<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/NCT04413734</url>
  </required_header>
  <id_info>
    <org_study_id>CISLD-9</org_study_id>
    <nct_id>NCT04413734</nct_id>
  </id_info>
  <brief_title>Combination of Anti-PD-1 Antibody and Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma</brief_title>
  <official_title>Combination of Anti-PD-1 Antibody and Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma: A Exploratory Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zhejiang University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Zhejiang University</source>
  <oversight_info>
    <has_dmc>No</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>
      This study is designed to observe and evaluate the safety and the efficacy of the&#xD;
      anti-programmed-death-1 antibody (anti-PD-1) Triprilumab in combination with chemotherapy of&#xD;
      Gemcitabine PLUS Cisplatin in patients who were advanced intrahepatic cholangiocarcinoma with&#xD;
      no chance for primary surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Intrahepatic cholangiocarcinoma, also known as intrahepatic cholangiocarcinoma, is derived&#xD;
      from intrahepatic bile duct epithelial cells, the second most common primary liver malignant&#xD;
      tumor in china. but most (60% -70%) patients is diagnosed at the advanced stage . Gemcitabine&#xD;
      plus cisplatin is the standard first-line advanced treatment recommended in international and&#xD;
      domestic guidelines, but the treatment effect remains to be improved.&#xD;
&#xD;
      The clinical benefits of immune therapies for HCC are emerging. Early clinical data already&#xD;
      show the safety of immune checkpoint inhibition. This study is to analyze the safety and&#xD;
      efficacy of immunotherapy Triprilumab Injection combined with Gemcitabine Injection plus&#xD;
      Cisplatin Injection in patients with advanced intrahepatic cholangiocarcinoma.&#xD;
&#xD;
      Patients who were aged 18 to 80 years with a histological or cytological diagnosis of&#xD;
      intrahepatic cholangiocarcinoma，locally advanced or multiple liver metastases, including&#xD;
      postoperative occurrence, will be enrolled in this trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 22, 2020</start_date>
  <completion_date type="Anticipated">April 22, 2024</completion_date>
  <primary_completion_date type="Anticipated">April 22, 2022</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>Progression-Free Survival (PFS)</measure>
    <time_frame>Observation period 48 months</time_frame>
    <description>Time from first randomization to the first documented disease progression or death due to any cause, whichever occurs first.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 48 months</time_frame>
    <description>Overall survival is defined as the time from randomization to death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR) per RECIST 1.1</measure>
    <time_frame>Up to 48 months</time_frame>
    <description>ORR is defined as the percentage of participants who have a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: a ≥30% decrease in the sum of diameters [SOD] of target lesions) as assessed by RECIST 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate(DCR)</measure>
    <time_frame>Up to 48 months</time_frame>
    <description>DCR is defined as the percentage of participants who have a confirmed Complete Response or Partial Response as assessed by RECIST 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Myopathologic response(MPR)</measure>
    <time_frame>Up to 48 months</time_frame>
    <description>DCR is defined as the proportion of patients with residual survival tumor ≤10%, the evaluation requires two liver cancer pathologists to evaluate and judge. If the difference between the two pathologists' evaluation is ≤10%, the average value is taken as the pathological remission rate. If the difference is greater than 10%, a third pathologist is required to evaluate, and then the average of the two with a difference of less than 10% will be taken</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Conversion surgical resection(R0) rate</measure>
    <time_frame>Up to 48 months</time_frame>
    <description>the ratio of patients successfully converted into radical surgical resection by the treatment plan, in which the margin of the liver is negative</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events (AE)</measure>
    <time_frame>Up to 48 months</time_frame>
    <description>Safety evaluation was done continuously during treatment by using CTCAE 5.0</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Intrahepatic Cholangiocarcinoma by AJCC V8 Stage</condition>
  <arm_group>
    <arm_group_label>Triprilumab in combination with chemotherapy of GP</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Triprilumab, 240 mg, every 3 weeks (Q3W), Day 1 of each 3 week cycle PLUS Gemcitabine, 1000 mg/m^2, Q3W, Day 1 and Day 8 of each cycle PLUS Cisplatin, 25 mg/m^2, Q3W, Day 1 and Day 8 of each cycle until progressive disease or unacceptable toxicity .</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Mono-chemotherapy of GP</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Gemcitabine, 1000 mg/m^2, Q3W, Day 1 and Day 8 of each cycle PLUS Cisplatin, 25 mg/m^2, Q3W, Day 1 and Day 8 of each cycle until progressive disease or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Combination therapy</intervention_name>
    <description>Triprilumab by intravenous infusion accompanying with Gemcitabine plus Cisplatin</description>
    <arm_group_label>Triprilumab in combination with chemotherapy of GP</arm_group_label>
    <other_name>Triprilumab</other_name>
    <other_name>Immunotherapy</other_name>
    <other_name>Anti-PD-1 therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mono-chemotherapy</intervention_name>
    <description>Gemcitabine plus Cisplatin by intravenous infusion</description>
    <arm_group_label>Mono-chemotherapy of GP</arm_group_label>
    <other_name>Gemcitabine Injection plus Cisplatin Injection</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Has histologically confirmed diagnosis of advanced (metastatic) and/or unresectable&#xD;
             (locally advanced) biliary tract cancer (intra-or extrahepatic cholangiocarcinoma)&#xD;
&#xD;
          -  Has at least one measurable, evaluable lesions based on Response Evaluation Criteria&#xD;
             in Solid Tumors (RECIST 1.1), as determined by the research center investigator&#xD;
&#xD;
          -  Participants with a history of hepatitis B or hepatitis C can be enrolled if they meet&#xD;
             study criteria&#xD;
&#xD;
          -  Is willing to provide archival tumor tissue sample or newly obtained core or&#xD;
             excisional biopsy of a tumor lesion&#xD;
&#xD;
          -  Has a life expectancy of greater than 3 months&#xD;
&#xD;
          -  Has adequate organ function&#xD;
&#xD;
          -  Has EOCG score 0 or 1&#xD;
&#xD;
          -  Has willing to voluntarily participate in clinical trial and sign informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Histology includes fibrolamellar, hepatocytes, sarcomatoid liver cancer, hepatocytes,&#xD;
             hepatocellular carcinoma and other components. Or has had previous biliary tract&#xD;
             cancer (intra-or extra hepatic cholangiocarcinoma) or combined with other cancer with&#xD;
             an exception of basal cell carcinoma and squamous cell carcinoma of the skin carcinoma&#xD;
             in situ that has been radical treated.&#xD;
&#xD;
          -  Has active tuberculosis and were receiving anti-tb treatment, or receiving anti-tb&#xD;
             treatment within a year before were randomly assigned.&#xD;
&#xD;
          -  Has symptomatic or poorly controlled circulatory disease, such as Congestive heart&#xD;
             failure(NYHA III-IV), arrhythmia instability, type I angina, coronary heart disease,&#xD;
             etc&#xD;
&#xD;
          -  Has esophageal and gastric varices bleeding due to portal hypertension, or with&#xD;
             history of inflammatory bowel disease, gastrointestinal perforation and intestinal&#xD;
             obstruction, abdominal abscess, or chronic diarrhea.&#xD;
&#xD;
          -  Has life-threatening bleeding or venous thromboembolism events occurred in the first&#xD;
             six months before enrollment, or the patient was prone to severe bleeding or&#xD;
             coagulation dysfunction, or was undergoing thrombolytic therapy&#xD;
&#xD;
          -  Has active autoimmune disease requiring systemic treatment within the two years before&#xD;
             enrollment , especially those with immunosuppressive drugs, who were unable to control&#xD;
             or who needed large amounts of immunosuppressive drugs to control the disease,&#xD;
             excluding topical glucose-corticosteroids or systemic use, and prednisone less than 10&#xD;
             milligrams per day&#xD;
&#xD;
          -  Has central nervous system disease with symptoms, such as primary brain tumor, stroke,&#xD;
             epilepsy, etc. Patients who have undergone central nervous system or known brain&#xD;
             metastases&#xD;
&#xD;
          -  Has acute or severe hepatitis infection, or a severe bacterial or bacterial infection&#xD;
             in an active or clinically poorly controlled, or with congenital or acquired immune&#xD;
             deficiency such human immunodeficiency virus (HIV) infected&#xD;
&#xD;
          -  Has previous allogeneic stem cell or parenchymal organ transplantation, including&#xD;
             after liver transplantation&#xD;
&#xD;
          -  Has history of allergies to drugs involved in this study&#xD;
&#xD;
          -  Women who are pregnant or lactating, or who do not want to use contraception during&#xD;
             the trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Tingbo Liang</last_name>
    <phone>+8613666676128</phone>
    <email>liangtingbo@zju.edu.cn</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Xueli Bai</last_name>
    <phone>+8613757166693</phone>
    <email>shirleybai@zju.edu.cn</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>the First Affiliated Hospital, School of Medicine, Zhejiang University</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <zip>310003</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Liang TingBo, MD, PHD</last_name>
      <phone>086-571-87236688</phone>
      <email>liangtingbo@zju.edu.cn</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 30, 2020</study_first_submitted>
  <study_first_submitted_qc>May 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>May 30, 2020</last_update_submitted>
  <last_update_submitted_qc>May 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Zhejiang University</investigator_affiliation>
    <investigator_full_name>TingBo Liang</investigator_full_name>
    <investigator_title>Clinical Professor</investigator_title>
  </responsible_party>
  <keyword>Intrahepatic Cholangiocarcinoma</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>anti-programmed-death-1 antibody</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cholangiocarcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Gemcitabine</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/NCT04413734
org study id: CISLD-9
nct id: NCT04413734
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study is designed to observe and evaluate the safety and the efficacy of the
      anti-programmed-death-1 antibody (anti-PD-1) Triprilumab in combination with chemotherapy of
      Gemcitabine PLUS Cisplatin in patients who were advanced intrahepatic cholangiocarcinoma with
      no chance for primary surgery.
Intrahepatic cholangiocarcinoma, also known as intrahepatic cholangiocarcinoma, is derived
      from intrahepatic bile duct epithelial cells, the second most common primary liver malignant
      tumor in china. but most (60% -70%) patients is diagnosed at the advanced stage . Gemcitabine
      plus cisplatin is the standard first-line advanced treatment recommended in international and
      domestic guidelines, but the treatment effect remains to be improved.

      The clinical benefits of immune therapies for HCC are emerging. Early clinical data already
      show the safety of immune checkpoint inhibition. This study is to analyze the safety and
      efficacy of immunotherapy Triprilumab Injection combined with Gemcitabine Injection plus
      Cisplatin Injection in patients with advanced intrahepatic cholangiocarcinoma.

      Patients who were aged 18 to 80 years with a histological or cytological diagnosis of
      intrahepatic cholangiocarcinoma，locally advanced or multiple liver metastases, including
      postoperative occurrence, will be enrolled in this trial.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-Free Survival (PFS)
time frame: Observation period 48 months
description: Time from first randomization to the first documented disease progression or death due to any cause, whichever occurs first.
measure: Overall Survival (OS)
time frame: Up to 48 months
description: Overall survival is defined as the time from randomization to death due to any cause.
measure: Objective Response Rate (ORR) per RECIST 1.1
time frame: Up to 48 months
description: ORR is defined as the percentage of participants who have a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: a ≥30% decrease in the sum of diameters [SOD] of target lesions) as assessed by RECIST 1.1
measure: Disease Control Rate(DCR)
time frame: Up to 48 months
description: DCR is defined as the percentage of participants who have a confirmed Complete Response or Partial Response as assessed by RECIST 1.1
measure: Myopathologic response(MPR)
time frame: Up to 48 months
description: DCR is defined as the proportion of patients with residual survival tumor ≤10%, the evaluation requires two liver cancer pathologists to evaluate and judge. If the difference between the two pathologists' evaluation is ≤10%, the average value is taken as the pathological remission rate. If the difference is greater than 10%, a third pathologist is required to evaluate, and then the average of the two with a difference of less than 10% will be taken
measure: Conversion surgical resection(R0) rate
time frame: Up to 48 months
description: the ratio of patients successfully converted into radical surgical resection by the treatment plan, in which the margin of the liver is negative
measure: Adverse Events (AE)
time frame: Up to 48 months
description: Safety evaluation was done continuously during treatment by using CTCAE 5.0
arm group label: Triprilumab in combination with chemotherapy of GP
arm group type: Experimental
description: Triprilumab, 240 mg, every 3 weeks (Q3W), Day 1 of each 3 week cycle PLUS Gemcitabine, 1000 mg/m^2, Q3W, Day 1 and Day 8 of each cycle PLUS Cisplatin, 25 mg/m^2, Q3W, Day 1 and Day 8 of each cycle until progressive disease or unacceptable toxicity .
arm group label: Mono-chemotherapy of GP
arm group type: Active Comparator
description: Gemcitabine, 1000 mg/m^2, Q3W, Day 1 and Day 8 of each cycle PLUS Cisplatin, 25 mg/m^2, Q3W, Day 1 and Day 8 of each cycle until progressive disease or unacceptable toxicity.
intervention type: Drug
intervention name: Combination therapy
description: Triprilumab by intravenous infusion accompanying with Gemcitabine plus Cisplatin
arm group label: Triprilumab in combination with chemotherapy of GP
other name: Triprilumab
other name: Immunotherapy
other name: Anti-PD-1 therapy
intervention type: Drug
intervention name: Mono-chemotherapy
description: Gemcitabine plus Cisplatin by intravenous infusion
arm group label: Mono-chemotherapy of GP
other name: Gemcitabine Injection plus Cisplatin Injection
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Tingbo Liang
phone: +8613666676128
email: liangtingbo@zju.edu.cn
last name: Xueli Bai
phone: +8613757166693
email: shirleybai@zju.edu.cn
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Zhejiang University
investigator full name: TingBo Liang
investigator title: Clinical Professor
mesh term: Cholangiocarcinoma
mesh term: Cisplatin
mesh term: Gemcitabine