<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/NCT02196688</url>
  </required_header>
  <id_info>
    <org_study_id>2012-013-00CH1</org_study_id>
    <nct_id>NCT02196688</nct_id>
  </id_info>
  <brief_title>Study of Fruquintinib in Patients With Metastatic Colorectal Cancer</brief_title>
  <official_title>A Randomized, Double-blind, Placebo-controlled, Multicenter Phase II Trial to Compare the Efficacy and Safety of Fruquintinib Plus Best Supportive Care (BSC) Versus Placebo Plus BSC in Patients With Colorectal Cancer as 3rd or Above Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hutchison Medipharma Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fudan University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sun Yat-sen University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hutchmed</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Fruquintinib administered at 5mg once daily in 4 weeks treatment cycle (three weeks on and&#xD;
      one week off) was well tolerated and demonstrated encouraging preliminary clinical antitumor&#xD;
      activity in patients with advanced Colorectal Cancer (CRC) in Phase Ib study.&#xD;
&#xD;
      This study is aimed to evaluate the efficacy and safety of Fruquintinib in the treatment of&#xD;
      patients with metastatic CRC who have progressed after metastatic CRC second line or above&#xD;
      standard chemotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomized, double-blind, placebo-controlled, multicenter Phase II clinical trial&#xD;
      to compare the efficacy and safety of Fruquintinib plus Best Supportive Care (BSC) versus&#xD;
      placebo plus BSC in patients with metastatic colorectal cancer who have progressed after&#xD;
      second-line or above standard chemotherapy.&#xD;
&#xD;
      After checking eligibility criteria, subjects will be randomized into Fruquintinib plus BSC&#xD;
      group (treatment group) or placebo plus BSC group (control group) in a ration of 2:1.&#xD;
&#xD;
      Primary Efficacy Endpoint:&#xD;
&#xD;
      Progression free survival (PFS) (According to RECIST Version 1.1).&#xD;
&#xD;
      Secondary Efficacy Endpoints:&#xD;
&#xD;
      Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS).&#xD;
&#xD;
      Safety and tolerance will be evaluated by incidence, severity and outcomes of adverse events&#xD;
      (AEs) and categorized by severity in accordance with the NCI common terminology criteria for&#xD;
      adverse events (CTC AE) Version 4.0.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2014</start_date>
  <completion_date type="Actual">November 2015</completion_date>
  <primary_completion_date type="Actual">April 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>From randomization until the date of first documented progression or date of death from any cause, whichever came first.</time_frame>
    <description>PFS refers to the time interval between the randomization date and the initial record of PD or date of death, whichever is earlier. The presence of PD shall be determined in accordance with the result of the evaluation performed by the investigator, using with RECIST v1.1 criteria. The date of final tumor evaluation will be used as the censoring date for subjects who have not presented with disease progression or death by that date. The date of randomization will be used as the censoring date for subjects which have no death and post-baseline tumor evaluation. If a subject has no post-baseline tumor evaluation but recorded as dead, death will be count as PFS event.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>From randomization up to progressive disease or end of treatment (EOT) due to any cause.</time_frame>
    <description>The ORR is defined as the rate of complete response (CR) or partial response (PR) as the best overall response (BOR), based on evaluation of target lesions and non-target lesions with corroborant radiological method and determined by RECIST v1.1, for the ITT set of response evaluable subjects. Subjects who have no post-baseline tumor evaluation shall be regarded as subjects without ORR. Subjects who qualify for evaluation of CR or PR should have at least one available lesion for measurement with RECIST v1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>From randomization up to progressive disease or EOT due to any cause.</time_frame>
    <description>The DCR is defined as the rate of corroborant CR, PR and stable disease (SD) as the BOR, based on evaluation of target lesions and non-target lesions with corroborant radiological method and determined according to RECIST v1.1, for the ITT set of response evaluable subjects.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Over Survival (OS)</measure>
    <time_frame>From randomization until death due to any cause.</time_frame>
    <description>The OS refers to the time interval between the randomization date and the date of death (any cause). The final known date of survival will be used as the censoring date for subjects that have not been reported to have died by the time of analysis.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">71</enrollment>
  <condition>Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>treatment arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>treatment arm- subjects will receive Fruquintinib 5mg orally, once daily (QD), plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>control arm</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>control arm- subjects will receive Fruquintinib placebo 5mg orally, once daily (QD), plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>fruquintinib</intervention_name>
    <description>fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
    <arm_group_label>treatment arm</arm_group_label>
    <other_name>HMPL-013</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
    <arm_group_label>control arm</arm_group_label>
    <other_name>HMPL-013 placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥ 18 and ≤ 75 years of age , with ≥ 40 Kg&#xD;
&#xD;
          -  Histological or cytological confirmed metastatic colorectal cancer&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1&#xD;
&#xD;
          -  Failed 2 or more lines of chemotherapy&#xD;
&#xD;
          -  Adequate hepatic, renal, heart, and hematologic functions&#xD;
&#xD;
          -  At least one measurable lesion (larger than 10 mm in diameter by spiral CT scan)&#xD;
&#xD;
          -  Signed and dated informed consent.&#xD;
&#xD;
          -  Willingness and ability to comply with scheduled visits, treatment plans, laboratory&#xD;
             tests, and other study procedure&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Any factors that influence the usage of oral administration&#xD;
&#xD;
          -  Central nervous system (CNS) metastasis&#xD;
&#xD;
          -  One of the following conditions: non-controlled hypertension, coronary artery disease,&#xD;
             arrhythmia and heart failure&#xD;
&#xD;
          -  Abuse of alcohol or drugs&#xD;
&#xD;
          -  Less than 4 weeks from the last clinical trial - Previous treatment with VEGFR&#xD;
             inhibition&#xD;
&#xD;
          -  Disability of serious uncontrolled intercurrence infection&#xD;
&#xD;
          -  Proteinuria ≥ 2+ (1.0g/24hr)&#xD;
&#xD;
          -  Evidence or a history of bleeding tendency within two months of the enrollment,&#xD;
             regardless of seriousness&#xD;
&#xD;
          -  History of artery/venous thromboembolic events in 12 months, such as cerebral vascular&#xD;
             accident (including transient ischemic attack) etc.&#xD;
&#xD;
          -  History of acute myocardial infarction, acute coronary syndrome or coronary artery&#xD;
             bypass graft (CABG) in 6 months&#xD;
&#xD;
          -  Bone fracture or wounds that was not cured for a long time&#xD;
&#xD;
          -  Coagulation dysfunction, hemorrhagic tendency or receiving anticoagulant therapy&#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>Jin Li, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fudan University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hutchison Medi Pharma Investigational Site</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100071</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hutchison Medi Pharma Investigational Site</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hutchison Medi Pharma</name>
      <address>
        <city>Harbin</city>
        <state>Heilongjiang</state>
        <zip>150081</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hutchison Medi Pharma Investigational Site</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <zip>310016</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hutchison Medi Pharma Investigational Site</name>
      <address>
        <city>Shanghai</city>
        <zip>200032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <results_reference>
    <citation>Xu RH, Li J, Bai Y, Xu J, Liu T, Shen L, Wang L, Pan H, Cao J, Zhang D, Fan S, Hua Y, Su W. Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study. J Hematol Oncol. 2017 Jan 19;10(1):22. doi: 10.1186/s13045-016-0384-9.</citation>
    <PMID>28103904</PMID>
  </results_reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>July 14, 2014</study_first_submitted>
  <study_first_submitted_qc>July 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <results_first_submitted>June 24, 2019</results_first_submitted>
  <results_first_submitted_qc>June 24, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">August 13, 2019</results_first_posted>
  <last_update_submitted>June 12, 2020</last_update_submitted>
  <last_update_submitted_qc>June 12, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Colorectal cancer</keyword>
  <keyword>Fruquintinib</keyword>
  <keyword>013</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment Arm</title>
          <description>treatment arm- subjects will receive Fruquintinib 5mg orally, Once Daily (QD), plus Best Supportive Care (BSC) for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
fruquintinib: fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
        </group>
        <group group_id="P2">
          <title>Control Arm</title>
          <description>control arm- subjects will receive Fruquintinib placebo 5mg orally, Once Daily (QD), plus Best Supportive Care (BSC) for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
placebo: Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="47"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
                <participants group_id="P2" count="23"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment Arm</title>
          <description>treatment arm- subjects will receive Fruquintinib 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
fruquintinib: fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
        </group>
        <group group_id="B2">
          <title>Control Arm</title>
          <description>control arm- subjects will receive Fruquintinib placebo 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
placebo: Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</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="47"/>
            <count group_id="B2" value="24"/>
            <count group_id="B3" value="71"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</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>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="41"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="61"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </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="12"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="52"/>
                  </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="47"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="71"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>ETHNICITY</title>
              <category_list>
                <category>
                  <title>HAN</title>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="71"/>
                  </measurement_list>
                </category>
                <category>
                  <title>NOT HAN</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>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>China</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression Free Survival (PFS)</title>
        <description>PFS refers to the time interval between the randomization date and the initial record of PD or date of death, whichever is earlier. The presence of PD shall be determined in accordance with the result of the evaluation performed by the investigator, using with RECIST v1.1 criteria. The date of final tumor evaluation will be used as the censoring date for subjects who have not presented with disease progression or death by that date. The date of randomization will be used as the censoring date for subjects which have no death and post-baseline tumor evaluation. If a subject has no post-baseline tumor evaluation but recorded as dead, death will be count as PFS event.</description>
        <time_frame>From randomization until the date of first documented progression or date of death from any cause, whichever came first.</time_frame>
        <population>The intention-to-treat set will contain all subjects in the Randomized set (RND) set subjects will be classified according to randomized treatment. The intent-to-treat principle is preserved. The Intention to Treat (ITT) will be used for analyses of PFS, OS, ORR and DCR.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>treatment arm- subjects will receive Fruquintinib 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
fruquintinib: fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
          </group>
          <group group_id="O2">
            <title>Control Arm</title>
            <description>control arm- subjects will receive Fruquintinib placebo 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
placebo: Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS)</title>
          <description>PFS refers to the time interval between the randomization date and the initial record of PD or date of death, whichever is earlier. The presence of PD shall be determined in accordance with the result of the evaluation performed by the investigator, using with RECIST v1.1 criteria. The date of final tumor evaluation will be used as the censoring date for subjects who have not presented with disease progression or death by that date. The date of randomization will be used as the censoring date for subjects which have no death and post-baseline tumor evaluation. If a subject has no post-baseline tumor evaluation but recorded as dead, death will be count as PFS event.</description>
          <population>The intention-to-treat set will contain all subjects in the Randomized set (RND) set subjects will be classified according to randomized treatment. The intent-to-treat principle is preserved. The Intention to Treat (ITT) will be used for analyses of PFS, OS, ORR and DCR.</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="47"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.731" lower_limit="2.858" upper_limit="5.585"/>
                    <measurement group_id="O2" value="0.986" lower_limit="0.953" upper_limit="1.577"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rate (ORR)</title>
        <description>The ORR is defined as the rate of complete response (CR) or partial response (PR) as the best overall response (BOR), based on evaluation of target lesions and non-target lesions with corroborant radiological method and determined by RECIST v1.1, for the ITT set of response evaluable subjects. Subjects who have no post-baseline tumor evaluation shall be regarded as subjects without ORR. Subjects who qualify for evaluation of CR or PR should have at least one available lesion for measurement with RECIST v1.1.</description>
        <time_frame>From randomization up to progressive disease or end of treatment (EOT) due to any cause.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>treatment arm- subjects will receive Fruquintinib 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
fruquintinib: fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
          </group>
          <group group_id="O2">
            <title>Control Arm</title>
            <description>control arm- subjects will receive Fruquintinib placebo 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
placebo: Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate (ORR)</title>
          <description>The ORR is defined as the rate of complete response (CR) or partial response (PR) as the best overall response (BOR), based on evaluation of target lesions and non-target lesions with corroborant radiological method and determined by RECIST v1.1, for the ITT set of response evaluable subjects. Subjects who have no post-baseline tumor evaluation shall be regarded as subjects without ORR. Subjects who qualify for evaluation of CR or PR should have at least one available lesion for measurement with RECIST v1.1.</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="47"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Disease Control Rate (DCR)</title>
        <description>The DCR is defined as the rate of corroborant CR, PR and stable disease (SD) as the BOR, based on evaluation of target lesions and non-target lesions with corroborant radiological method and determined according to RECIST v1.1, for the ITT set of response evaluable subjects.</description>
        <time_frame>From randomization up to progressive disease or EOT due to any cause.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>treatment arm- subjects will receive Fruquintinib 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
fruquintinib: fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
          </group>
          <group group_id="O2">
            <title>Control Arm</title>
            <description>control arm- subjects will receive Fruquintinib placebo 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
placebo: Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
          </group>
        </group_list>
        <measure>
          <title>Disease Control Rate (DCR)</title>
          <description>The DCR is defined as the rate of corroborant CR, PR and stable disease (SD) as the BOR, based on evaluation of target lesions and non-target lesions with corroborant radiological method and determined according to RECIST v1.1, for the ITT set of response evaluable subjects.</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="47"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Over Survival (OS)</title>
        <description>The OS refers to the time interval between the randomization date and the date of death (any cause). The final known date of survival will be used as the censoring date for subjects that have not been reported to have died by the time of analysis.</description>
        <time_frame>From randomization until death due to any cause.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>treatment arm- subjects will receive Fruquintinib 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
fruquintinib: fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
          </group>
          <group group_id="O2">
            <title>Control Arm</title>
            <description>control arm- subjects will receive Fruquintinib placebo 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
placebo: Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
          </group>
        </group_list>
        <measure>
          <title>Over Survival (OS)</title>
          <description>The OS refers to the time interval between the randomization date and the date of death (any cause). The final known date of survival will be used as the censoring date for subjects that have not been reported to have died by the time of analysis.</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="47"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.721" lower_limit="6.899" upper_limit="10.283"/>
                    <measurement group_id="O2" value="5.520" lower_limit="3.614" upper_limit="11.302"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event (AE) should be collected from first dose to 30 days after EOT. AEs and laboratory abnormalities that could not be restored or unexplained needed to be collected till recovery or until they could be explained. Serious adverse event (SAE) was collected from informed consent. Only SAEs related to the study drugs should be collected until 30 days after the last dose.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment Arm</title>
          <description>treatment arm- subjects will receive Fruquintinib 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
fruquintinib: fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
        </group>
        <group group_id="E2">
          <title>Control Arm</title>
          <description>control arm- subjects will receive Fruquintinib placebo 5mg orally, QD, plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.&#xD;
placebo: Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (17.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="38" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Obstruction intestinal</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Pancreatitis acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Upper gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Functional ileus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Sudden death</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatic function abnormal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Hepatic damage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Jaundice cholestatic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dyskinesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Hepatic coma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Haemoptysis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </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="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Embolism arterial</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Superior vena cava syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (17.1)</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="47" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>ANAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>SINUS TACHYCARDIA</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>TINNITUS</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>HYPOTHYROIDISM</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>DIARRHOEA</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>STOMATITIS</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>CONSTIPATION</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>ABDOMINAL PAIN UPPER</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>VOMITING</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>ABDOMINAL PAIN</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>NAUSEA</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>ABDOMINAL DISTENSION</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>APHTHOUS STOMATITIS</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>FATIGUE</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>MALAISE</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>PYREXIA</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>ASTHENIA</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>INFLUENZA LIKE ILLNESS</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>HEPATIC PAIN</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>UPPER RESPIRATORY TRACT INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>URINARY TRACT INFECTION</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>ASPARTATE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>BLOOD THYROID STIMULATING HORMONE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>ALANINE AMINOTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>BLOOD BILIRUBIN INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>OCCULT BLOOD POSITIVE</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>PLATELET COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>BLOOD ALKALINE PHOSPHATASE</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>WHITE BLOOD CELL COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>ELECTROCARDIOGRAM T WAVE AMPLITUDE DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>NEUTROPHIL COUNT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>WEIGHT DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>BLOOD PRESSURE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>BLOOD URINE PRESENT</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>GAMMA-GLUTAMYLTRANSFERASE INCREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>BLOOD POTASSIUM DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>HAEMOGLOBIN DECREASED</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>DECREASED APPETITE</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>HYPOALBUMINAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>HYPERGLYCAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>HYPOKALAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>HYPONATRAEMIA</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </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="8" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>BACK PAIN</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>MYALGIA</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>PAIN IN EXTREMITY</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>DIZZINESS</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>INSOMNIA</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>PROTEINURIA</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>HAEMATURIA</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>DYSPHONIA</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>COUGH</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>NAIL DISCOLOURATION</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>RASH</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>DERMATITIS ACNEIFORM</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>RASH MACULO-PAPULAR</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>HYPERTENSION</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="47"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Songhua Fan</name_or_title>
      <organization>Hutchison Medipharma Ltd</organization>
      <phone>+86 21 2067 3058 ext 5058</phone>
      <email>songhuaf@hmplglobal.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02196688
org study id: 2012-013-00CH1
nct id: NCT02196688
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Fruquintinib administered at 5mg once daily in 4 weeks treatment cycle (three weeks on and
      one week off) was well tolerated and demonstrated encouraging preliminary clinical antitumor
      activity in patients with advanced Colorectal Cancer (CRC) in Phase Ib study.

      This study is aimed to evaluate the efficacy and safety of Fruquintinib in the treatment of
      patients with metastatic CRC who have progressed after metastatic CRC second line or above
      standard chemotherapy.
This is a randomized, double-blind, placebo-controlled, multicenter Phase II clinical trial
      to compare the efficacy and safety of Fruquintinib plus Best Supportive Care (BSC) versus
      placebo plus BSC in patients with metastatic colorectal cancer who have progressed after
      second-line or above standard chemotherapy.

      After checking eligibility criteria, subjects will be randomized into Fruquintinib plus BSC
      group (treatment group) or placebo plus BSC group (control group) in a ration of 2:1.

      Primary Efficacy Endpoint:

      Progression free survival (PFS) (According to RECIST Version 1.1).

      Secondary Efficacy Endpoints:

      Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS).

      Safety and tolerance will be evaluated by incidence, severity and outcomes of adverse events
      (AEs) and categorized by severity in accordance with the NCI common terminology criteria for
      adverse events (CTC AE) Version 4.0.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Progression Free Survival (PFS)
time frame: From randomization until the date of first documented progression or date of death from any cause, whichever came first.
description: PFS refers to the time interval between the randomization date and the initial record of PD or date of death, whichever is earlier. The presence of PD shall be determined in accordance with the result of the evaluation performed by the investigator, using with RECIST v1.1 criteria. The date of final tumor evaluation will be used as the censoring date for subjects who have not presented with disease progression or death by that date. The date of randomization will be used as the censoring date for subjects which have no death and post-baseline tumor evaluation. If a subject has no post-baseline tumor evaluation but recorded as dead, death will be count as PFS event.
measure: Objective Response Rate (ORR)
time frame: From randomization up to progressive disease or end of treatment (EOT) due to any cause.
description: The ORR is defined as the rate of complete response (CR) or partial response (PR) as the best overall response (BOR), based on evaluation of target lesions and non-target lesions with corroborant radiological method and determined by RECIST v1.1, for the ITT set of response evaluable subjects. Subjects who have no post-baseline tumor evaluation shall be regarded as subjects without ORR. Subjects who qualify for evaluation of CR or PR should have at least one available lesion for measurement with RECIST v1.1.
measure: Disease Control Rate (DCR)
time frame: From randomization up to progressive disease or EOT due to any cause.
description: The DCR is defined as the rate of corroborant CR, PR and stable disease (SD) as the BOR, based on evaluation of target lesions and non-target lesions with corroborant radiological method and determined according to RECIST v1.1, for the ITT set of response evaluable subjects.
measure: Over Survival (OS)
time frame: From randomization until death due to any cause.
description: The OS refers to the time interval between the randomization date and the date of death (any cause). The final known date of survival will be used as the censoring date for subjects that have not been reported to have died by the time of analysis.
arm group label: treatment arm
arm group type: Active Comparator
description: treatment arm- subjects will receive Fruquintinib 5mg orally, once daily (QD), plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.
arm group label: control arm
arm group type: Placebo Comparator
description: control arm- subjects will receive Fruquintinib placebo 5mg orally, once daily (QD), plus BSC for 3 wks on/ 1 wk off. Patients will receive a cycles of 4 weeks of study treatment (1 cycle of study treatment includes 3 weeks of treatment and 1 week of drug discontinuation) or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria.
intervention type: Drug
intervention name: fruquintinib
description: fruquintinib is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off
arm group label: treatment arm
other name: HMPL-013
intervention type: Drug
intervention name: placebo
description: Placebo is a capsule in the form of 1mg and 5mg, orally, once daily, 3 weeks on/ 1 week off
arm group label: control arm
other name: HMPL-013 placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Jin Li, MD
role: Principal Investigator
affiliation: Fudan University
facility: 
facility: 
facility: 
facility: 
facility: 
country: China
citation: Xu RH, Li J, Bai Y, Xu J, Liu T, Shen L, Wang L, Pan H, Cao J, Zhang D, Fan S, Hua Y, Su W. Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study. J Hematol Oncol. 2017 Jan 19;10(1):22. doi: 10.1186/s13045-016-0384-9.
PMID: 28103904
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 