<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/NCT03251378</url>
  </required_header>
  <id_info>
    <org_study_id>2015-013-00US1</org_study_id>
    <nct_id>NCT03251378</nct_id>
  </id_info>
  <brief_title>A Multi-Center, Open-Label Study of Fruquintinib in Solid Tumors, Colorectal, and Breast Cancer</brief_title>
  <official_title>A Multi-Center, Open-Label, Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anticancer Activity of Fruquintinib in Patients With Advanced Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hutchmed</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hutchmed</source>
  <oversight_info>
    <has_dmc>No</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>
      An open-label, dose escalation and expansion clinical trial to evaluate the safety,&#xD;
      tolerability, and PK of fruquintinib in patients with advanced solid tumors, metastatic&#xD;
      colorectal cancer and metastatic breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is an open-label, dose escalation and expansion clinical trial to evaluate the&#xD;
      safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors. The&#xD;
      study will consist of two phases:&#xD;
&#xD;
        -  A dose escalation phase - A 3+3 design will be used for this portion of the study.&#xD;
&#xD;
        -  A dose expansion phase - Five cohorts will be evaluated in Dose Expansion. Cohort A will&#xD;
           evaluate the MTD/RP2D in patients with advanced solid tumors. Cohort B and Cohort C will&#xD;
           evaluate the MTD/RP2D in metastatic colorectal cancer patients. Cohort D and Cohort E&#xD;
           will evaluate the MTD/RP2D in metastatic breast cancer patients.&#xD;
&#xD;
      Study will be conducted in up to 9 sites in the US.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 10, 2017</start_date>
  <completion_date type="Anticipated">March 31, 2023</completion_date>
  <primary_completion_date type="Actual">December 13, 2022</primary_completion_date>
  <phase>Phase 1</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>The incidence of DLT in each cohort</measure>
    <time_frame>At the end of Cycle 1 (each cycle is 28 days)</time_frame>
    <description>The primary endpoint of the dose escalation phase is the incidence of DLT in each cohort.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression free survival (PFS) at 12 weeks</measure>
    <time_frame>From first dose of study drug through 12 weeks of treatment</time_frame>
    <description>Primary outcome expansion: progression free survival (PFS) at 12 weeks</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum plasma concentration calculated with blood samples</measure>
    <time_frame>within 30 days after the first dose</time_frame>
    <description>Blood samples will be taken to measure the levels of study drug</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach maximum concentration calculated with blood samples</measure>
    <time_frame>within 30 days after the first dose</time_frame>
    <description>Blood samples will be taken to measure the levels of study drug</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate</measure>
    <time_frame>every 4 weeks or every 8 weeks depending on cohort, through study completion, an average of 6 months</time_frame>
    <description>the proportion of of subjects who have a Complete Response or Partial Response</description>
  </secondary_outcome>
  <number_of_arms>7</number_of_arms>
  <enrollment type="Actual">129</enrollment>
  <condition>Advanced Solid Tumors</condition>
  <condition>Metastatic Colon Cancer</condition>
  <condition>Metastatic Breast Cancer</condition>
  <condition>Triple Negative Breast Cancer</condition>
  <condition>HER2-negative Breast Cancer</condition>
  <condition>Hormone Receptor Positive Breast Carcinoma</condition>
  <condition>Rectal Cancer</condition>
  <arm_group>
    <arm_group_label>3 mg Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3 mg of Fruquintinib (HMPL-013), tablet taken daily, 3 weeks on, 1 week off</description>
  </arm_group>
  <arm_group>
    <arm_group_label>5 mg Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 mg of Fruquintinib (HMPL-013), tablet taken daily, 3 weeks on, 1 week off</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fruquintinib Expansion Cohort A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with advanced solid tumors.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Metastatic Colorectal Cancer Expansion Cohort B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with metastatic colorectal cancer who have progressed on or had intolerable toxicity to TAS-102, regoragenib, or both.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Metastatic Colorectal Cancer Expansion Cohort C</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with metastatic colorectal cancer who have not been treated with TAS-102 or regorafenib.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Metastatic Breast Cancer Expansion Cohort D</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with metastatic Her2-negative, hormone receptor positive breast cancer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Metastatic Breast Cancer Expansion Cohort E</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with metastatic triple negative (Her2-negative, ER-negative, PR-negative) breast cancer.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fruquintinib (HMPL-013)</intervention_name>
    <description>Fruquintinib is a small molecule tyrosine kinase inhibitor (TKI) that targets VEGFR-1, -2, and -3, with a novel chemical structure which belongs to the quinazoline class.</description>
    <arm_group_label>3 mg Dose Escalation</arm_group_label>
    <arm_group_label>5 mg Dose Escalation</arm_group_label>
    <arm_group_label>Fruquintinib Expansion Cohort A</arm_group_label>
    <arm_group_label>Metastatic Breast Cancer Expansion Cohort D</arm_group_label>
    <arm_group_label>Metastatic Breast Cancer Expansion Cohort E</arm_group_label>
    <arm_group_label>Metastatic Colorectal Cancer Expansion Cohort B</arm_group_label>
    <arm_group_label>Metastatic Colorectal Cancer Expansion Cohort C</arm_group_label>
    <other_name>HMPL-013</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  Fully understand the study and voluntarily sign the ICF;&#xD;
&#xD;
          -  ≥18years of age;&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;&#xD;
&#xD;
        Dose Escalation Phase:&#xD;
&#xD;
        • Histologically or cytologically documented, locally advanced or metastatic solid&#xD;
        malignancy of any type (except squamous NSCLC) that has progressed on approved systemic&#xD;
        therapy, and for whom no effective therapy or standard of care exists. This cohort is&#xD;
        closed to enrollment.&#xD;
&#xD;
        Dose Expansion Phase:&#xD;
&#xD;
          -  Cohort A: Histologically or cytologically documented, locally advanced or metastatic&#xD;
             solid malignancy of any type (except squamous NSCLC), that has progressed on approved&#xD;
             systemic therapy, and for whom no effective therapy or standard of care exists. This&#xD;
             cohort is closed to enrollment.&#xD;
&#xD;
          -  Cohort B: Histologically or cytologically documented mCRC in patients that have&#xD;
             progressed on, or had intolerable toxicity with at least 1 FDA-approved third-line&#xD;
             systemic therapy (trifluridine/tipiracil or regorafenib). Patients must also have been&#xD;
             previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based&#xD;
             chemotherapy, an anti-VEGF biological therapy, and an anti-EGFR therapy for patients&#xD;
             who had RAS wild-type tumors. This cohort is currently enrolling.&#xD;
&#xD;
          -  Cohort C: Histologically or cytologically documented adenocarcinoma of the colon or&#xD;
             rectum. Patients must have progressed on, or had intolerable toxicity to, at least 2&#xD;
             prior regimens of standard chemotherapy, but must not have received prior TAS-102 or&#xD;
             regorafenib. Prior therapy could have included adjuvant chemotherapy if a tumor had&#xD;
             recurred within 6 months after the last administration of treatment. Patients must&#xD;
             have been previously treated with fluoropyrimidine-, oxaliplatin-, and&#xD;
             irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type,&#xD;
             an anti-EGFR therapy&#xD;
&#xD;
          -  Cohort D only: Histologically- or cytologically-confirmed Her2-negative, hormone&#xD;
             receptor positive (ER+ and/or PR+) breast cancer&#xD;
&#xD;
          -  Cohort E only: Histologically- or cytologically- confirmed triple negative breast&#xD;
             cancer&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
        Patients will be excluded from the study, if any of the following criteria is met:&#xD;
&#xD;
          -  Severe anemia, neutropenia, thrombocytopenia&#xD;
&#xD;
          -  Moderate to severe renal or hepatic impairment&#xD;
&#xD;
          -  Uncontrolled hypertension&#xD;
&#xD;
          -  Risk of, or active hemorrhage: history or presence of active gastric/duodenal ulcer or&#xD;
             ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history&#xD;
             of perforation of fistulas; or any other condition that could possibly result in&#xD;
             gastrointestinal tract hemorrhage or perforation within 6 months prior to screening;&#xD;
&#xD;
          -  History of a thromboembolic event (including deep vein thrombosis [DVT], pulmonary&#xD;
             embolism, stroke and/or transient ischemic attack) within 6 months prior to screening;&#xD;
&#xD;
          -  Patients with squamous NSCLC;&#xD;
&#xD;
          -  Clinically significant cardiovascular disease, including but not limited to acute&#xD;
             myocardial infarction or coronary artery bypass surgery within 6 months prior to&#xD;
             enrollment, severe or unstable angina pectoris, New York Heart Association Class&#xD;
             III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left&#xD;
             ventricular ejection fraction (LVEF) &lt;50%;&#xD;
&#xD;
          -  Patients who have ever received a VEGFR inhibitor, except for patients with mCRC&#xD;
             enrolled in the dose expansion phase;&#xD;
&#xD;
          -  Systemic anti-neoplastic therapies or any investigational therapy within 4 weeks prior&#xD;
             to the first dose of study drug, including chemotherapy, radical radiotherapy,&#xD;
             hormonotherapy, biotherapy and immunotherapy;&#xD;
&#xD;
          -  Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5&#xD;
             half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;&#xD;
&#xD;
          -  Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the&#xD;
             initiation of study drug;&#xD;
&#xD;
          -  Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the&#xD;
             first dose of study drug;&#xD;
&#xD;
          -  Known human immunodeficiency virus (HIV) infection;&#xD;
&#xD;
          -  Known clinically significant history of liver disease, including cirrhosis, current&#xD;
             alcohol abuse or active viral hepatitis. For patients with evidence of chronic&#xD;
             hepatitis B (HBV), the HBV viral load must be undetectable on suppressive therapy, if&#xD;
             indicated. Patients with a history of hepatitis C virus (HCV) infection must have been&#xD;
             treated and cured. For patients with HCV who are currently on treatment, they are&#xD;
             eligible if they have an undetectable HCV viral load;&#xD;
&#xD;
          -  Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or&#xD;
             inferior vena cava.;&#xD;
&#xD;
          -  Women who are pregnant or lactating;&#xD;
&#xD;
          -  Brain metastases and/or spinal cord compression untreated with surgery and/or&#xD;
             radiotherapy, and without clinical imaging evidence of stable disease for 14 days or&#xD;
             longer; patients requiring steroids within 4 weeks prior to start of study treatment&#xD;
             will be excluded;&#xD;
&#xD;
          -  No other malignancy, except for non-melanoma skin cancer, during the 5 years prior to&#xD;
             screening;&#xD;
&#xD;
          -  Inability to take medication orally, dysphagia or an active gastric ulcer resulting&#xD;
             from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or&#xD;
             any other condition that investigators believe may affect absorption of the&#xD;
             investigational product;&#xD;
&#xD;
          -  Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory&#xD;
             result, or any other condition that investigators suspect may prohibit use of the&#xD;
             investigational product, affect interpretation of study results, or put the patient at&#xD;
             undue risk of harm based on the investigator's assessment;&#xD;
&#xD;
          -  Known hypersensitivity to fruquintinib or any of its excipients.&#xD;
&#xD;
          -  For Cohort C only: patients who have been previously treated with TAS-102 or&#xD;
             regorafenib&#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>William Schelman</last_name>
    <role>Study Director</role>
    <affiliation>HUTCHMED International</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic Arizona</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>California Cancer Care Associates for Research &amp; Excellence, Inc.</name>
      <address>
        <city>San Marcos</city>
        <state>California</state>
        <zip>92069</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph Heritage Healthcare</name>
      <address>
        <city>Santa Rosa</city>
        <state>California</state>
        <zip>95403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Colorado Cancer Center</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hem-Onc Associates of the Treasure Coast</name>
      <address>
        <city>Port Saint Lucie</city>
        <state>Florida</state>
        <zip>34952</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55902</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt Ingram Cancer Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 19, 2017</study_first_submitted>
  <study_first_submitted_qc>August 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 16, 2017</study_first_posted>
  <last_update_submitted>February 8, 2023</last_update_submitted>
  <last_update_submitted_qc>February 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>VEGF</keyword>
  <keyword>colorectal</keyword>
  <keyword>breast</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Triple Negative Breast Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03251378
org study id: 2015-013-00US1
nct id: NCT03251378
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
An open-label, dose escalation and expansion clinical trial to evaluate the safety,
      tolerability, and PK of fruquintinib in patients with advanced solid tumors, metastatic
      colorectal cancer and metastatic breast cancer.
The study is an open-label, dose escalation and expansion clinical trial to evaluate the
      safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors. The
      study will consist of two phases:

        -  A dose escalation phase - A 3+3 design will be used for this portion of the study.

        -  A dose expansion phase - Five cohorts will be evaluated in Dose Expansion. Cohort A will
           evaluate the MTD/RP2D in patients with advanced solid tumors. Cohort B and Cohort C will
           evaluate the MTD/RP2D in metastatic colorectal cancer patients. Cohort D and Cohort E
           will evaluate the MTD/RP2D in metastatic breast cancer patients.

      Study will be conducted in up to 9 sites in the US.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The incidence of DLT in each cohort
time frame: At the end of Cycle 1 (each cycle is 28 days)
description: The primary endpoint of the dose escalation phase is the incidence of DLT in each cohort.
measure: Progression free survival (PFS) at 12 weeks
time frame: From first dose of study drug through 12 weeks of treatment
description: Primary outcome expansion: progression free survival (PFS) at 12 weeks
measure: Maximum plasma concentration calculated with blood samples
time frame: within 30 days after the first dose
description: Blood samples will be taken to measure the levels of study drug
measure: Time to reach maximum concentration calculated with blood samples
time frame: within 30 days after the first dose
description: Blood samples will be taken to measure the levels of study drug
measure: Objective response rate
time frame: every 4 weeks or every 8 weeks depending on cohort, through study completion, an average of 6 months
description: the proportion of of subjects who have a Complete Response or Partial Response
arm group label: 3 mg Dose Escalation
arm group type: Experimental
description: 3 mg of Fruquintinib (HMPL-013), tablet taken daily, 3 weeks on, 1 week off
arm group label: 5 mg Dose Escalation
arm group type: Experimental
description: 5 mg of Fruquintinib (HMPL-013), tablet taken daily, 3 weeks on, 1 week off
arm group label: Fruquintinib Expansion Cohort A
arm group type: Experimental
description: 5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with advanced solid tumors.
arm group label: Metastatic Colorectal Cancer Expansion Cohort B
arm group type: Experimental
description: 5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with metastatic colorectal cancer who have progressed on or had intolerable toxicity to TAS-102, regoragenib, or both.
arm group label: Metastatic Colorectal Cancer Expansion Cohort C
arm group type: Experimental
description: 5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with metastatic colorectal cancer who have not been treated with TAS-102 or regorafenib.
arm group label: Metastatic Breast Cancer Expansion Cohort D
arm group type: Experimental
description: 5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with metastatic Her2-negative, hormone receptor positive breast cancer.
arm group label: Metastatic Breast Cancer Expansion Cohort E
arm group type: Experimental
description: 5 mg fruquintinib (HMPL-013) tablet taken daily, 3 weeks on, 1 week off in patients with metastatic triple negative (Her2-negative, ER-negative, PR-negative) breast cancer.
intervention type: Drug
intervention name: Fruquintinib (HMPL-013)
description: Fruquintinib is a small molecule tyrosine kinase inhibitor (TKI) that targets VEGFR-1, -2, and -3, with a novel chemical structure which belongs to the quinazoline class.
arm group label: 3 mg Dose Escalation
arm group label: 5 mg Dose Escalation
arm group label: Fruquintinib Expansion Cohort A
arm group label: Metastatic Breast Cancer Expansion Cohort D
arm group label: Metastatic Breast Cancer Expansion Cohort E
arm group label: Metastatic Colorectal Cancer Expansion Cohort B
arm group label: Metastatic Colorectal Cancer Expansion Cohort C
other name: HMPL-013
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: William Schelman
role: Study Director
affiliation: HUTCHMED International
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Triple Negative Breast Neoplasms
sharing ipd: No