<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/NCT01661972</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00037688</org_study_id>
    <nct_id>NCT01661972</nct_id>
  </id_info>
  <brief_title>Phase I/II Study of Capecitabine Plus Aflibercept to Treat Metastatic Colorectal Cancer</brief_title>
  <acronym>X-TRAP</acronym>
  <official_title>X-TRAP: Phase I/II Study of Capecitabine Plus Aflibercept in Metastatic Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>John Strickler, M.D.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Duke University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The Primary Phase I objectives are to determine the recommended phase II dose for the&#xD;
      capecitabine and aflibercept doublet combination; and to describe any dose limiting and&#xD;
      non-dose limiting toxicities. The Phase II Primary objective is to determine progression free&#xD;
      survival associated with this regimen. The Phase II secondary objectives are to determine&#xD;
      response rate associated with this regimen; to determine overall survival associated with&#xD;
      this regimen; and to explore any correlation of clinical outcome with baseline and on&#xD;
      treatment changes in blood-based angiogenesis biomarkers.&#xD;
&#xD;
      This open-label, non-randomized phase I/II trial is designed to assess the safety,&#xD;
      tolerability and RPTD of capecitabine plus aflibercept in adult subjects with metastatic&#xD;
      colorectal cancer.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">June 12, 2016</completion_date>
  <primary_completion_date type="Actual">June 12, 2016</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination</measure>
    <time_frame>RPTD for the study will be determined at the completion of Phase I; up to 1 year.</time_frame>
    <description>Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Dose-Limiting Toxicities (Phase 1)</measure>
    <time_frame>28 days</time_frame>
    <description>Number of patients experiencing a dose-limiting toxicity in each cohort.&#xD;
A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST &gt; 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Median Progression Free Survival (PFS)</measure>
    <time_frame>approximately 5 months</time_frame>
    <description>Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response Rate</measure>
    <time_frame>approximately every 9 weeks and/or restaging, through study completion</time_frame>
    <description>The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Survival</measure>
    <time_frame>Subjects will be followed until death which is estimated to be on average 6 months - 1 year after coming off protocol therapy</time_frame>
    <description>Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">63</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Phase 1: Capecitabine and Aflibercept</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A standard 3+3 dose escalation format will be used. Capecitabine will start at 850mg/m2 to be given on days 1-14 and off days 15-21. If tolerated, the dose will then be escalated to 1000mg/m2 for the next cohort, given on the same schedule. The dose of aflibercept will be held constant at 6 mg/kg, given intravenously every 3 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase 2: Capecitabine and Aflibercept</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Once the RPTD of the doublet combination has been identified, an additional 50 subjects with metastatic colorectal cancer will be added to a single, Phase 2 arm</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine and aflibercept</intervention_name>
    <description>Capecitabine given on days 1-14 and off days 15-21. Dose: Phase 1 cohort 1 850mg/m2 Phase 1 cohort 2 1000mg/m2, Phase 2 RPTD.&#xD;
Aflibercept will be held constant at 6 mg/kg, given intravenously every 3 weeks.&#xD;
Both agents will be administered on a 21-day cycle.</description>
    <arm_group_label>Phase 1: Capecitabine and Aflibercept</arm_group_label>
    <arm_group_label>Phase 2: Capecitabine and Aflibercept</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. For the phase I portion, patients must have histologically and/or cytologically&#xD;
             confirmed malignant solid tumor that is refractory to standard therapies.&#xD;
&#xD;
             For the phase II portion, patients must have histologically and/or cytologically&#xD;
             confirmed metastatic colorectal carcinoma that has progressed on, is intolerant of, or&#xD;
             is inappropriate for all standard therapies. Subjects must have been treated with a&#xD;
             fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan and&#xD;
             bevacizumab or have contraindication to such treatment. Prior epithelial growth factor&#xD;
             receptor (EGFR)-targeting agent (or contraindication to these drugs) is required for&#xD;
             subjects with K-Ras wildtype tumors&#xD;
&#xD;
          2. Measurable disease by RECIST 1.1 criteria (see Appendix 1). Previously irradiated&#xD;
             sites can be included if there is documented progression of disease in that site.&#xD;
&#xD;
          3. Age 18 years and older.&#xD;
&#xD;
          4. KPS &gt; 70% (see Appendix 2)&#xD;
&#xD;
          5. Life expectancy &gt; 3 months.&#xD;
&#xD;
          6. Adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  Absolute neutrophil count &gt; 1.5 x 109/L&#xD;
&#xD;
               -  Platelet count &gt; 100 x 109/L&#xD;
&#xD;
               -  Hemoglobin &gt; 9 g/dl&#xD;
&#xD;
               -  Total bilirubin &lt; 1.5 x ULN&#xD;
&#xD;
               -  AST (SGOT)/ALT (SGPT) &lt; 2.5 x ULN (or &lt;5 x ULN if liver metastases)&#xD;
&#xD;
               -  Creatinine clearance ≥50 mls/min by Cockcroft-Gault&#xD;
&#xD;
               -  Urine Protein/Creatinine ratio &lt; 1 (or protein &lt; 1+ on urinalysis or 24hour urine&#xD;
                  protein &lt; 1gram/24 hours)&#xD;
&#xD;
          7. Previous radiotherapy for palliation of recurrent disease is allowed if &gt;4 weeks have&#xD;
             elapsed since completion of therapy.&#xD;
&#xD;
          8. Ability to take oral medications.&#xD;
&#xD;
          9. Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
         10. Women of childbearing potential must have a negative serum pregnancy test within 7&#xD;
             days from day 1 of study drug; both men and women must be willing to use two methods&#xD;
             of contraception, one of them being a barrier method during the study and for 6 months&#xD;
             after last study drug administration.&#xD;
&#xD;
         11. Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients currently receiving anticancer therapies or who have received anticancer&#xD;
             therapies within 4 weeks from day 1 of study drug (including investigational agents,&#xD;
             chemotherapy, radiation therapy, antibody based therapy, etc.)&#xD;
&#xD;
          2. History of severe hypersensitivity reactions/anaphylaxis attributed to humanized&#xD;
             and/or chimeric monoclonal antibodies or other such proteins.&#xD;
&#xD;
          3. History of significant intolerance to capecitabine or 5FU (ie. Grade 4 toxicity&#xD;
             related to one of these agents; grade 3-4 toxicity related to other concurrently&#xD;
             administered agents is not an exclusion).&#xD;
&#xD;
          4. History of abdominal fistula or gastrointestinal perforation at any point within 6&#xD;
             months prior to day 1 of study drug, unless surgically repaired.&#xD;
&#xD;
          5. Active peptic ulcer disease, inflammatory bowel disease (e.g. ulcerative colitis,&#xD;
             Crohn's disease), diverticular disease or other gastrointestinal conditions with&#xD;
             increased risk of perforation or gastrointestinal bleeding.&#xD;
&#xD;
          6. Active bleeding diathesis or history of any major bleeding, CNS bleeding, or&#xD;
             significant hemoptysis within 6 months of enrollment.&#xD;
&#xD;
          7. Anticoagulation with warfarin (anticoagulation with low molecular weight heparin is&#xD;
             not an exclusion).&#xD;
&#xD;
          8. History of arterial thromboembolic events or symptomatic pulmonary embolism within 6&#xD;
             months of study enrollment.&#xD;
&#xD;
          9. Poorly controlled hypertension [defined as systolic blood pressure (SBP of &gt;150 mmHg&#xD;
             or diastolic blood pressure (DBP) of &gt;90 mmHg]&#xD;
&#xD;
         10. Patients who have had a major surgery or significant traumatic injury within 4 weeks&#xD;
             from day 1 of study drug.&#xD;
&#xD;
         11. History of active brain metastases or carcinomatous meningitis (treated metastases are&#xD;
             permitted, provided the patient is asymptomatic and off steroids for 28 days).&#xD;
&#xD;
         12. Female patients who are pregnant or breast feeding, or adults of reproductive&#xD;
             potential who are not using effective birth control methods. Two acceptable forms of&#xD;
             contraceptives must be continued throughout the trial by either sex. Hormonal&#xD;
             contraceptives are not acceptable as a sole method of contraception. (Women of&#xD;
             childbearing potential must have a negative serum pregnancy test within 7 days prior&#xD;
             to day 1 of study drug).&#xD;
&#xD;
         13. Any active infection, intercurrent illness, severe acute or chronic medical or&#xD;
             psychiatric condition or laboratory abnormality that may increase the risk associated&#xD;
             with study participation or study drug administration, or may interfere with the&#xD;
             interpretation of study results, and in the judgment of the investigator would make&#xD;
             the patient inappropriate for entry into this study.&#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>John Strickler, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Duke Cancer Center, Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Virginia Oncology Associates</name>
      <address>
        <city>Norfolk</city>
        <state>Virginia</state>
        <zip>23502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>July 31, 2012</study_first_submitted>
  <study_first_submitted_qc>August 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 10, 2012</study_first_posted>
  <results_first_submitted>June 9, 2017</results_first_submitted>
  <results_first_submitted_qc>June 9, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">July 11, 2017</results_first_posted>
  <last_update_submitted>October 25, 2018</last_update_submitted>
  <last_update_submitted_qc>October 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 29, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Duke University</investigator_affiliation>
    <investigator_full_name>John Strickler, M.D.</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>colorectal cancer</keyword>
  <keyword>all solid tumors</keyword>
  <keyword>metastatic</keyword>
  <keyword>refractory</keyword>
  <keyword>advanced solid tumors</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>Capecitabine</mesh_term>
    <mesh_term>Aflibercept</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Phase 1</title>
          <description>Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks.</description>
        </group>
        <group group_id="P2">
          <title>Phase 2</title>
          <description>Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="50"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="46"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death during Treatment period</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Phase 1</title>
          <description>Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks.</description>
        </group>
        <group group_id="B2">
          <title>Phase 2</title>
          <description>Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="13"/>
            <count group_id="B2" value="50"/>
            <count group_id="B3" value="63"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58.1" spread="12.3"/>
                    <measurement group_id="B2" value="57.7" spread="9.9"/>
                    <measurement group_id="B3" value="57.8" spread="10.3"/>
                  </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="6"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="37"/>
                  </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="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </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="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="40"/>
                  </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="4"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="50"/>
                    <measurement group_id="B3" value="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination</title>
        <description>Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I).</description>
        <time_frame>RPTD for the study will be determined at the completion of Phase I; up to 1 year.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Phase 1</title>
            <description>Aflibercept 6 mg/kg given intravenously every 3 weeks. Capecitabine was given at 850mg/m2 for the first cohort and at 1000mg/m2 for the second cohort.</description>
          </group>
        </group_list>
        <measure>
          <title>Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination</title>
          <description>Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I).</description>
          <units>mg/m2</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="850"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Dose-Limiting Toxicities (Phase 1)</title>
        <description>Number of patients experiencing a dose-limiting toxicity in each cohort.&#xD;
A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST &gt; 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization</description>
        <time_frame>28 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Phase 1 Cohort 1</title>
            <description>Capecitabine 850mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.</description>
          </group>
          <group group_id="O2">
            <title>Phase 1 Cohort 2</title>
            <description>Capecitabine 1000 mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Dose-Limiting Toxicities (Phase 1)</title>
          <description>Number of patients experiencing a dose-limiting toxicity in each cohort.&#xD;
A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST &gt; 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization</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="7"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Median Progression Free Survival (PFS)</title>
        <description>Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.</description>
        <time_frame>approximately 5 months</time_frame>
        <population>Patients enrolled in Phase 2 were included in the analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 2</title>
            <description>Capecitabine at the recommended dose based on Phase 1, given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Progression Free Survival (PFS)</title>
          <description>Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.</description>
          <population>Patients enrolled in Phase 2 were included in the analysis</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.91" lower_limit="2.30" upper_limit="4.47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Response Rate</title>
        <description>The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.</description>
        <time_frame>approximately every 9 weeks and/or restaging, through study completion</time_frame>
        <population>All evaluable Phase 2 patients. 5 patients were not evaluable for response and were not included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 2</title>
            <description>Capecitabine at the recommended dose based on Phase 1, given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Response Rate</title>
          <description>The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.</description>
          <population>All evaluable Phase 2 patients. 5 patients were not evaluable for response and were not included in the analysis.</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="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.22" lower_limit="0.06" upper_limit="11.77"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Survival</title>
        <description>Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.</description>
        <time_frame>Subjects will be followed until death which is estimated to be on average 6 months - 1 year after coming off protocol therapy</time_frame>
        <population>Patients enrolled in Phase 2 were included in the analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 2</title>
            <description>Capecitabine at the recommended dose based on Phase 1, given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Survival</title>
          <description>Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.</description>
          <population>Patients enrolled in Phase 2 were included in the analysis</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.43" lower_limit="5.78" upper_limit="10.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>All serious and non-serious adverse events will be collected from time of informed consent to 30 days after a subject's last dose of study agent.</time_frame>
      <desc>Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.</desc>
      <group_list>
        <group group_id="E1">
          <title>Phase 1</title>
          <description>Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks.</description>
        </group>
        <group group_id="E2">
          <title>Phase 2</title>
          <description>Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="50"/>
              </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="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Aortic valve disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Supraventricular tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Anal fistula</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Colonic obstruction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Colonic perforation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Gastric hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death NOS</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </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="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hepatic failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Depressed level of consciousness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Intracranial hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="46" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Anal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Esophagitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Rectal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Rectal ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Anorectal infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Rhinitis infective</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Urine output decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </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="5" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </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="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic kidney disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Urinary urgency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Gynecomastia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </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="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </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" subjects_affected="6" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Surgical and medical procedures - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vascular disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>John Strickler, M.D.</name_or_title>
      <organization>Duke University Medical Center</organization>
      <phone>919-668-1861</phone>
      <email>john.strickler@duke.edu</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/NCT01661972
org study id: Pro00037688
nct id: NCT01661972
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The Primary Phase I objectives are to determine the recommended phase II dose for the
      capecitabine and aflibercept doublet combination; and to describe any dose limiting and
      non-dose limiting toxicities. The Phase II Primary objective is to determine progression free
      survival associated with this regimen. The Phase II secondary objectives are to determine
      response rate associated with this regimen; to determine overall survival associated with
      this regimen; and to explore any correlation of clinical outcome with baseline and on
      treatment changes in blood-based angiogenesis biomarkers.

      This open-label, non-randomized phase I/II trial is designed to assess the safety,
      tolerability and RPTD of capecitabine plus aflibercept in adult subjects with metastatic
      colorectal cancer.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination
time frame: RPTD for the study will be determined at the completion of Phase I; up to 1 year.
description: Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I).
measure: Number of Dose-Limiting Toxicities (Phase 1)
time frame: 28 days
description: Number of patients experiencing a dose-limiting toxicity in each cohort.
A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST > 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization
measure: Median Progression Free Survival (PFS)
time frame: approximately 5 months
description: Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.
measure: Response Rate
time frame: approximately every 9 weeks and/or restaging, through study completion
description: The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.
measure: Median Survival
time frame: Subjects will be followed until death which is estimated to be on average 6 months - 1 year after coming off protocol therapy
description: Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.
arm group label: Phase 1: Capecitabine and Aflibercept
arm group type: Experimental
description: A standard 3+3 dose escalation format will be used. Capecitabine will start at 850mg/m2 to be given on days 1-14 and off days 15-21. If tolerated, the dose will then be escalated to 1000mg/m2 for the next cohort, given on the same schedule. The dose of aflibercept will be held constant at 6 mg/kg, given intravenously every 3 weeks.
arm group label: Phase 2: Capecitabine and Aflibercept
arm group type: Experimental
description: Once the RPTD of the doublet combination has been identified, an additional 50 subjects with metastatic colorectal cancer will be added to a single, Phase 2 arm
intervention type: Drug
intervention name: Capecitabine and aflibercept
description: Capecitabine given on days 1-14 and off days 15-21. Dose: Phase 1 cohort 1 850mg/m2 Phase 1 cohort 2 1000mg/m2, Phase 2 RPTD.
Aflibercept will be held constant at 6 mg/kg, given intravenously every 3 weeks.
Both agents will be administered on a 21-day cycle.
arm group label: Phase 1: Capecitabine and Aflibercept
arm group label: Phase 2: Capecitabine and Aflibercept
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: John Strickler, MD
role: Principal Investigator
affiliation: Duke University
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Duke University
investigator full name: John Strickler, M.D.
investigator title: Associate Professor
mesh term: Colorectal Neoplasms
mesh term: Capecitabine
mesh term: Aflibercept
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 