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.11</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was set to 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>FGF2 prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.23</p_value>
            <p_value_desc>The p-value was adjusted for multiple comparisons. The a prior threshold for statistical significance was set to 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>PDGF--AA prior to cycle 2</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.37</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was set to 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>PDGF--AA prior to cycle 3</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two sided hypothesis. Wilcoxon rank-sum test comparing the two arms in terms of the ratio of the post-treatment levels divided by the baseline.</non_inferiority_desc>
            <p_value>0.35</p_value>
            <p_value_desc>The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was set to 0.05.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>8 weeks for adverse events. Until removal from the study or to death for late adverse events, up to 12 weeks</time_frame>
      <desc>CTCAE version 4.0 will be used until March 31, 2018. CTCAE version 5.0 will be used from April 1, 2018.</desc>
      <group_list>
        <group group_id="E1">
          <title>Arm I (Trebananib Monotherapy)</title>
          <description>Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Trebananib: Given IV</description>
        </group>
        <group group_id="E2">
          <title>Arm II (Trebananib and Anti-VEGF Therapy)</title>
          <description>Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.&#xD;
Bevacizumab: Given IV&#xD;
Pazopanib Hydrochloride: Given PO&#xD;
Sorafenib Tosylate: Given PO&#xD;
Sunitinib Malate: Given PO&#xD;
Trebananib: Given IV</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE 5.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Suspected pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Urosepsis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Progressive Disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tumor pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Chronic kidney disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchopulmonary hemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE 5.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="17"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="17"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Decreased RBC count</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Hearing impaired</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Glaucoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Watering eyes</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>redness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Solitary Diverticulm in Caecum</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dry heaves</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="17"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Oral hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>belching</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Atrophic Dermatitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Claudication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Decreased Monocytes</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Facial pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="17"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypoproteinemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Leucocytes in urine</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Leukocytes in urine</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>general edema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>generalised edema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>high triglycerides</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>increased Urobilinogen</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>sweaty</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Epididymidis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Otitis media</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Cellulitis of left hand</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Cholesterol high</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hemoglobin increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Acidosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="17"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Obesity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="17"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Gout flare</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Muscle weakness left-sided</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>left rotator cuff tendinitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>neurogenic claudication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>right shoulder pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>jerking sensation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic kidney disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Nocturia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Urine discoloration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>urinary hesitancy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Gynecomastia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="17"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Postnasal drip</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Sleep apnea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>shortness of breath</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Epidermoid cyst</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Nail loss</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Periorbital edema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Telangiectasia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="17"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="17"/>
                <counts group_id="E2" events="11" subjects_affected="11" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="17"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="18"/>
              </event>
              <event>
                <sub_title>Lymphedema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="17"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="18"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Thomas J Semrad, MD, MAS</name_or_title>
      <organization>Gene Upshaw Memorial Tahoe Forest Cancer Center, Truckee, CA 96161</organization>
      <phone>+1 530 582 6450</phone>
      <email>tsemrad@tfhd.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/NCT01664182
org study id: NCI-2012-01289
secondary id: NCI-2012-01289
secondary id: PHII-122
secondary id: P9048_A12PAMDREVW01
secondary id: CDR0000738785
secondary id: 9048
secondary id: 9048
secondary id: N01CM00038
secondary id: P30CA033572
nct id: NCT01664182
lead sponsor: 
This randomized phase II trial studies how well trebananib with or without bevacizumab,
      pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate works in treating patients
      with kidney cancer that has spread to other places in the body and usually cannot be cured or
      controlled with treatment (advanced). Trebananib may stop the growth of tumor cells by
      blocking blood flow to the tumor. Immunotherapy with monoclonal, such as bevacizumab, may
      help the body's immune system attack the cancer, and may interfere with the ability of tumor
      cells to grow and spread. Pazopanib hydrochloride, sorafenib tosylate, and sunitinib malate
      may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or
      by blocking blood flow to the tumor. It is not yet known whether giving trebananib with or
      without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate is more
      effective in treating kidney cancer.
PRIMARY OBJECTIVE:

      I. To evaluate the overall response rate (complete response [CR] + partial response [PR]) of
      trebananib (AMG 386) alone and in combination with continuation of previously administered
      bevacizumab, pazopanib hydrochloride (pazopanib), sorafenib tosylate (sorafenib), or
      sunitinib malate (sunitinib) in advanced renal cell carcinoma.

      SECONDARY OBJECTIVES:

      I. To evaluate progression free survival in each arm. II. To evaluate the tolerance and
      toxicity of AMG 386 alone and in combination with continuation of the prior VEGF targeted
      agent.

      CORRELATIVE OBJECTIVES:

      I. To evaluate the association between pretreatment tumor gene expression levels and response
      to AMG 386 in combination with continuation of the prior VEGF targeted agent.

      II. To evaluate the association between single nucleotide polymorphisms (SNPs) in angiogenic
      genes and response to AMG 386 in combination with continuation of the prior VEGF targeted
      agent.

      III. To compare changes in circulating angiogenic factors in patients treated with AMG 386
      monotherapy to those treated with AMG 386 in combination with VEGF-targeted therapy.

      IV. To compare expression of angiogenic genes from archival tumor specimens to the expression
      in biopsy specimens obtained after progression on anti-VEGF therapy.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive trebananib intravenously (IV) over 30-60 minutes on days 1, 8, 15,
      22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or
      unacceptable toxicity.

      ARM II: Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes
      on days 1, 15, and 29, pazopanib hydrochloride orally (PO) once daily (QD) on days 1-42,
      sorafenib tosylate PO twice daily (BID) on days 1-42, or sunitinib malate PO QD on days 1-28.
      Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 4-8 weeks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Observed Response Rate
time frame: Up to 8 weeks
description: Defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by RECIST version 1.1 criteria, assessed by MRI: Complete Response (CR), Disappearance of all target lesions:
any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Best response will be listed for each patient and summarized using standard descriptive methods-point estimate and associated confidence intervals.
measure: Tumor Response
time frame: at 8 weeks
description: Tumor Response Classification
measure: Progression Free Survival (PFS)
time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 8 weeks
description: Time to reach Kaplan-Meier median survival (outcome being death or progression) (95% Confidence Interval) is reported. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered a progression.)
measure: Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs
time frame: 8 weeks for adverse events. Until removal from the study or to death for late adverse events, up to 12 weeks
description: Adverse events were graded using CTCAE version 5.0. Grades 3, 4, 5 (on a scale of 1 to 5, 5 being the worst grade - death) toxicities related ('Possibly', 'Probably', or 'Definitely') to the treatment drugs (AMG 386 alone or in combination with prior VEGF targeted agent).
measure: Changes in Circulating Angiogenic Factors
time frame: Baseline to up to 8 weeks
description: Analyzed as continuous variables (most likely after transformation). The gene expression results from the pretreatment tumor biopsies are expressed as ratios between that of the gene of interest and the internal reference gene beta-actin and can be analyzed as continuous variables - generally after log transformation.
arm group label: Arm I (trebananib monotherapy)
arm group type: Experimental
description: Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
arm group label: Arm II (trebananib and anti-VEGF therapy)
arm group type: Experimental
description: Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
intervention type: Biological
intervention name: Bevacizumab
description: Given IV
arm group label: Arm II (trebananib and anti-VEGF therapy)
other name: Anti-VEGF
other name: Anti-VEGF Humanized Monoclonal Antibody
other name: Anti-VEGF rhuMAb
other name: Avastin
other name: Bevacizumab awwb
other name: Bevacizumab Biosimilar BEVZ92
other name: Bevacizumab Biosimilar BI 695502
other name: Bevacizumab Biosimilar CBT 124
other name: Bevacizumab Biosimilar CT-P16
other name: Bevacizumab Biosimilar FKB238
other name: Bevacizumab Biosimilar GB-222
other name: Bevacizumab Biosimilar HD204
other name: Bevacizumab Biosimilar HLX04
other name: Bevacizumab Biosimilar IBI305
other name: Bevacizumab Biosimilar LY01008
other name: Bevacizumab Biosimilar MIL60
other name: Bevacizumab Biosimilar QL 1101
other name: Bevacizumab Biosimilar RPH-001
other name: Bevacizumab Biosimilar SCT501
other name: BP102
other name: BP102 Biosimilar
other name: HD204
other name: Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
other name: Recombinant Humanized Anti-VEGF Monoclonal Antibody
other name: rhuMab-VEGF
other name: SCT501
intervention type: Drug
intervention name: Pazopanib Hydrochloride
description: Given PO
arm group label: Arm II (trebananib and anti-VEGF therapy)
other name: GW786034B
other name: Votrient
intervention type: Drug
intervention name: Sorafenib Tosylate
description: Given PO
arm group label: Arm II (trebananib and anti-VEGF therapy)
other name: BAY 43-9006 Tosylate
other name: BAY 54-9085
other name: Nexavar
other name: sorafenib
intervention type: Drug
intervention name: Sunitinib Malate
description: Given PO
arm group label: Arm II (trebananib and anti-VEGF therapy)
other name: SU011248
other name: SU11248
other name: sunitinib
other name: Sutent
intervention type: Biological
intervention name: Trebananib
description: Given IV
arm group label: Arm I (trebananib monotherapy)
arm group label: Arm II (trebananib and anti-VEGF therapy)
other name: AMG 386
other name: AMG386
other name: Angiopoietin 1/2-Neutralizing Peptibody AMG 386
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Thomas J Semrad
role: Principal Investigator
affiliation: City of Hope Comprehensive Cancer Center
facility: 
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country: United States
country: Singapore
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Renal Cell
mesh term: Bevacizumab
mesh term: Antineoplastic Agents, Immunological
mesh term: Sunitinib
mesh term: Trebananib
mesh term: Sorafenib
mesh term: Endothelial Growth Factors
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal
mesh term: Immunoglobulin G
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 