<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/NCT01730950</url>
  </required_header>
  <id_info>
    <org_study_id>RTOG-1205</org_study_id>
    <secondary_id>NCI-2012-01732</secondary_id>
    <secondary_id>U10CA021661</secondary_id>
    <nct_id>NCT01730950</nct_id>
    <nct_alias>NCT02671981</nct_alias>
  </id_info>
  <brief_title>Bevacizumab With or Without Radiation Therapy in Treating Patients With Recurrent Glioblastoma</brief_title>
  <official_title>Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radiation Therapy Oncology Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Radiation Therapy Oncology Group</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This randomized phase II trial studies how well bevacizumab with or without radiation therapy&#xD;
      works in treating patients with recurrent glioblastoma. Monoclonal antibodies, such as&#xD;
      bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells&#xD;
      to grow and spread. Others find tumor cells and help kill them or carry cancer-killing&#xD;
      substances to them. Specialized radiation therapy that delivers a high dose of radiation&#xD;
      directly to the tumor may kill more tumor cells and cause less damage to normal tissue. It is&#xD;
      not yet know whether bevacizumab is more effective with or without radiation therapy in&#xD;
      treating patients with recurrent glioblastoma&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To establish an improvement in overall survival in recurrent glioblastoma (GBM) patients&#xD;
      receiving bevacizumab and re-irradiation compared with patients receiving bevacizumab alone.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To estimate and compare the rate of objective response in patients with measurable&#xD;
      disease.&#xD;
&#xD;
      II. To estimate and compare the 6-month progression-free survival rate. III. To estimate and&#xD;
      compare progression-free survival. IV. To estimate and compare the rate of treatment adverse&#xD;
      events. V. To estimate and compare the rate of grade 3+ acute or delayed central nervous&#xD;
      system (CNS) toxicity.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 treatment arms.&#xD;
&#xD;
      In both arms, courses repeat every 2 weeks in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 2 months for 1 year,&#xD;
      every 6 months for 1 year and then annually thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 20, 2012</start_date>
  <completion_date type="Actual">December 22, 2022</completion_date>
  <primary_completion_date type="Actual">September 3, 2018</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>Overall Survival</measure>
    <time_frame>From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
    <description>Survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Complete or Partial Best Response</measure>
    <time_frame>From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
    <description>Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria:&#xD;
Complete Response (CR): complete disappearance of measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and no corticosteroids.&#xD;
Partial Response (PR): ≥ 50% decrease from baseline in sum of products of the measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and stable/reduced corticosteroid dose.&#xD;
Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy.&#xD;
Stable Disease (SD): all of following: does not qualify for CR, PR, or P; receiving stable/decreasing doses of steroids.&#xD;
Estimated using an exact binomial distribution.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Progression-free at 6 Months</measure>
    <time_frame>From randomization to six months</time_frame>
    <description>Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria:&#xD;
Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free at 6 months means patient alive without progression at 6 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
    <description>Progression using using MacDonald Criteria is defined as ≥ 25% increase from baseline in sum of products of the two largest perpendicular cross-sectional diameters of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Grade 3+ Central Nervous System (CNS) Toxicity Within 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment</measure>
    <time_frame>From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
    <description>Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Grade 3+ CNS Toxicity More Than 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment</measure>
    <time_frame>From 91 days after the start of radiation therapy to end of follow-up. Maximum follow-up at the time of analysis is 58.2 months.</time_frame>
    <description>Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Estimated using an exact binomial distribution together with 95% confidence interval. The difference between the two groups will be tested using a chi square test.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">182</enrollment>
  <condition>Adult Giant Cell Glioblastoma</condition>
  <condition>Adult Glioblastoma</condition>
  <condition>Adult Gliosarcoma</condition>
  <condition>Recurrent Adult Brain Tumor</condition>
  <arm_group>
    <arm_group_label>Bevacizumab</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bevacizumab every 2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bevacizumab + RT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Radiation therapy with bevacizumab every 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>bevacizumab</intervention_name>
    <description>Staring within 14 days of randomization, IV 10mg/kg every two weeks until disease progression.</description>
    <arm_group_label>Bevacizumab</arm_group_label>
    <arm_group_label>Bevacizumab + RT</arm_group_label>
    <other_name>anti-VEGF humanized monoclonal antibody</other_name>
    <other_name>anti-VEGF monoclonal antibody</other_name>
    <other_name>Avastin</other_name>
    <other_name>rhuMAb VEGF</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>radiation therapy</intervention_name>
    <description>Starting with second dose of bevacizumab, 35 Gy in 10 fractions of 3.5 Gy each delivered on consecutive treatment days (typically 5 fractions per week).</description>
    <arm_group_label>Bevacizumab + RT</arm_group_label>
    <other_name>3D conformal radiation therapy</other_name>
    <other_name>photon beam radiation therapy</other_name>
    <other_name>proton beam radiation therapy</other_name>
    <other_name>Intensity Modulated Radiation Therapy (IMRT)</other_name>
    <other_name>Image-Guided Radiation Treatment (IGRT)</other_name>
    <other_name>3D-CRT</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histopathologically proven diagnosis of glioblastoma or variants (gliosarcoma, giant&#xD;
             cell glioblastoma etc); patients will be eligible if the original histology was&#xD;
             lower-grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made&#xD;
&#xD;
          -  Patients who did not have recent surgery for their glioblastoma must have shown&#xD;
             unequivocal radiographic evidence for tumor progression by contrast-enhanced magnetic&#xD;
             resonance imaging (MRI) scan (or computed tomography [CT] scan for patients with&#xD;
             non-compatible devices) CT scan within 21 days prior to registration.&#xD;
&#xD;
             * Note: Patients who did have surgery with a post-operative contrast-enhance scan&#xD;
             falling outside the 5 week window prior to registration, must have a repeat MRI scan&#xD;
             (or CT scan for patients with non-compatible devices) within 21 days prior to&#xD;
             registration.&#xD;
&#xD;
          -  Patients also must have passed an interval of 6 months or greater between completion&#xD;
             of prior radiotherapy and registration; if patients have not passed an interval of at&#xD;
             least 6 months, they may still be eligible if they meet one or more of the following&#xD;
             criteria:&#xD;
&#xD;
               -  New areas of tumor outside the original radiotherapy fields as determined by the&#xD;
                  investigator, or&#xD;
&#xD;
               -  Histologic confirmation of tumor through biopsy or resection, or&#xD;
&#xD;
               -  Nuclear medicine imaging, magnetic resonance (MR) spectroscopy, or MR perfusion&#xD;
                  imaging consistent with true progressive disease, rather than radiation necrosis&#xD;
                  obtained within 28 days of registration AND an interval of at least 90 days&#xD;
                  between completion of radiotherapy and registration&#xD;
&#xD;
          -  Patients unable to undergo MR imaging because of non-compatible devices can be&#xD;
             enrolled provided CT scans are obtained and are of sufficient quality; patients&#xD;
             without non-compatible devices may not use CT scans performed to meet this requirement&#xD;
&#xD;
          -  Prior history of standard dose CNS radiation of 60 Gy in 30 fractions or 59.4 Gy in&#xD;
             1.8 Gy fractions, or equivalent or lower doses&#xD;
&#xD;
          -  Patients who have received prior treatment with non-standard radiation therapy (RT)&#xD;
             dose and fractionation, interstitial brachytherapy, stereotactic radiosurgery, etc.&#xD;
             are eligible&#xD;
&#xD;
          -  Patients must have recovered from the toxic effects of prior therapy, and there must&#xD;
             be a minimum time of 28 days prior to registration from the administration of any&#xD;
             investigational agent or prior cytotoxic therapy with the following exceptions:&#xD;
&#xD;
               -  14 days from administration of vincristine&#xD;
&#xD;
               -  42 days from administration of nitrosoureas&#xD;
&#xD;
               -  21 days from administration of procarbazine&#xD;
&#xD;
          -  Patients having undergone recent resection of their glioblastoma (within 5 weeks prior&#xD;
             to registration) must have recovered from the effects of surgery; for CNS related core&#xD;
             or needle biopsies, a minimum of 7 days must have elapsed prior to registration&#xD;
&#xD;
          -  Residual disease following resection of recurrent glioblastoma is not mandated for&#xD;
             eligibility into the study; to best assess the extent of residual disease&#xD;
             post-operatively, a post-operative or intra-operative MRI scan (or CT scan for&#xD;
             patients with non-compatible devices) must be performed prior to registration and&#xD;
             should be within 96 hours post surgery (although 24 hours would be optimum)&#xD;
&#xD;
          -  History/physical examination, including neurologic examination, within 14 days prior&#xD;
             to registration&#xD;
&#xD;
          -  Karnofsky performance status &gt;= 60 within 14 days prior to registration&#xD;
&#xD;
          -  Complete blood count (CBC)/differential obtained within 14 days prior to registration,&#xD;
             with adequate bone marrow function&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1,500 cells/mm^3&#xD;
&#xD;
          -  Platelets &gt;= 75,000 cells/mm^3&#xD;
&#xD;
          -  Hemoglobin &gt;= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve&#xD;
             hemoglobin (Hgb) &gt;= 9.0 g/dl is acceptable)&#xD;
&#xD;
          -  Total bilirubin =&lt; 2.0 mg/dL&#xD;
&#xD;
          -  Serum glutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST) =&lt;&#xD;
             2.5 times the upper limit of normal&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.8 mg/dL&#xD;
&#xD;
          -  Urine protein creatinine (UPC) ratio &gt;= 1.0 within 14 days prior to registration OR&#xD;
             urine dipstick for proteinuria &gt;= 2+ (patients discovered to have &gt;= 2+ proteinuria on&#xD;
             dipstick urinalysis at baseline should undergo a 24-hour urine collection and must&#xD;
             demonstrate =&lt; 1g of protein in 24 hours to be eligible)&#xD;
&#xD;
               -  Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein&#xD;
                  excretion; a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1&#xD;
                  gm; UPC ratio is calculated using one of the following formulas:&#xD;
&#xD;
                    -  [urine protein]/[urine creatinine]: if both protein and creatinine are&#xD;
                       reported in mg/dL&#xD;
&#xD;
                    -  [(urine protein) x 0.088]/[urine creatinine]: if urine creatinine is&#xD;
                       reported in mmol/L&#xD;
&#xD;
          -  Patients must not be pregnant (positive pregnancy test) or breast feeding; pregnancy&#xD;
             test must be done within 14 days prior to registration; effective contraception (men&#xD;
             and women) must be used in patients of child-bearing potential while on trial and for&#xD;
             6 months after&#xD;
&#xD;
          -  Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight (LMW)&#xD;
             heparin) must meet both of the following criteria:&#xD;
&#xD;
               -  No active bleeding or pathological condition that carries a high risk of bleeding&#xD;
                  (e.g., tumor involving major vessels or known varices)&#xD;
&#xD;
               -  In-range international normalized ratio (INR) (usually between 2 and 3) on a&#xD;
                  stable dose of oral anticoagulant or on a stable dose of low molecular weight&#xD;
                  heparin, within 14 days prior to registration&#xD;
&#xD;
          -  Patient must be able to provide study-specific informed consent prior to study entry&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  More than three relapses&#xD;
&#xD;
          -  Infratentorial or leptomeningeal evidence of recurrent disease&#xD;
&#xD;
          -  Recurrent or persistent tumor greater than 6 cm in maximum diameter&#xD;
&#xD;
          -  Prior therapy with an inhibitor of vascular endothelial growth factor (VEGF) or VEGFR&#xD;
             (including bevacizumab)&#xD;
&#xD;
          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free&#xD;
             for a minimum of 1 year (for example, carcinoma in situ of the breast, oral cavity, or&#xD;
             cervix are all permissible)&#xD;
&#xD;
          -  Severe, active co-morbidity, defined as follows:&#xD;
&#xD;
               -  Unstable angina and/or congestive heart failure requiring hospitalization within&#xD;
                  the last 6 months prior to registration&#xD;
&#xD;
               -  Transmural myocardial infarction within the last 6 months prior to registration&#xD;
&#xD;
               -  History of stroke or transient ischemic attack within 6 months prior to&#xD;
                  registration&#xD;
&#xD;
               -  Significant vascular disease (e.g., aortic aneurysm, history of aortic&#xD;
                  dissection) or clinically significant peripheral vascular disease&#xD;
&#xD;
               -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time&#xD;
                  of registration&#xD;
&#xD;
               -  Chronic obstructive pulmonary disease exacerbation or other respiratory illness&#xD;
                  requiring hospitalization or precluding study therapy at the time of registration&#xD;
&#xD;
               -  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;&#xD;
                  note, however, that laboratory tests for liver function other than screening&#xD;
                  panel and coagulation parameters are not required for entry into this protocol&#xD;
&#xD;
               -  Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease&#xD;
                  Control and Prevention (CDC) definition; note, however, that human&#xD;
                  immunodeficiency virus (HIV) testing is not required for entry into this&#xD;
                  protocol; the need to exclude patients with AIDS from this protocol is necessary&#xD;
                  because the treatments involved in this protocol may be significantly&#xD;
                  immunosuppressive; protocol specific requirements may also exclude&#xD;
                  immuno-compromised patients&#xD;
&#xD;
          -  Pregnancy or women of childbearing potential and men who are sexually active and not&#xD;
             willing/able to use medically acceptable forms of contraception; this exclusion is&#xD;
             necessary because the treatment involved in this study may be significantly&#xD;
             teratogenic&#xD;
&#xD;
          -  Prior allergic reaction to the study drug (bevacizumab)&#xD;
&#xD;
          -  Prior history of hypertensive crisis or hypertensive encephalopathy&#xD;
&#xD;
          -  History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months)&#xD;
             prior to registration&#xD;
&#xD;
          -  Gastrointestinal bleeding or any other hemorrhage/bleeding event Common Terminology&#xD;
             Criteria for adverse Events (CTCAE), v. 4 grade 3 or greater within 30 days prior to&#xD;
             registration&#xD;
&#xD;
          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days&#xD;
             prior to registration (with the exception of craniotomy)&#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>Christina Tsien</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jeffrey Raizer, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Northwestern University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Adam P. Dicker, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Jefferson Medical College of Thomas Jefferson University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Martha M. Matuszak, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>University of Michigan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Arizona Oncology Services Foundation</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Arizona Oncology-Deer Valley Center</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>John Muir Medical Center</name>
      <address>
        <city>Walnut Creek</city>
        <state>California</state>
        <zip>94598</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520-8032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami Miller School of Medicine-Sylvester Cancer Center</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen's Medical Center</name>
      <address>
        <city>Honolulu</city>
        <state>Hawaii</state>
        <zip>96813</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Radiation Oncology Associates PC</name>
      <address>
        <city>Fort Wayne</city>
        <state>Indiana</state>
        <zip>46804</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IU Health Methodist Hospital</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Hospital of South Bend</name>
      <address>
        <city>South Bend</city>
        <state>Indiana</state>
        <zip>46601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norton Health Care Pavilion - Downtown</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maine Medical Center- Scarborough Campus</name>
      <address>
        <city>Scarborough</city>
        <state>Maine</state>
        <zip>04074</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lowell General Hospital</name>
      <address>
        <city>Lowell</city>
        <state>Massachusetts</state>
        <zip>01854</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan University Hospital</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Michigan Cancer Center</name>
      <address>
        <city>Kalamazoo</city>
        <state>Michigan</state>
        <zip>49007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nebraska Methodist Hospital</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Rochester</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cone Health Cancer Center</name>
      <address>
        <city>Greensboro</city>
        <state>North Carolina</state>
        <zip>27403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Summa Akron City Hospital</name>
      <address>
        <city>Akron</city>
        <state>Ohio</state>
        <zip>44304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Summa Barberton Hospital</name>
      <address>
        <city>Barberton</city>
        <state>Ohio</state>
        <zip>44203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lancaster General Hospital</name>
      <address>
        <city>Lancaster</city>
        <state>Pennsylvania</state>
        <zip>17604</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Radiation Therapy Oncology Group</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allegheny Cancer Center at Allegheny General Hospital</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15212</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical University of South Carolina</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Texas Medical Branch</name>
      <address>
        <city>Galveston</city>
        <state>Texas</state>
        <zip>77555-0565</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>North Star Lodge Cancer Center at Yakima Valley Memorial Hospital</name>
      <address>
        <city>Yakima</city>
        <state>Washington</state>
        <zip>98902</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Vincent Hospital</name>
      <address>
        <city>Green Bay</city>
        <state>Wisconsin</state>
        <zip>54301</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Mary's Hospital</name>
      <address>
        <city>Green Bay</city>
        <state>Wisconsin</state>
        <zip>54303</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bay Area Medical Center</name>
      <address>
        <city>Marinette</city>
        <state>Wisconsin</state>
        <zip>54143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Door County Cancer Center</name>
      <address>
        <city>Sturgeon Bay</city>
        <state>Wisconsin</state>
        <zip>54235-1495</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>November 15, 2012</study_first_submitted>
  <study_first_submitted_qc>November 15, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2012</study_first_posted>
  <results_first_submitted>February 20, 2020</results_first_submitted>
  <results_first_submitted_qc>March 13, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">March 17, 2020</results_first_posted>
  <last_update_submitted>December 27, 2022</last_update_submitted>
  <last_update_submitted_qc>December 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 29, 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>Glioblastoma</mesh_term>
    <mesh_term>Gliosarcoma</mesh_term>
    <mesh_term>Recurrence</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>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</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>October 3, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/50/NCT01730950/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 3, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/50/NCT01730950/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Bevacizumab</title>
          <description>Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
        </group>
        <group group_id="P2">
          <title>Bevacizumab + RT</title>
          <description>Radiation therapy (35Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="90"/>
                <participants group_id="P2" count="92"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Eligible Population</title>
              <participants_list>
                <participants group_id="P1" count="84"/>
                <participants group_id="P2" count="86"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Adverse Event Population</title>
              <participants_list>
                <participants group_id="P1" count="76"/>
                <participants group_id="P2" count="83"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Response Population</title>
              <participants_list>
                <participants group_id="P1" count="78"/>
                <participants group_id="P2" count="77"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>6-month Progression-free Analysis</title>
              <participants_list>
                <participants group_id="P1" count="79"/>
                <participants group_id="P2" count="81"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Delayed Toxicity Population</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="83"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="84"/>
                <participants group_id="P2" count="86"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Eligible participants</population>
      <group_list>
        <group group_id="B1">
          <title>Bevacizumab</title>
          <description>Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
        </group>
        <group group_id="B2">
          <title>Bevacizumab + RT</title>
          <description>Radiation therapy (35Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</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="84"/>
            <count group_id="B2" value="86"/>
            <count group_id="B3" value="170"/>
          </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="57" lower_limit="25" upper_limit="87"/>
                    <measurement group_id="B2" value="60" lower_limit="28" upper_limit="81"/>
                    <measurement group_id="B3" value="59" lower_limit="25" upper_limit="87"/>
                  </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="38"/>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="81"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="89"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="72"/>
                    <measurement group_id="B2" value="81"/>
                    <measurement group_id="B3" value="153"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="66"/>
                    <measurement group_id="B2" value="75"/>
                    <measurement group_id="B3" value="141"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Karnofsky Performance Status</title>
          <description>60 = Requires occasional assistance, but is able to care for most personal needs; 70 = Cares for self; unable to carry on normal activity or to do active work; 80 = Normal activity with effort; some signs or symptoms of disease; 90 = Able to carry on normal activity, minor signs or symptoms of disease; 100 = Normal no complaints; no evidence of disease.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>60</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>70-80</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                    <measurement group_id="B2" value="41"/>
                    <measurement group_id="B3" value="83"/>
                  </measurement_list>
                </category>
                <category>
                  <title>90-100</title>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                    <measurement group_id="B2" value="37"/>
                    <measurement group_id="B3" value="76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Neurologic Function</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>No symptoms</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="45"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Minor symptoms</title>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                    <measurement group_id="B2" value="36"/>
                    <measurement group_id="B3" value="76"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Moderate symptoms (fully active)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Moderate symptoms (required assistance)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Severe symptoms</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Surgery for Initial Brain Tumor</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Biopsy only</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Subtotal resection</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="45"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Gross total resection</title>
                  <measurement_list>
                    <measurement group_id="B1" value="56"/>
                    <measurement group_id="B2" value="52"/>
                    <measurement group_id="B3" value="108"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Recent Resection</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>No / biopsy only</title>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                    <measurement group_id="B2" value="57"/>
                    <measurement group_id="B3" value="106"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Histologic Tumor Type</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Glioblastoma (WHO Grade IV)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="79"/>
                    <measurement group_id="B2" value="82"/>
                    <measurement group_id="B3" value="161"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Gliosarcoma</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>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <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>Overall Survival</title>
        <description>Survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.</description>
        <time_frame>From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
        <population>Eligible participants</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab</title>
            <description>Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + RT</title>
            <description>Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.</description>
          <population>Eligible participants</population>
          <units>percentage of participants</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="84"/>
                <count group_id="O2" value="86"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.1" lower_limit="15.2" upper_limit="35.0"/>
                    <measurement group_id="O2" value="21.6" lower_limit="12.1" upper_limit="31.1"/>
                  </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>Null hypothesis: median survival time for both arms is 9 months; alternative hypothesis: participants receiving radiation therapy plus bevacizumab will have an improvement in median survival time to 13 months. One hundred and sixty eligible participants provides 80% power to detect a 31% reduction in the hazard ratio to 0.69 at a one-sided significance level of 0.10. Analysis was planned to occur when 135 deaths were reported, expected to occur 16 to 21 months after trial closure.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.46</p_value>
            <method>Log Rank</method>
            <method_desc>Two-side significance level = 0.05</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.98</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.70</ci_lower_limit>
            <ci_upper_limit>1.38</ci_upper_limit>
            <estimate_desc>Reference level = Bevacizumab</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Complete or Partial Best Response</title>
        <description>Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria:&#xD;
Complete Response (CR): complete disappearance of measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and no corticosteroids.&#xD;
Partial Response (PR): ≥ 50% decrease from baseline in sum of products of the measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and stable/reduced corticosteroid dose.&#xD;
Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy.&#xD;
Stable Disease (SD): all of following: does not qualify for CR, PR, or P; receiving stable/decreasing doses of steroids.&#xD;
Estimated using an exact binomial distribution.</description>
        <time_frame>From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
        <population>Eligible participants with response evaluations</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab</title>
            <description>Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + RT</title>
            <description>Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Complete or Partial Best Response</title>
          <description>Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria:&#xD;
Complete Response (CR): complete disappearance of measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and no corticosteroids.&#xD;
Partial Response (PR): ≥ 50% decrease from baseline in sum of products of the measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and stable/reduced corticosteroid dose.&#xD;
Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy.&#xD;
Stable Disease (SD): all of following: does not qualify for CR, PR, or P; receiving stable/decreasing doses of steroids.&#xD;
Estimated using an exact binomial distribution.</description>
          <population>Eligible participants with response evaluations</population>
          <units>percentage of participants</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="78"/>
                <count group_id="O2" value="77"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.5" lower_limit="12.2" upper_limit="31.2"/>
                    <measurement group_id="O2" value="29.9" lower_limit="20.0" upper_limit="41.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.18</p_value>
            <method>Chi-squared</method>
            <method_desc>Two-sided significance level = 0.05</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Progression-free at 6 Months</title>
        <description>Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria:&#xD;
Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free at 6 months means patient alive without progression at 6 months.</description>
        <time_frame>From randomization to six months</time_frame>
        <population>Eligible participants with data at six months</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab</title>
            <description>Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + RT</title>
            <description>Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Progression-free at 6 Months</title>
          <description>Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria:&#xD;
Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free at 6 months means patient alive without progression at 6 months.</description>
          <population>Eligible participants with data at six months</population>
          <units>percentage of participants</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="79"/>
                <count group_id="O2" value="81"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.1" lower_limit="19.4" upper_limit="40.4"/>
                    <measurement group_id="O2" value="54.3" lower_limit="42.9" upper_limit="65.4"/>
                  </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>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.001</p_value>
            <method>Chi-squared</method>
            <method_desc>Two-sided significance level = 0.05</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival</title>
        <description>Progression using using MacDonald Criteria is defined as ≥ 25% increase from baseline in sum of products of the two largest perpendicular cross-sectional diameters of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.</description>
        <time_frame>From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
        <population>Eligible participants</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab</title>
            <description>Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + RT</title>
            <description>Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival</title>
          <description>Progression using using MacDonald Criteria is defined as ≥ 25% increase from baseline in sum of products of the two largest perpendicular cross-sectional diameters of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.</description>
          <population>Eligible participants</population>
          <units>percentage of participants</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="84"/>
                <count group_id="O2" value="86"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.9" lower_limit="2.6" upper_limit="15.2"/>
                    <measurement group_id="O2" value="7.9" lower_limit="1.9" upper_limit="13.9"/>
                  </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>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.05</p_value>
            <method>Log Rank</method>
            <method_desc>Two-sided significance level = 0.05</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.73</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.53</ci_lower_limit>
            <ci_upper_limit>1.00</ci_upper_limit>
            <estimate_desc>Reference level = Bevacizumab</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Grade 3+ Central Nervous System (CNS) Toxicity Within 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment</title>
        <description>Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.</description>
        <time_frame>From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
        <population>Eligible participants on the radiation therapy arm who started radiation therapy</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab + RT</title>
            <description>Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Grade 3+ Central Nervous System (CNS) Toxicity Within 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment</title>
          <description>Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.</description>
          <population>Eligible participants on the radiation therapy arm who started radiation therapy</population>
          <units>percentage of participants</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="83"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.8" lower_limit="1.3" upper_limit="11.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Grade 3+ CNS Toxicity More Than 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment</title>
        <description>Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Estimated using an exact binomial distribution together with 95% confidence interval. The difference between the two groups will be tested using a chi square test.</description>
        <time_frame>From 91 days after the start of radiation therapy to end of follow-up. Maximum follow-up at the time of analysis is 58.2 months.</time_frame>
        <population>Eligible participants on the radiation therapy arm who started radiation therapy and were alive at least 91 days from the start of radiation therapy</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab + RT</title>
            <description>Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Grade 3+ CNS Toxicity More Than 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment</title>
          <description>Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Estimated using an exact binomial distribution together with 95% confidence interval. The difference between the two groups will be tested using a chi square test.</description>
          <population>Eligible participants on the radiation therapy arm who started radiation therapy and were alive at least 91 days from the start of radiation therapy</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="83"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were to be reported every 2 months for first year, every 6 months for second year, then annually until study completion. Maximum follow-up at time of analysis was 52.8 months.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Bevacizumab</title>
          <description>Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
        </group>
        <group group_id="E2">
          <title>Bevacizumab + RT</title>
          <description>Radiation therapy (35Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="27" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenic purpura</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colonic obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Colonic perforation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Upper gastrointestinal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death NOS</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Neck edema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Sudden death NOS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections and infestations - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Wound dehiscence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Investigations - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Alkalosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Muscle weakness left-sided</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Muscle weakness right-sided</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Musculoskeletal deformity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebrospinal fluid leakage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Intracranial hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Stroke</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Aspiration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hematoma</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Vasculitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="70" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="73" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Eye disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="34" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="47" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections and infestations - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Muscle weakness left-sided</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Muscle weakness right-sided</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Muscle weakness upper limb</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Ataxia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="37" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="83"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="33" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="83"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="76"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="83"/>
              </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>PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Wendy Seiferheld</name_or_title>
      <organization>NRG Oncology</organization>
      <phone>215-574-3208</phone>
      <email>seiferheldw@nrgoncology.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01730950
org study id: RTOG-1205
secondary id: NCI-2012-01732
secondary id: U10CA021661
nct id: NCT01730950
nct alias: NCT02671981
lead sponsor: 
collaborator: 
has dmc: Yes
This randomized phase II trial studies how well bevacizumab with or without radiation therapy
      works in treating patients with recurrent glioblastoma. Monoclonal antibodies, such as
      bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells
      to grow and spread. Others find tumor cells and help kill them or carry cancer-killing
      substances to them. Specialized radiation therapy that delivers a high dose of radiation
      directly to the tumor may kill more tumor cells and cause less damage to normal tissue. It is
      not yet know whether bevacizumab is more effective with or without radiation therapy in
      treating patients with recurrent glioblastoma
PRIMARY OBJECTIVES:

      I. To establish an improvement in overall survival in recurrent glioblastoma (GBM) patients
      receiving bevacizumab and re-irradiation compared with patients receiving bevacizumab alone.

      SECONDARY OBJECTIVES:

      I. To estimate and compare the rate of objective response in patients with measurable
      disease.

      II. To estimate and compare the 6-month progression-free survival rate. III. To estimate and
      compare progression-free survival. IV. To estimate and compare the rate of treatment adverse
      events. V. To estimate and compare the rate of grade 3+ acute or delayed central nervous
      system (CNS) toxicity.

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

      In both arms, courses repeat every 2 weeks in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 2 months for 1 year,
      every 6 months for 1 year and then annually thereafter.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Survival
time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.
description: Survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.
measure: Percentage of Participants With Complete or Partial Best Response
time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.
description: Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria:
Complete Response (CR): complete disappearance of measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and no corticosteroids.
Partial Response (PR): ≥ 50% decrease from baseline in sum of products of the measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and stable/reduced corticosteroid dose.
Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy.
Stable Disease (SD): all of following: does not qualify for CR, PR, or P; receiving stable/decreasing doses of steroids.
Estimated using an exact binomial distribution.
measure: Percentage of Participants Progression-free at 6 Months
time frame: From randomization to six months
description: Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria:
Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free at 6 months means patient alive without progression at 6 months.
measure: Progression-free Survival
time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.
description: Progression using using MacDonald Criteria is defined as ≥ 25% increase from baseline in sum of products of the two largest perpendicular cross-sectional diameters of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.
measure: Percentage of Participants With Grade 3+ Central Nervous System (CNS) Toxicity Within 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment
time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.
description: Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.
measure: Number of Participants With Grade 3+ CNS Toxicity More Than 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment
time frame: From 91 days after the start of radiation therapy to end of follow-up. Maximum follow-up at the time of analysis is 58.2 months.
description: Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Estimated using an exact binomial distribution together with 95% confidence interval. The difference between the two groups will be tested using a chi square test.
arm group label: Bevacizumab
arm group type: Active Comparator
description: Bevacizumab every 2 weeks
arm group label: Bevacizumab + RT
arm group type: Experimental
description: Radiation therapy with bevacizumab every 2 weeks
intervention type: Biological
intervention name: bevacizumab
description: Staring within 14 days of randomization, IV 10mg/kg every two weeks until disease progression.
arm group label: Bevacizumab
arm group label: Bevacizumab + RT
other name: anti-VEGF humanized monoclonal antibody
other name: anti-VEGF monoclonal antibody
other name: Avastin
other name: rhuMAb VEGF
intervention type: Radiation
intervention name: radiation therapy
description: Starting with second dose of bevacizumab, 35 Gy in 10 fractions of 3.5 Gy each delivered on consecutive treatment days (typically 5 fractions per week).
arm group label: Bevacizumab + RT
other name: 3D conformal radiation therapy
other name: photon beam radiation therapy
other name: proton beam radiation therapy
other name: Intensity Modulated Radiation Therapy (IMRT)
other name: Image-Guided Radiation Treatment (IGRT)
other name: 3D-CRT
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Christina Tsien
role: Principal Investigator
affiliation: Washington University School of Medicine
last name: Jeffrey Raizer, MD
role: Study Chair
affiliation: Northwestern University
last name: Adam P. Dicker, MD, PhD
role: Study Chair
affiliation: Jefferson Medical College of Thomas Jefferson University
last name: Martha M. Matuszak, PhD
role: Study Chair
affiliation: University of Michigan
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country: United States
responsible party type: Sponsor
mesh term: Glioblastoma
mesh term: Gliosarcoma
mesh term: Recurrence
mesh term: Bevacizumab
mesh term: Antineoplastic Agents, Immunological
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal
provided document: 
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participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 