<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/NCT01718873</url>
  </required_header>
  <id_info>
    <org_study_id>OBELICS</org_study_id>
    <secondary_id>2011-004997-27</secondary_id>
    <nct_id>NCT01718873</nct_id>
  </id_info>
  <brief_title>Optimization of Bevacizumab Scheduling With Chemotherapy for Metastatic Colorectal Cancer</brief_title>
  <acronym>OBELICS</acronym>
  <official_title>Randomized Phase 3 Study on the Optimization of Bevacizumab With mFOLFOX/mOXXEL in the Treatment of Patients With Metastatic Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute, Naples</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute, Naples</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate if giving bevacizumab prior to chemotherapy compared&#xD;
      to giving bevacizumab at the same time as chemotherapy improves patient overall response to&#xD;
      treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OBELICS is a two-arm phase 3 trial comparing in mCRC patients (1:1): concurrent&#xD;
      administration of bevacizumab in combination with modified FOLFOX-6 regimen (mFOLFOX-6) or&#xD;
      modified OXXEL regimen (mOXXEL), in which bevacizumab is administered the same day as&#xD;
      oxaliplatin, (standard arm); and sequential administration of bevacizumab with the same&#xD;
      chemotherapeutic regimens, in which bevacizumab is administered 4 days before oxaliplatin at&#xD;
      each cycle (experimental arm) Oxaliplatin regimen (mFOLFOX/mOXXEL) is chosen according to&#xD;
      local clinical practice at the beginning of the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2012</start_date>
  <completion_date type="Actual">December 2019</completion_date>
  <primary_completion_date type="Actual">December 2015</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>Objective response was assessed by computed tomographic scan or other appropriate imaging at weeks 12 and 24 from randomization, and every 3 months thereafter, assessed up to 90 months.</time_frame>
    <description>Objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, was the primary end point and was defined as the number of complete plus partial responses divided by the number of enrolled patients.&#xD;
Per RECIST v 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate</measure>
    <time_frame>At weeks 12 and 24 from randomization and every 3 months thereafter, assessed up to 90 months</time_frame>
    <description>Disease control rate was calculated by adding complete and partial responses and stable disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>assessed up to 90 months</time_frame>
    <description>Overall survival was defined as the time from randomization to the date of death. Patients alive at the time of the final analysis were censored on the date of the last follow-up information available.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>assessed up to 90 months</time_frame>
    <description>Progression-free survival was defined as the time from randomization to the date of progression or death, whichever occurred first. Patients without progression were censored on the date of the last follow-up visit.&#xD;
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxic Effects</measure>
    <time_frame>up to 4 weeks after the end of the treatment</time_frame>
    <description>Toxic effects were scored according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. For the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 scale score range from 1 to 4. A high score, that is 3 and 4, represents a high level of toxicity, whereas the minimum values, that is 1 and 2, represents a mild/modest level of toxicity.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">230</enrollment>
  <condition>Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>bevacizumab before chemotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>bevacizumab with chemotherapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.</description>
    <arm_group_label>bevacizumab before chemotherapy</arm_group_label>
    <arm_group_label>bevacizumab with chemotherapy</arm_group_label>
    <other_name>Avastin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>85mg/m2 IV every 2 weeks for up to 24 weeks</description>
    <arm_group_label>bevacizumab before chemotherapy</arm_group_label>
    <arm_group_label>bevacizumab with chemotherapy</arm_group_label>
    <other_name>Eloxatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>levo-folinic acid</intervention_name>
    <description>200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks</description>
    <arm_group_label>bevacizumab before chemotherapy</arm_group_label>
    <arm_group_label>bevacizumab with chemotherapy</arm_group_label>
    <other_name>Lederfolin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-fluorouracil</intervention_name>
    <description>400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)</description>
    <arm_group_label>bevacizumab before chemotherapy</arm_group_label>
    <arm_group_label>bevacizumab with chemotherapy</arm_group_label>
    <other_name>Fluorouracil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine</intervention_name>
    <description>1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
    <arm_group_label>bevacizumab before chemotherapy</arm_group_label>
    <arm_group_label>bevacizumab with chemotherapy</arm_group_label>
    <other_name>Xeloda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histological diagnosis of colorectal adenoma carcinoma&#xD;
&#xD;
          -  Stage IV disease&#xD;
&#xD;
          -  Presence of at least one measurable target lesion (according to RECIST), and not&#xD;
             previously radiated.&#xD;
&#xD;
          -  Age ≥ 18 e ≤ 75 years&#xD;
&#xD;
          -  ECOG Performance status 0-1&#xD;
&#xD;
          -  Life expectancy &gt;3 months&#xD;
&#xD;
          -  Adequate recovery from surgery, with at least 28 days from surgery to date of&#xD;
             pre-study biopsy.&#xD;
&#xD;
          -  Adequate contraception for male and female patients of child bearing potential&#xD;
&#xD;
          -  informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  More than one previous line of therapy for metastatic disease&#xD;
&#xD;
          -  Prior treatment with bevacizumab or oxaliplatin (previous treatment with irinotecan,,&#xD;
             cetuximab, fluoropyrimidine, folic acid are permitted)&#xD;
&#xD;
          -  Primary tumor that is stenosing and/or that infiltrates the entire thickness of the&#xD;
             intestinal wall&#xD;
&#xD;
          -  Regular use of NSAIDs or aspirin&#xD;
&#xD;
          -  Bleeding disorders or coagulopathy&#xD;
&#xD;
          -  Concurrent anticoagulant therapy&#xD;
&#xD;
          -  Suspected or cerebral metastases (to verify in the presence of symptoms)&#xD;
&#xD;
          -  Neutrophils &lt; 2000 / mm3, platelets &lt; 100,000 / mm3, hemoglobin &lt; 9g/dl&#xD;
&#xD;
          -  Creatinine &gt; 1.5 times the upper normal limit&#xD;
&#xD;
          -  GOT and/or GPT &gt; 2.5 times the upper normal limit, bilirubin &gt; 1.5 times the upper&#xD;
             normal limit in absence of liver metastases&#xD;
&#xD;
          -  GOT and/or GPT &gt; 5 times the upper normal limit, bilirubin &gt; 3 times the upper normal&#xD;
             limit in presence of liver metastases&#xD;
&#xD;
          -  Other co-existing malignancies or malignancies diagnosed within the last 5 years with&#xD;
             the exception of basal and squamous cell carcinoma or cervical cancer in situ&#xD;
&#xD;
          -  Congestive heart failure, ischemic coronary events within past 12 months, uncontrolled&#xD;
             cardiac arrhythmia&#xD;
&#xD;
          -  Uncontrolled hypertension&#xD;
&#xD;
          -  Active or uncontrolled infection&#xD;
&#xD;
          -  Any concomitant condition that, in the investigator's opinion, would contraindicate&#xD;
             the use of any of the study drugs&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Central nervous system disorders or peripheral neuropathy &gt; grade 1 (CTCAE v. 4.0)&#xD;
&#xD;
          -  Inability to comply with follow up procedures of the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Antonio Avallone, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute, Naples</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Istituto Nazionale Tumori Fondazione G. Pascale</name>
      <address>
        <city>Napoli</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>October 29, 2012</study_first_submitted>
  <study_first_submitted_qc>October 29, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 31, 2012</study_first_posted>
  <results_first_submitted>August 20, 2021</results_first_submitted>
  <results_first_submitted_qc>April 11, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">April 12, 2023</results_first_posted>
  <last_update_submitted>April 11, 2023</last_update_submitted>
  <last_update_submitted_qc>April 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>metastatic</keyword>
  <keyword>stage IV</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Folic Acid</mesh_term>
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Levoleucovorin</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 6, 2011</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/73/NCT01718873/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Bevacizumab Before Chemotherapy</title>
          <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
        </group>
        <group group_id="P2">
          <title>Bevacizumab With Chemotherapy</title>
          <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="115"/>
                <participants group_id="P2" count="115"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="115"/>
                <participants group_id="P2" count="115"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Bevacizumab Before Chemotherapy</title>
          <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
        </group>
        <group group_id="B2">
          <title>Bevacizumab With Chemotherapy</title>
          <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</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="115"/>
            <count group_id="B2" value="115"/>
            <count group_id="B3" value="230"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61" lower_limit="53" upper_limit="68"/>
                    <measurement group_id="B2" value="63" lower_limit="56" upper_limit="68"/>
                    <measurement group_id="B3" value="62.3" lower_limit="53.3" upper_limit="67.6"/>
                  </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="46"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="94"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="69"/>
                    <measurement group_id="B2" value="67"/>
                    <measurement group_id="B3" value="136"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="115"/>
                    <measurement group_id="B2" value="115"/>
                    <measurement group_id="B3" value="230"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Rate</title>
        <description>Objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, was the primary end point and was defined as the number of complete plus partial responses divided by the number of enrolled patients.&#xD;
Per RECIST v 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
        <time_frame>Objective response was assessed by computed tomographic scan or other appropriate imaging at weeks 12 and 24 from randomization, and every 3 months thereafter, assessed up to 90 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab Before Chemotherapy</title>
            <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab With Chemotherapy</title>
            <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate</title>
          <description>Objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, was the primary end point and was defined as the number of complete plus partial responses divided by the number of enrolled patients.&#xD;
Per RECIST v 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
          <units>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="115"/>
                <count group_id="O2" value="115"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="65" lower_limit="47.0" upper_limit="65.7"/>
                    <measurement group_id="O2" value="66" lower_limit="47.8" upper_limit="66.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Disease Control Rate</title>
        <description>Disease control rate was calculated by adding complete and partial responses and stable disease.</description>
        <time_frame>At weeks 12 and 24 from randomization and every 3 months thereafter, assessed up to 90 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab Before Chemotherapy</title>
            <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab With Chemotherapy</title>
            <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
        </group_list>
        <measure>
          <title>Disease Control Rate</title>
          <description>Disease control rate was calculated by adding complete and partial responses and stable disease.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="115"/>
                <count group_id="O2" value="115"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="107"/>
                    <measurement group_id="O2" value="103"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall survival was defined as the time from randomization to the date of death. Patients alive at the time of the final analysis were censored on the date of the last follow-up information available.</description>
        <time_frame>assessed up to 90 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab Before Chemotherapy</title>
            <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab With Chemotherapy</title>
            <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Overall survival was defined as the time from randomization to the date of death. Patients alive at the time of the final analysis were censored on the date of the last follow-up information available.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="115"/>
                <count group_id="O2" value="115"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.8" lower_limit="22.5" upper_limit="41.1"/>
                    <measurement group_id="O2" value="24.1" lower_limit="18.6" upper_limit="29.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS)</title>
        <description>Progression-free survival was defined as the time from randomization to the date of progression or death, whichever occurred first. Patients without progression were censored on the date of the last follow-up visit.&#xD;
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
        <time_frame>assessed up to 90 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab Before Chemotherapy</title>
            <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab With Chemotherapy</title>
            <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS)</title>
          <description>Progression-free survival was defined as the time from randomization to the date of progression or death, whichever occurred first. Patients without progression were censored on the date of the last follow-up visit.&#xD;
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="115"/>
                <count group_id="O2" value="115"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.7" lower_limit="9.9" upper_limit="12.9"/>
                    <measurement group_id="O2" value="10.5" lower_limit="9.1" upper_limit="12.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Toxic Effects</title>
        <description>Toxic effects were scored according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. For the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 scale score range from 1 to 4. A high score, that is 3 and 4, represents a high level of toxicity, whereas the minimum values, that is 1 and 2, represents a mild/modest level of toxicity.</description>
        <time_frame>up to 4 weeks after the end of the treatment</time_frame>
        <population>any grade of toxic effects</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab Before Chemotherapy</title>
            <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab With Chemotherapy</title>
            <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
          </group>
        </group_list>
        <measure>
          <title>Toxic Effects</title>
          <description>Toxic effects were scored according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. For the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 scale score range from 1 to 4. A high score, that is 3 and 4, represents a high level of toxicity, whereas the minimum values, that is 1 and 2, represents a mild/modest level of toxicity.</description>
          <population>any grade of toxic effects</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="114"/>
                <count group_id="O2" value="115"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="108"/>
                    <measurement group_id="O2" value="113"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Evaluated every 2 weeks up to 6 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Bevacizumab Before Chemotherapy</title>
          <description>Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
        </group>
        <group group_id="E2">
          <title>Bevacizumab With Chemotherapy</title>
          <description>Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)&#xD;
Bevacizumab: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.&#xD;
Oxaliplatin: 85mg/m2 IV every 2 weeks for up to 24 weeks&#xD;
levo-folinic acid: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks&#xD;
5-fluorouracil: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)&#xD;
Capecitabine: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="115"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="65" subjects_at_risk="115"/>
                <counts group_id="E2" subjects_affected="75" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="115"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="23" subjects_affected="23" subjects_at_risk="115"/>
                <counts group_id="E2" events="28" subjects_affected="28" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="115"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="115"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="115"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="115"/>
                <counts group_id="E2" events="19" subjects_affected="19" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="115"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="115"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="115"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="115"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="115"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="115"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase level increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="115"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase level increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="115"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="115"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="115"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral neuropathy</sub_title>
                <counts group_id="E1" events="15" subjects_affected="15" subjects_at_risk="115"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="115"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="115"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="108" subjects_at_risk="115"/>
                <counts group_id="E2" subjects_affected="113" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="28" subjects_affected="28" subjects_at_risk="115"/>
                <counts group_id="E2" events="27" subjects_affected="27" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="42" subjects_affected="42" subjects_at_risk="115"/>
                <counts group_id="E2" events="44" subjects_affected="44" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="20" subjects_affected="20" subjects_at_risk="115"/>
                <counts group_id="E2" events="32" subjects_affected="32" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" events="28" subjects_affected="28" subjects_at_risk="115"/>
                <counts group_id="E2" events="35" subjects_affected="35" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="32" subjects_affected="32" subjects_at_risk="115"/>
                <counts group_id="E2" events="25" subjects_affected="25" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="115"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="27" subjects_affected="27" subjects_at_risk="115"/>
                <counts group_id="E2" events="44" subjects_affected="44" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="44" subjects_affected="44" subjects_at_risk="115"/>
                <counts group_id="E2" events="44" subjects_affected="44" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="115"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="16" subjects_affected="16" subjects_at_risk="115"/>
                <counts group_id="E2" events="30" subjects_affected="30" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="115"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="115"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="115"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase level increased</sub_title>
                <counts group_id="E1" events="23" subjects_affected="23" subjects_at_risk="115"/>
                <counts group_id="E2" events="23" subjects_affected="23" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase level increased</sub_title>
                <counts group_id="E1" events="22" subjects_affected="22" subjects_at_risk="115"/>
                <counts group_id="E2" events="23" subjects_affected="23" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="115"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="26" subjects_affected="26" subjects_at_risk="115"/>
                <counts group_id="E2" events="34" subjects_affected="34" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral neuropathy</sub_title>
                <counts group_id="E1" events="64" subjects_affected="64" subjects_at_risk="115"/>
                <counts group_id="E2" events="70" subjects_affected="70" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="115"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="19" subjects_affected="19" subjects_at_risk="115"/>
                <counts group_id="E2" events="23" subjects_affected="23" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="157" subjects_affected="15" subjects_at_risk="115"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="115"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="115"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="115"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Considering that the accuracy of conventional evaluation of tumor response by RECIST criteria to bevacizumab combination treatment has been questioned, we acknowledge that our choice of ORR as primary end point may have been inadequate.&#xD;
We are also aware that balancing out unmeasurable differences in patient outcome through randomization is not always achieved with confidence in trials with a relatively small sample size.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Antonio Avallone, Dierctor of Experimental Abdominal Medcial Oncology</name_or_title>
      <organization>National Cancer Institute, IRCCS, G. Pascale Foundation</organization>
      <phone>+390815903629</phone>
      <email>a.avallone@istitutotumori.na.it</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/NCT01718873
org study id: OBELICS
secondary id: 2011-004997-27
nct id: NCT01718873
lead sponsor: 
has dmc: No
The purpose of this study is to evaluate if giving bevacizumab prior to chemotherapy compared
      to giving bevacizumab at the same time as chemotherapy improves patient overall response to
      treatment.
OBELICS is a two-arm phase 3 trial comparing in mCRC patients (1:1): concurrent
      administration of bevacizumab in combination with modified FOLFOX-6 regimen (mFOLFOX-6) or
      modified OXXEL regimen (mOXXEL), in which bevacizumab is administered the same day as
      oxaliplatin, (standard arm); and sequential administration of bevacizumab with the same
      chemotherapeutic regimens, in which bevacizumab is administered 4 days before oxaliplatin at
      each cycle (experimental arm) Oxaliplatin regimen (mFOLFOX/mOXXEL) is chosen according to
      local clinical practice at the beginning of the study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response Rate
time frame: Objective response was assessed by computed tomographic scan or other appropriate imaging at weeks 12 and 24 from randomization, and every 3 months thereafter, assessed up to 90 months.
description: Objective response rate (ORR), according to Response Evaluation Criteria in Solid Tumors (RECIST),version 1.1, was the primary end point and was defined as the number of complete plus partial responses divided by the number of enrolled patients.
Per RECIST v 1.1 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
measure: Disease Control Rate
time frame: At weeks 12 and 24 from randomization and every 3 months thereafter, assessed up to 90 months
description: Disease control rate was calculated by adding complete and partial responses and stable disease.
measure: Overall Survival
time frame: assessed up to 90 months
description: Overall survival was defined as the time from randomization to the date of death. Patients alive at the time of the final analysis were censored on the date of the last follow-up information available.
measure: Progression-free Survival (PFS)
time frame: assessed up to 90 months
description: Progression-free survival was defined as the time from randomization to the date of progression or death, whichever occurred first. Patients without progression were censored on the date of the last follow-up visit.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
measure: Toxic Effects
time frame: up to 4 weeks after the end of the treatment
description: Toxic effects were scored according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. For the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 scale score range from 1 to 4. A high score, that is 3 and 4, represents a high level of toxicity, whereas the minimum values, that is 1 and 2, represents a mild/modest level of toxicity.
arm group label: bevacizumab before chemotherapy
arm group type: Experimental
description: Bevacizumab administered 4 days before each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
arm group label: bevacizumab with chemotherapy
arm group type: Active Comparator
description: Bevacizumab administered on the first day of each cycle of chemotherapy containing oxaliplatin (mFOLFOX-6 / mOXXEL)
intervention type: Drug
intervention name: Bevacizumab
description: 5 mg/kg every 2 weeks for up to 24 weeks. After 24 weeks, those patients without disease progression will receive bevacizumab 7.5 mg/kg every 3 weeks until progression of disease or unacceptable toxicity.
arm group label: bevacizumab before chemotherapy
arm group label: bevacizumab with chemotherapy
other name: Avastin
intervention type: Drug
intervention name: Oxaliplatin
description: 85mg/m2 IV every 2 weeks for up to 24 weeks
arm group label: bevacizumab before chemotherapy
arm group label: bevacizumab with chemotherapy
other name: Eloxatin
intervention type: Drug
intervention name: levo-folinic acid
description: 200 mg/m2 IV before 5-fluorouracil infusion, every 2 weeks up to 24 weeks
arm group label: bevacizumab before chemotherapy
arm group label: bevacizumab with chemotherapy
other name: Lederfolin
intervention type: Drug
intervention name: 5-fluorouracil
description: 400 mg/m2 IV bolus followed by 2400 mg/m2 IV infusion over 46 hours, every 2 weeks for up to 24 weeks (given in mFOLFOX-6 schedule)
arm group label: bevacizumab before chemotherapy
arm group label: bevacizumab with chemotherapy
other name: Fluorouracil
intervention type: Drug
intervention name: Capecitabine
description: 1000mg/m2 by mouth, twice a day for 10 days, every 2 weeks for up to 24 weeks(given in mOXXEL schedule)
arm group label: bevacizumab before chemotherapy
arm group label: bevacizumab with chemotherapy
other name: Xeloda
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Antonio Avallone, M.D.
role: Principal Investigator
affiliation: National Cancer Institute, Naples
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Leucovorin
mesh term: Folic Acid
mesh term: Bevacizumab
mesh term: Fluorouracil
mesh term: Capecitabine
mesh term: Oxaliplatin
mesh term: Levoleucovorin
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Considering that the accuracy of conventional evaluation of tumor response by RECIST criteria to bevacizumab combination treatment has been questioned, we acknowledge that our choice of ORR as primary end point may have been inadequate.
We are also aware that balancing out unmeasurable differences in patient outcome through randomization is not always achieved with confidence in trials with a relatively small sample size.
point of contact: 