<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/NCT03839550</url>
  </required_header>
  <id_info>
    <org_study_id>CancerIHCAMS-HCC-SHR1210</org_study_id>
    <nct_id>NCT03839550</nct_id>
  </id_info>
  <brief_title>Combine Apatinib Mesylate With PD-1 Antibody SHR-1210 for HCC With High Risk of Recurrence After Radical Resection</brief_title>
  <official_title>The Multi-center, Randomized and Controlled Phase II Trail of Apatinib Mesylate Tablets Combined With PD-1 Antibody SHR-1210 for Adjuvant Treatment of Patients With High Recurrence Risk After Radical Operation of Hepatocellular Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to assess the efficacy and safety of Apatinib Mesylate combined&#xD;
      with PD-1 antibody SHR-1210 in HCC patients with high risk of disease recurrence contained&#xD;
      microsatellite lesions, microvascular invasion(MVI) or secondary and above portal vein tumor&#xD;
      thrombosis (PVTT) after radical resection. Patients will be randomized 1:1 either to the&#xD;
      experimental arm to receive Apatinib Mesylate and PD-1 antibody SHR-1210 or to the standard&#xD;
      therapy arm of hepatic arterial infusion(HAI) .&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hepatocellular carcinoma (HCC) is a common malignancy worldwide, which is the third cause of&#xD;
      cancer related deaths. Radical hepatic resection is one of the most potentially curative&#xD;
      treatments for HCC. Unfortunately, the long-term survival after radical hepatic resection is&#xD;
      unsatisfactory because of the high incidence of tumor recurrence with the recurrence rates at&#xD;
      2 and 5 years are approximately 50 % to 60 % and 80 %,respectively. Microsatellite lesions,&#xD;
      microvascular invasion (MVI) , or portal vein tumor thrombosis (PVTT) are the main risk&#xD;
      factors for poor prognosis in HCC.&#xD;
&#xD;
      HCC is a typical vascular-rich tumor, and its occurrence, development, metastasis and&#xD;
      invasion are closely related to angiogenesis. Due to the long-term chronic inflammatory&#xD;
      response of the liver, the establishment and development of HCC can be induced by creating an&#xD;
      immunosuppressive microenvironment, including up-regulation of PD-1 receptors. Therefore,&#xD;
      immunotherapy is also considered to be a potential effective method for advanced HCC&#xD;
      treatment. And there is little convincing evidence indicating that adjuvant therapy reduces&#xD;
      the risk of recurrence after hepatic resection. Furthermore, no standard regimen has been&#xD;
      established.&#xD;
&#xD;
      In the present study, we assessed the efficacy and safety of Apatinib Mesylate that is Small&#xD;
      molecule anti-angiogenic targeted drugs /PD-1 antibody SHR-1210 combination therapy for&#xD;
      surgically resected HCCs with high incidence of tumor recurrence containing microsatellite&#xD;
      lesions, microvascular invasion(MVI) or secondary and above portal vein tumor thrombosis&#xD;
      (PVTT).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">February 15, 2019</start_date>
  <completion_date type="Anticipated">February 28, 2023</completion_date>
  <primary_completion_date type="Anticipated">February 28, 2020</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recurrence-free survival(RFS)</measure>
    <time_frame>72 month</time_frame>
    <description>Duration from surgery to tumor recurrence or death for any reason will be recorded to assess the clinical efficacy of Apatinib Mesylate plus PD-1 antibody SHR-1210 for HCC with high incidence of tumor recurrence after radical resection</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Apatinib Mesylate +SHR-1210</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental arm: Apatinib mesylate +PD-1 antibody SHR-1210 for adjuvant therapy of HCC with high incidence of tumor recurrence after hepatic resection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hepatic Arterial Infusion(HAI)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Active Comparator arm: HAI for adjuvant therapy of HCC with high incidence of tumor recurrence after hepatic resection</description>
  </arm_group>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Apatinib Mesylate +SHR-1210</intervention_name>
    <description>Apatinib mesylate tablets: 250 mg, orally once a day. Take about half an hour after a meal with warm water (the daily dose should be as much as possible.&#xD;
SHR-1210: 200mg, intravenous infusion for 30 minutes (including the time of the tube, the overall infusion time is not shorter than 20 minutes, no longer than 60 minutes), once every 2 weeks. A total of 6 months of treatment,starting 4-8 weeks after radical hepatic resection.</description>
    <arm_group_label>Apatinib Mesylate +SHR-1210</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Hepatic Arterial Infusion(HAI)</intervention_name>
    <description>Twice standard HAI treatment, the first treatment was performed 4-8 weeks after radical hepatic resection, and the second treatment was given 4-8 weeks after the first treatment (the specific time interval depends on the recovery of liver function of the patient). The specific dosage regimen is 80-100 mg of epirubicin or 50 mg of epirubicin + oxaliplatin 50 mg per HAI treatment.</description>
    <arm_group_label>Hepatic Arterial Infusion(HAI)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age between 18-75 years old.&#xD;
&#xD;
          2. Patients were primary Hepatocellular carcinoma according to standardization of&#xD;
             diagnosis and treatment for Hepatocellular carcinoma(2017 edition)&#xD;
&#xD;
          3. The imaging examination confirmed complete response (CR) after 1 month radical surgery&#xD;
             ,and consented to postoperative adjuvant therapy&#xD;
&#xD;
          4. Preoperative imaging (CT/MRI/PET-CT), intraoperative or postoperative pathology&#xD;
             confirmed HCC patients with high risk of disease recurrence contained microsatellite&#xD;
             lesions, microvascular invation(MVI) or secondary and above portal vein branches tumor&#xD;
             thrombosis (PVTT) after radical resection.&#xD;
&#xD;
          5. Preoperative imaging and perioperative outcomes confirmed no lymph node metastasis and&#xD;
             distant metastasis.&#xD;
&#xD;
          6. Child-Pugh A.&#xD;
&#xD;
          7. No anti-tumor treatment before radical hepatic resection.&#xD;
&#xD;
          8. BCLC A-B&#xD;
&#xD;
          9. Eastern Cooperative Oncology Group(ECOG) body condition score 0-1.&#xD;
&#xD;
         10. Adequate main organ function:&#xD;
&#xD;
             Hemoglobin ≥ 90g/L. Absolute neutrophil count (ANC) ≥ 1,500/mm3. Platelets ≥&#xD;
             100,000/ul. Albumin ≥ 29g/L. Alanine aminotransferase (ALT) or aspartate&#xD;
             aminotransferase (AST) &lt; 3 the upper limit of normal (ULN). Total bilirubin (TBIL) ≤&#xD;
             1.5 ULN. Creatinine ≤ 1.5 ULN.&#xD;
&#xD;
         11. Women of childbearing age (generally 15-49 years of age) are required to have a&#xD;
             negative pregnancy test (serum or urine) within 14 days prior to enrollment, and will&#xD;
             voluntarily use the appropriate method of contraception during the observation period&#xD;
             and within 8 weeks after the last administration of the study drug; For men,&#xD;
             appropriate methods of contraception should be used during the observation period and&#xD;
             within 8 weeks after the last administration of the study drug.&#xD;
&#xD;
         12. Be willing and able to provide written informed consent for the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of liver transplantation.&#xD;
&#xD;
          2. Tumor rupture or invasion of adjacent organs.&#xD;
&#xD;
          3. History of immunosuppressive drugs used for 14 days prior to the first use of&#xD;
             SHR-1210, excluding nasal and inhaled corticosteroids or physiological doses of&#xD;
             systemic steroid hormones .&#xD;
&#xD;
          4. Subjects are allergic to Apatinib Mesylate Tablets, SHR-1210, pharmaceutical&#xD;
             excipients, o other monoclonal antibodies.&#xD;
&#xD;
          5. Attenuated Live Vaccine in four weeks before study or during study.&#xD;
&#xD;
          6. Uncontrolled or symptomatic active central nervous system (CNS) metastases (if these&#xD;
             patients have been treated to clinically stable and discontinuation of anticonvulsants&#xD;
             and steroids in four weeks before study may be enrolled).&#xD;
&#xD;
          7. Peripheral neuropathy grade&gt; 1.&#xD;
&#xD;
          8. History of autoimmune disease(Subjects with vitiligo or asthma in childhood but&#xD;
             complete remission after adult intervention after adulthood may be enrolled)&#xD;
&#xD;
          9. Subjectes diagnosed any other malignant tumor within 3 years prior to study, except&#xD;
             for adequately treated basal or squamous cell skin cancer or cervical carcinoma in&#xD;
             situ&#xD;
&#xD;
         10. History of Human Immunodeficiency Virus (HIV).&#xD;
&#xD;
         11. Cardiovascular disease: Myocardial infarction, severe/unstable angina, NYHA class 2 or&#xD;
             higher cardiac dysfunction, poorly controlled arrhythmias (including QTcF interval men&#xD;
             &gt;450 ms, women &gt;470 ms, QTcF interval calculated by Fridericia formula), symptomatic&#xD;
             hyperemia Sexual heart failure, cerebrovascular accident (including transient ischemic&#xD;
             attack or symptomatic pulmonary embolism)&#xD;
&#xD;
         12. High blood pressure, and can not be well controlled by antihypertensive drugs&#xD;
             (systolic blood pressure ≥140mmHg or diastolic blood pressure ≥90 mmHg)&#xD;
&#xD;
         13. Abnormal coagulation (INR &gt; 1.5 × ULN or activated partial thromboplastin time (APTT)&#xD;
             &gt; 1.5 × ULN), with bleeding tendency or receiving thrombolysis or anticoagulant&#xD;
             therapy.&#xD;
&#xD;
         14. Hereditary or acquired bleeding and thrombosis trends, such as: hemophilia,&#xD;
             coagulopathy, thrombocytopenia, hypersplenism, etc.&#xD;
&#xD;
         15. Obvious hemoptysis in the first 2 months before the study or daily hemoptysis exceed&#xD;
             2.5ml.&#xD;
&#xD;
         16. Significant clinically bleeding symptoms or clear bleeding tendency within 3 months&#xD;
             prior to the study, such as gastrointestinal bleeding, hemorrhagic gastric ulcer,&#xD;
             baseline fecal occult blood (++) and above, or vasculitis.&#xD;
&#xD;
         17. Artery/ venous thrombosis, such as cerebrovascular accidents (including transient&#xD;
             ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and&#xD;
             pulmonary embolism,etc.&#xD;
&#xD;
         18. Long-term anticoagulant therapy with warfarin or heparin or antiplatelet therapy&#xD;
             (aspirin ≥ 300 mg/day or clopidogrel ≥ 75 mg/day).&#xD;
&#xD;
         19. Severe infection within 4 weeks prior to first drug administration (eg, intravenous&#xD;
             infusion of antibiotics, antifungal or antiviral drugs), or unexplained fever &gt;38.5℃&#xD;
             during screening period/first drug administration.&#xD;
&#xD;
         20. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell&#xD;
             transplantation.&#xD;
&#xD;
         21. Participated in any other drug clinical study within 4 weeks prior to first drug&#xD;
             administration , or no more than 5 half-lives from the last study.&#xD;
&#xD;
         22. History of psychotropic substance abuse or drug abuse.&#xD;
&#xD;
         23. Sserious physical or mental illness, laboratory abnormalities, increasing risk of&#xD;
             participating in the study, interfere with the results of the study, and patients&#xD;
             considered by the investigator to be unfit for the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hong Zhao</last_name>
    <role>Study Director</role>
    <affiliation>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Hong Zhao</last_name>
    <phone>+86-13381106850</phone>
    <email>pumczhaohong@126.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100021</zip>
        <country>China</country>
      </address>
    </facility>
    <contact>
      <last_name>Hong Zhao</last_name>
      <phone>+86-13381106850</phone>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>February 11, 2019</study_first_submitted>
  <study_first_submitted_qc>February 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <last_update_submitted>February 11, 2019</last_update_submitted>
  <last_update_submitted_qc>February 11, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</investigator_affiliation>
    <investigator_full_name>Hong Zhao</investigator_full_name>
    <investigator_title>chief physician</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>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Apatinib</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03839550
org study id: CancerIHCAMS-HCC-SHR1210
nct id: NCT03839550
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to assess the efficacy and safety of Apatinib Mesylate combined
      with PD-1 antibody SHR-1210 in HCC patients with high risk of disease recurrence contained
      microsatellite lesions, microvascular invasion(MVI) or secondary and above portal vein tumor
      thrombosis (PVTT) after radical resection. Patients will be randomized 1:1 either to the
      experimental arm to receive Apatinib Mesylate and PD-1 antibody SHR-1210 or to the standard
      therapy arm of hepatic arterial infusion(HAI) .
Hepatocellular carcinoma (HCC) is a common malignancy worldwide, which is the third cause of
      cancer related deaths. Radical hepatic resection is one of the most potentially curative
      treatments for HCC. Unfortunately, the long-term survival after radical hepatic resection is
      unsatisfactory because of the high incidence of tumor recurrence with the recurrence rates at
      2 and 5 years are approximately 50 % to 60 % and 80 %,respectively. Microsatellite lesions,
      microvascular invasion (MVI) , or portal vein tumor thrombosis (PVTT) are the main risk
      factors for poor prognosis in HCC.

      HCC is a typical vascular-rich tumor, and its occurrence, development, metastasis and
      invasion are closely related to angiogenesis. Due to the long-term chronic inflammatory
      response of the liver, the establishment and development of HCC can be induced by creating an
      immunosuppressive microenvironment, including up-regulation of PD-1 receptors. Therefore,
      immunotherapy is also considered to be a potential effective method for advanced HCC
      treatment. And there is little convincing evidence indicating that adjuvant therapy reduces
      the risk of recurrence after hepatic resection. Furthermore, no standard regimen has been
      established.

      In the present study, we assessed the efficacy and safety of Apatinib Mesylate that is Small
      molecule anti-angiogenic targeted drugs /PD-1 antibody SHR-1210 combination therapy for
      surgically resected HCCs with high incidence of tumor recurrence containing microsatellite
      lesions, microvascular invasion(MVI) or secondary and above portal vein tumor thrombosis
      (PVTT).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recurrence-free survival(RFS)
time frame: 72 month
description: Duration from surgery to tumor recurrence or death for any reason will be recorded to assess the clinical efficacy of Apatinib Mesylate plus PD-1 antibody SHR-1210 for HCC with high incidence of tumor recurrence after radical resection
arm group label: Apatinib Mesylate +SHR-1210
arm group type: Experimental
description: Experimental arm: Apatinib mesylate +PD-1 antibody SHR-1210 for adjuvant therapy of HCC with high incidence of tumor recurrence after hepatic resection
arm group label: Hepatic Arterial Infusion(HAI)
arm group type: Active Comparator
description: Active Comparator arm: HAI for adjuvant therapy of HCC with high incidence of tumor recurrence after hepatic resection
intervention type: Combination Product
intervention name: Apatinib Mesylate +SHR-1210
description: Apatinib mesylate tablets: 250 mg, orally once a day. Take about half an hour after a meal with warm water (the daily dose should be as much as possible.
SHR-1210: 200mg, intravenous infusion for 30 minutes (including the time of the tube, the overall infusion time is not shorter than 20 minutes, no longer than 60 minutes), once every 2 weeks. A total of 6 months of treatment,starting 4-8 weeks after radical hepatic resection.
arm group label: Apatinib Mesylate +SHR-1210
intervention type: Procedure
intervention name: Hepatic Arterial Infusion(HAI)
description: Twice standard HAI treatment, the first treatment was performed 4-8 weeks after radical hepatic resection, and the second treatment was given 4-8 weeks after the first treatment (the specific time interval depends on the recovery of liver function of the patient). The specific dosage regimen is 80-100 mg of epirubicin or 50 mg of epirubicin + oxaliplatin 50 mg per HAI treatment.
arm group label: Hepatic Arterial Infusion(HAI)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Hong Zhao
role: Study Director
affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
last name: Hong Zhao
phone: +86-13381106850
email: pumczhaohong@126.com
facility: 
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
investigator full name: Hong Zhao
investigator title: chief physician
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Recurrence
mesh term: Apatinib