xml: <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/NCT05971199</url>
    </required_header>
    <id_info>
      <org_study_id>IRB-2021-385</org_study_id>
      <nct_id>NCT05971199</nct_id>
    </id_info>
    <brief_title>Phase II Study of Fruquintinib Combined With Sintilimab and TACE for Inoperable Primary Hepatocellular Carcinoma</brief_title>
    <official_title>Phase II Study of Fruquintinib Combined With Sintilimab and TACE for Inoperable Primary Hepatocellular Carcinoma</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Zhejiang Cancer Hospital</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Zhejiang Cancer Hospital</source>
    <oversight_info>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The goal of this prospective, interventional clinical trial is to evaluation of fruquintinib&#xD;
        in combination with sintulimab and TACE for inoperable primary hepatocellular carcinoma for&#xD;
        progression-free survival (PFS).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide,&#xD;
        accounting for approximately 745,000 deaths annually and 9.1% of all cancer-related deaths&#xD;
        worldwide, with only about 30% of HCC patients having access to curative therapies. Most&#xD;
        patients have intermediate to advanced disease and are usually treated with palliative&#xD;
        therapy using TACE or systemic therapy (e.g., sorafenib, lenvatinib).&#xD;
  &#xD;
        The efficacy of either sorafenib or lenvatinib as a single agent in the treatment of&#xD;
        hepatocellular liver cancer remains limited, therefore, exploring combination therapy is one&#xD;
        of the current research hotspots. A recent randomized, open, multicenter clinical study&#xD;
        (TACTICS) enrolling patients with unresectable HCC showed that PFS was significantly&#xD;
        prolonged to 25.2 months in the TACE combined with sorafenib treatment group, compared to&#xD;
        25.2 months in the TACE alone group. PFS was only 13.5 months in the TACE treatment group&#xD;
        (HR=0. 59, 95%CI: 0.41-0. 87, P=0. 006). Median TTP was 24.1 months in the combination&#xD;
        treatment group and 13.5 months in the TACE treatment group alone (HR=0. 56, 95%CL 0. 38-0.&#xD;
        83, P=0. 004).&#xD;
  &#xD;
        Sintilimab, a recombinant fully human IgG4-type PD-1 monoclonal antibody, is an innovative&#xD;
        drug developed by Sintilimab (Suzhou) Co. At the end of 2018, Sintilimab was officially&#xD;
        approved by the NMPA of china for the treatment of relapsed or refractory classic Hodgkin's&#xD;
        lymphoma (cHL) after at least second-line systemic chemotherapy. As a biosimilar to&#xD;
        pembrolizumab, sintilimab has great potential to play a role similar to that played by&#xD;
        pembrolizumab in primary hepatocellular carcinoma.&#xD;
  &#xD;
        Fruquintinib is a potent small molecule VEGFR inhibitor developed by Hutchmed Ltd. with full&#xD;
        intellectual property rights, with high kinase selectivity and inhibitory activity only for&#xD;
        the VEGFR kinase family (VEGFR1, 2 and 3).On September 5, 2018, the NMPA of china officially&#xD;
        approved fruquintinib for patients who have previously received fluorouracil-based,&#xD;
        oxaliplatin and irinotecan-based chemotherapy, and for patients with metastatic colorectal&#xD;
        cancer (mCRC) who have received prior or are not suitable for prior anti-vascular endothelial&#xD;
        growth factor (VEGF) therapy, anti-epidermal growth factor receptor (EGFR) therapy (RAS wild&#xD;
        type).&#xD;
  &#xD;
        Therefore, based on previous studies, this study intended to select patients with&#xD;
        unresectable primary hepatocellular carcinoma, and prospectively observe the efficacy and&#xD;
        safety of fruquintinib in combination with sintilimab and TACE in the treatment of&#xD;
        unresectable CNLC(China liver cancer staging) 2b-3a patients.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">November 23, 2021</start_date>
    <completion_date type="Anticipated">December 23, 2024</completion_date>
    <primary_completion_date type="Anticipated">December 23, 2024</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <intervention_model_description>fruquintinib+sintilimab+TACE</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Progression-free survival(PFS)</measure>
      <time_frame>1 year</time_frame>
      <description>Progression free survival period refers to the period from the beginning of treatment to the time when patients with cancer progress is observed or death occurs for any reason.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Object response rate(ORR)</measure>
      <time_frame>Change from baseline tumor volume at 6 months</time_frame>
      <description>The proportion of patients whose tumor volume reduction reaches the predetermined value and can maintain the minimum time limit. It is the sum of the proportion of complete response (CR) and partial response(PR).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time to response(TTR)</measure>
      <time_frame>through study completion, an average of 1 year</time_frame>
      <description>Time to response</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Disease control rate(DCR)</measure>
      <time_frame>1 year</time_frame>
      <description>It is the sum of the proportion of complete response (CR), partial response(PR) and stable disease(SD).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall survival(OS)</measure>
      <time_frame>1 year</time_frame>
      <description>(OS) is defined as the time from the patient's first dose of study drug until any cause of their death.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time to progression(TTP)</measure>
      <time_frame>24 months</time_frame>
      <description>Time from the beginning of treatment to the objective progression of tumor</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">27</enrollment>
    <condition>Hepatocellular Carcinoma</condition>
    <arm_group>
      <arm_group_label>treatment</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Fruquintinib+sintilimab+TACE</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Fruquintinib</intervention_name>
      <description>Fruquintinib:5 mg capsule orally once daily on day 1-21 in 28-day cycles；</description>
      <arm_group_label>treatment</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Sintilimab</intervention_name>
      <description>Sintilimab: 200 mg i.v. every 3 weeks</description>
      <arm_group_label>treatment</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Transcatheter arterial chemoembolization（TACE）</intervention_name>
      <description>Transcatheter arterial chemoembolization（TACE）</description>
      <arm_group_label>treatment</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Age 18-75 years, male or female;&#xD;
  &#xD;
            2. Patients diagnosed with primary hepatocellular carcinoma (HCC) based on clinical&#xD;
               diagnosis or pathology;&#xD;
  &#xD;
            3. Patients diagnosed with Chinese stage IIb-IIIa according to the Primary Liver Cancer&#xD;
               Diagnostic and Treatment Protocol (2019 version), and evaluated by the investigator to&#xD;
               be unable to undergo surgical treatment, such as resection, ablation or liver&#xD;
               transplantation;&#xD;
  &#xD;
            4. Imaging reports within 14 days prior to the intervention showed the presence of at&#xD;
               least 1 target lesion measurable by CT or MRI, and the lesion is suitable for repeated&#xD;
               accurate measurements;&#xD;
  &#xD;
            5. Child-Pugh liver function rating: grade A or better B (≤7 points);&#xD;
  &#xD;
            6. ECOG score: 0-1;&#xD;
  &#xD;
            7. all lesions amenable to phase 1 or 2 (fractionated TACE) TACE therapy;&#xD;
  &#xD;
            8. Good organ and bone marrow function. Blood count: WBC&gt;4. 0 × 109/L, Hb&gt;80g/L, PLT&gt;75&#xD;
               ×109/L, NEUT&gt;/ 1.5 × 109/L; coagulation function:International normalized (prothrombin&#xD;
               time) ratio(INR) &lt;1.2; liver function indexes: serum albumin (ALB) &gt;3.5 g/dl, serum&#xD;
               total bilirubin(TBIL) &lt;1.5 times the upper limit of normal value (excluding biliary&#xD;
               obstruction), serum transaminases (ALT and AST)&lt;3 times the upper limit of normal&#xD;
               value; renal function: serum myelin (CR) &lt;1.5 times the upper limit of normal value;&#xD;
  &#xD;
            9. Patients with positive hepatitis B surface antigen need to have received&#xD;
               anti-hepatitis B treatment prior to inclusion in the study;&#xD;
  &#xD;
           10. Signed an informed consent form, were compliant and cooperated with the follow-up.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Hepatobiliary cell carcinoma, sarcomatoid hepatocellular carcinoma, mixed cell&#xD;
               carcinoma and fibrous lamellar hepatocellular carcinoma;&#xD;
  &#xD;
            2. With portal trunk or vena cava invasion;&#xD;
  &#xD;
            3. Having received interventional treatment such as TACE within 2 years&#xD;
  &#xD;
            4. Combined with medical contraindications that preclude any contrast-enhanced imaging&#xD;
               (CT or MRI);&#xD;
  &#xD;
            5. Previous systemic therapy;&#xD;
  &#xD;
            6. Uncontrollable ascites, hepatic encephalopathy or bleeding esophagogastric fundic&#xD;
               varices;&#xD;
  &#xD;
            7. Hypertension that cannot be reduced to within normal limits with antihypertensive&#xD;
               medication (systolic blood pressure &gt; 140 mmHg or diastolic blood pressure &gt; 90 mmHg);&#xD;
  &#xD;
            8. Suffering from myocardial ischemia or myocardial infarction of grade II or higher,&#xD;
               poorly controlled arrhythmia of grade II or higher myocardial ischemia or infarction,&#xD;
               poorly controlled arrhythmia (QTc interval greater than or equal to 450 ms, QTc&#xD;
               interval calculated in Fridericia metric).&#xD;
  &#xD;
               (calculated in Fridericia formula);&#xD;
  &#xD;
            9. History of gastrointestinal bleeding within the past 3 months or a clear tendency of&#xD;
               gastrointestinal bleeding, such as: esophageal varices at risk of bleeding, locally&#xD;
               active ulcer lesions, fecal occult blood (++);&#xD;
  &#xD;
           10. Pregnant or breastfeeding women; patients of childbearing potential who are unwilling&#xD;
               or unable to use effective contraceptive measures&#xD;
  &#xD;
           11. HIV-infected patients;&#xD;
  &#xD;
           12. Those suspected of being allergic to the study drug;&#xD;
  &#xD;
           13. Other circumstances that, in the judgment of the investigator, may affect the conduct&#xD;
               of the clinical study and the determination of the study results.&#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>Guoliang Shao</last_name>
      <role>Principal Investigator</role>
      <affiliation>Zhejiang Cancer Hospital Hangzhou, Zhejiang, China</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Guoliang Shao</last_name>
      <phone>+8613958183472</phone>
      <email>shaoguoliang666@hotmail.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Hui Zeng</last_name>
      <phone>+8613989898089</phone>
      <email>zenghuiray@zjcc.org.com</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Guoliang Shao</name>
        <address>
          <city>Hangzhou</city>
          <state>Zhejiang</state>
          <country>China</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Guoliang Shao</last_name>
        <phone>+8613958183472</phone>
        <email>shaoguoliang666@hotmail.com</email>
      </contact>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 10, 2023</study_first_submitted>
    <study_first_submitted_qc>August 1, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 2, 2023</study_first_posted>
    <last_update_submitted>August 1, 2023</last_update_submitted>
    <last_update_submitted_qc>August 1, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 2, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Zhejiang Cancer Hospital</investigator_affiliation>
      <investigator_full_name>Guoliang Shao</investigator_full_name>
      <investigator_title>Head of Department of Interventional Therapy</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carcinoma</mesh_term>
      <mesh_term>Carcinoma, Hepatocellular</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05971199
  org study id: IRB-2021-385
  nct id: NCT05971199
  lead sponsor: 
  is fda regulated drug: No
  is fda regulated device: No
  The goal of this prospective, interventional clinical trial is to evaluation of fruquintinib
        in combination with sintulimab and TACE for inoperable primary hepatocellular carcinoma for
        progression-free survival (PFS).
  Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide,
        accounting for approximately 745,000 deaths annually and 9.1% of all cancer-related deaths
        worldwide, with only about 30% of HCC patients having access to curative therapies. Most
        patients have intermediate to advanced disease and are usually treated with palliative
        therapy using TACE or systemic therapy (e.g., sorafenib, lenvatinib).
  
        The efficacy of either sorafenib or lenvatinib as a single agent in the treatment of
        hepatocellular liver cancer remains limited, therefore, exploring combination therapy is one
        of the current research hotspots. A recent randomized, open, multicenter clinical study
        (TACTICS) enrolling patients with unresectable HCC showed that PFS was significantly
        prolonged to 25.2 months in the TACE combined with sorafenib treatment group, compared to
        25.2 months in the TACE alone group. PFS was only 13.5 months in the TACE treatment group
        (HR=0. 59, 95%CI: 0.41-0. 87, P=0. 006). Median TTP was 24.1 months in the combination
        treatment group and 13.5 months in the TACE treatment group alone (HR=0. 56, 95%CL 0. 38-0.
        83, P=0. 004).
  
        Sintilimab, a recombinant fully human IgG4-type PD-1 monoclonal antibody, is an innovative
        drug developed by Sintilimab (Suzhou) Co. At the end of 2018, Sintilimab was officially
        approved by the NMPA of china for the treatment of relapsed or refractory classic Hodgkin's
        lymphoma (cHL) after at least second-line systemic chemotherapy. As a biosimilar to
        pembrolizumab, sintilimab has great potential to play a role similar to that played by
        pembrolizumab in primary hepatocellular carcinoma.
  
        Fruquintinib is a potent small molecule VEGFR inhibitor developed by Hutchmed Ltd. with full
        intellectual property rights, with high kinase selectivity and inhibitory activity only for
        the VEGFR kinase family (VEGFR1, 2 and 3).On September 5, 2018, the NMPA of china officially
        approved fruquintinib for patients who have previously received fluorouracil-based,
        oxaliplatin and irinotecan-based chemotherapy, and for patients with metastatic colorectal
        cancer (mCRC) who have received prior or are not suitable for prior anti-vascular endothelial
        growth factor (VEGF) therapy, anti-epidermal growth factor receptor (EGFR) therapy (RAS wild
        type).
  
        Therefore, based on previous studies, this study intended to select patients with
        unresectable primary hepatocellular carcinoma, and prospectively observe the efficacy and
        safety of fruquintinib in combination with sintilimab and TACE in the treatment of
        unresectable CNLC(China liver cancer staging) 2b-3a patients.
  allocation: N/A
  intervention model: Single Group Assignment
  intervention model description: fruquintinib+sintilimab+TACE
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Progression-free survival(PFS)
  time frame: 1 year
  description: Progression free survival period refers to the period from the beginning of treatment to the time when patients with cancer progress is observed or death occurs for any reason.
  measure: Object response rate(ORR)
  time frame: Change from baseline tumor volume at 6 months
  description: The proportion of patients whose tumor volume reduction reaches the predetermined value and can maintain the minimum time limit. It is the sum of the proportion of complete response (CR) and partial response(PR).
  measure: Time to response(TTR)
  time frame: through study completion, an average of 1 year
  description: Time to response
  measure: Disease control rate(DCR)
  time frame: 1 year
  description: It is the sum of the proportion of complete response (CR), partial response(PR) and stable disease(SD).
  measure: Overall survival(OS)
  time frame: 1 year
  description: (OS) is defined as the time from the patient's first dose of study drug until any cause of their death.
  measure: Time to progression(TTP)
  time frame: 24 months
  description: Time from the beginning of treatment to the objective progression of tumor
  arm group label: treatment
  arm group type: Experimental
  description: Fruquintinib+sintilimab+TACE
  intervention type: Drug
  intervention name: Fruquintinib
  description: Fruquintinib:5 mg capsule orally once daily on day 1-21 in 28-day cycles；
  arm group label: treatment
  intervention type: Drug
  intervention name: Sintilimab
  description: Sintilimab: 200 mg i.v. every 3 weeks
  arm group label: treatment
  intervention type: Device
  intervention name: Transcatheter arterial chemoembolization（TACE）
  description: Transcatheter arterial chemoembolization（TACE）
  arm group label: treatment
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 75 Years
  healthy volunteers: No
  last name: Guoliang Shao
  role: Principal Investigator
  affiliation: Zhejiang Cancer Hospital Hangzhou, Zhejiang, China
  last name: Guoliang Shao
  phone: +8613958183472
  email: shaoguoliang666@hotmail.com
  last name: Hui Zeng
  phone: +8613989898089
  email: zenghuiray@zjcc.org.com
  facility: 
  status: Recruiting
  contact: 
  country: China
  responsible party type: Principal Investigator
  investigator affiliation: Zhejiang Cancer Hospital
  investigator full name: Guoliang Shao
  investigator title: Head of Department of Interventional Therapy
  mesh term: Carcinoma
  mesh term: Carcinoma, Hepatocellular