<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/NCT03796429</url>
  </required_header>
  <id_info>
    <org_study_id>JS001-ZS-BC001</org_study_id>
    <nct_id>NCT03796429</nct_id>
  </id_info>
  <brief_title>A Study of the Efficacy and Safety of Chemotherapy Combined With Toripalimab in Advanced Biliary Tract Cancer</brief_title>
  <official_title>A Single-arm, Single-center, Prospective Clinical Study of the Efficacy and Safety of Chemotherapy Combined With Toripalimab in the Treatment of Advanced Biliary Tract Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shanghai Zhongshan Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Shanghai Junshi Bioscience Co., Ltd.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>OrigiMed</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Shanghai Zhongshan Hospital</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>
      1. Target population: patients with advanced biliary tract cancer (including gallbladder&#xD;
           carcinoma, intrahepatic and extrahepatic cholangiocarcinoma) .&#xD;
&#xD;
        2. Primary objective: progression free survival (PFS)/ overall survival (OS) of first-line&#xD;
           chemotherapy plus PD-1 antibody (Toripalimab) in patients with advanced biliary tract&#xD;
           cancer.&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        1. objective response rate (ORR) of first-line chemotherapy plus PD-1 antibody&#xD;
           (Toripalimab)&#xD;
&#xD;
        2. safety of first-line chemotherapy plus PD-1 antibody (Toripalimab)&#xD;
&#xD;
      3.Trial design: This is a monocenter, single arm, phase II study to evaluate the efficacy and&#xD;
      safety of first-line chemotherapy plus PD-1 antibody (Toripalimab) in patients with advanced&#xD;
      advanced biliary tract cancer.&#xD;
&#xD;
      4.Treatment plan: Patients will be given treatment as below once recruited: PD-1 antibody&#xD;
      Toripalimab（240mg, iv, q3w），combined with GS regimen(gemcitabine 1000mg／m2 ，d1,d8 + S1&#xD;
      40-60mg bid*14d，Q21d).&#xD;
&#xD;
      The treatment will be continued until emerging of disease progression or intolerable adverse&#xD;
      effects (The upper time limit for treatment is 2 years).&#xD;
&#xD;
      5.Number of subjects: 40 patients. Number of centers: 1 sites ( Fudan University Affiliated&#xD;
      Zhongshan Hospital).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Backgrounds:&#xD;
&#xD;
      Toripalimab (JS-001) is a PD-1 antibody developed by Shanghai Jun Shi Biomedical technology&#xD;
      Co. Ltd. Nowadays, eighteen clinical trials of this drug have been conducted in patients with&#xD;
      different types of advanced malignant tumor. Until now, Toripalimab has exhibited favorable&#xD;
      safety in recruited patients. Incidence rate of SAE is 14.7%. JS001-Ib-CRP-1.0 is a phase&#xD;
      Ib/II basket trial, aiming at evaluating safety and efficacy of JS001 in treating advanced&#xD;
      gastric adenocarcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and head&#xD;
      and neck squamous cell carcinoma.The interim analyses results of 161 patients show that the&#xD;
      ORR is 22.4%.&#xD;
&#xD;
      Now, the standard chemotherapies regimen for advanced biliary tract cancer include&#xD;
      gemcitabine, platinum and fluorouracil; Considering the synergistic effect of chemotherapy&#xD;
      and immune therapy, we choose GS regimen (gemcitabine+S1) to combine Toripalimab.&#xD;
&#xD;
      We will shut down the study in advance, if unpredicted SAE or low efficacy occur.&#xD;
&#xD;
      Patients with abnormal autoimmune status, unfavorable body function, factors impeding drug&#xD;
      taking, absorption and metabolism will be excluded. Study participants with disease&#xD;
      progression or severe/ intolerant toxicity during treatment will withdraw the study.&#xD;
&#xD;
      Hyper-progressive disease is defined as 1) progression 2) more than doubled growth rate 3)&#xD;
      tumor volume increase &gt;50% in 2 months after initialing the treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 17, 2018</start_date>
  <completion_date type="Anticipated">June 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2022</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>progression free survival (PFS) of GS regimen plus PD-1 antibody (Toripalimab)</measure>
    <time_frame>36 months after the last subject participating in</time_frame>
    <description>PFS is defined as time interval from recruitment to tumor progression or censoring. Tumor progression is defined as below: 1) relapse of primary lesion 2) emerging of new lesion 3) distant metastasis 4) death of any reason 5)tumor progression according to RESIST 1.1 on CT/MRI.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>overall survival (OS) of GS regimen plus PD-1 antibody (Toripalimab)</measure>
    <time_frame>36 months after the last subject participating in</time_frame>
    <description>OS is defined as time interval from recruitment to all-caused death or censoring.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>objective response rate (ORR) of GS regimen plus PD-1 antibody (Toripalimab)</measure>
    <time_frame>36 months after the last subject participating in</time_frame>
    <description>rate of patients with complete remission (CR) or partial remission (PR) based on RESIST1.1. ORR was evaluated by chest, abdominal &amp; pelvic CT/MRI. Evaluation will be conducted every 6 weeks during treatment, and every 0.5 year after all treatments.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>safety of GS regimen plus PD-1 antibody (Toripalimab)</measure>
    <time_frame>1 month after the last date of treatment</time_frame>
    <description>Adverse events (AE) of chemotherapy will be graded and documented according to NCI-CTC AE v4.03 from the beginning of treatment to 1 months after the last date of treatment. Documentary will include severity, lasting period and occurrence time. Main AEs include vomiting, diarrhea, anemia, leukopenia, thrombocytopenia, hand-foot syndrome, immune related adverse events (including interstitial lung disease, AST/ALT elevations, hypothyroidism and hyperthyroidism,etc) and hyper-progressive tumor.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Biliary Tract Cancer</condition>
  <arm_group>
    <arm_group_label>GS+Toripalimab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GS+Toripalimab</intervention_name>
    <description>Patients will be given treatment as below once recruited: PD-1 antibody Toripalimab（240mg, iv, q3w），combined with GS regimen(gemcitabine 1000mg／m2 ，d1,d8 + S1 40-60mg bid*14d，Q21d).&#xD;
The treatment will be continued until emerging of disease progression or intolerable adverse effects (The upper time limit for treatment is 2 years).</description>
    <arm_group_label>GS+Toripalimab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female. Age ≥ 18 years and ≤75 years.&#xD;
&#xD;
          2. histologically documented advanced biliary duct cancer, including gallbladder cancer,&#xD;
             intrahepatic and extrahepatic cholangiocarcinoma, specimen within a year available for&#xD;
             test (at least 10 pathological sections) .&#xD;
&#xD;
          3. at least one measurable lesion in abdominal CT/MRI according to RESIST 1.1 is&#xD;
             required.&#xD;
&#xD;
          4. Karnofsky score≥ 80.&#xD;
&#xD;
          5. Adequate hematological function: Neutrophil count ≥ 1.5 × 109/L, Platelets ≥ 100 ×&#xD;
             109/L and Hemoglobin ≥90g/L.&#xD;
&#xD;
          6. Adequate liver function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN); AST&#xD;
             (SGOT) and ALT (SGPT) &lt; 2.5 × ULN in the absence of liver metastases, or &lt; 5 × ULN in&#xD;
             case of liver metastases. ALP ≤ 2.5 × upper limit of normal (ULN); ALB ≥30g/L.&#xD;
&#xD;
          7. Adequate renal function: Serum creatinine ≤ 1.5 x ULN, and creatinine clearance ≥ 60&#xD;
             ml/min.&#xD;
&#xD;
          8. Adequate coagulation function: INR/PT≤ 1.5 x ULN, aPTT≤ 1.5 x ULN.&#xD;
&#xD;
          9. No serious concomitant disease that will threaten the survival of patients to less&#xD;
             than 5 years.&#xD;
&#xD;
         10. Written (signed) informed consent.&#xD;
&#xD;
         11. Good compliance with the study procedures, including lab and auxiliary examination and&#xD;
             treatment.&#xD;
&#xD;
         12. Female patients should not be pregnant or breast feeding.&#xD;
&#xD;
         13. Agree to take contraception measures during treatment and in 120 days after last dose&#xD;
             of Toripalimab or in 180 days after last dose of chemo.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. history of chemo, radiation, immune therapy or radical resection for the biliary tract&#xD;
             cancer, except those patients who relapsed after 6 months since the last time of&#xD;
             adjuvant therapy.&#xD;
&#xD;
          2. patients with active autoimmune disease or history of refractory autoimmune disease.&#xD;
&#xD;
          3. patients with active malignant tumor in recent 2 years, except the tumor studied in&#xD;
             this research or cured locally tumor like resected basal cell or squamous cell skin&#xD;
             cancer, superficial bladder cancer, cervical or breast carcinoma in situ.&#xD;
&#xD;
          4. uncontrollable pleural effusion, pericardial effusion, or ascites in 2 weeks before&#xD;
             recruitment.&#xD;
&#xD;
          5. patients who have digestive tract bleeding in 2 weeks before recruitment or with high&#xD;
             risk of bleeding.&#xD;
&#xD;
          6. perforation / fistula of GI tract in 6 months before recruitment.&#xD;
&#xD;
          7. losing over 20% body weight in 2 months before recruitment.&#xD;
&#xD;
          8. pulmonary disease history: interstitial pulmonary disease, non-infective pneumonitis,&#xD;
             pulmonary fibrosis, acute pulmonary disease.&#xD;
&#xD;
          9. uncontrollable systemic diseases, including diabetes, hypertension, etc.&#xD;
&#xD;
         10. severe chronic or active infections in need of systemic antibacterial, antifungal, or&#xD;
             antiviral treatment, including TB or HIV, etc.&#xD;
&#xD;
         11. patients with untreated chronic hepatitis B or HBV DNA over 500 IU/ml or positive HCV&#xD;
             RNA.&#xD;
&#xD;
         12. patients with any cardiovascular risk factors below:&#xD;
&#xD;
               1. cardiac chest pain occurring in 28 days before recruitment, defined as moderate&#xD;
                  pain that limits daily activity.&#xD;
&#xD;
               2. pulmonary embolism with symptoms occurring in 28 days before recruitment.&#xD;
&#xD;
               3. acute myocardial infarction occurring in 6 months before recruitment.&#xD;
&#xD;
               4. any history of heart failure reaching grade 3/4 of NYHA in 6 months before&#xD;
                  recruitment.&#xD;
&#xD;
               5. ventricular arrhythmias of Grade 2 or grater in 6 months before recruitment, or&#xD;
                  accompanied by supraventricular tachyarrhythmias requiring medical treatment.&#xD;
&#xD;
               6. cerebrovascular accident within 6 months before recruitment.&#xD;
&#xD;
         13. patients with peripheral neuropathy NCI CTC AE grade 1, except those with only deep&#xD;
             tendon reflex disappearing.&#xD;
&#xD;
         14. moderate or severe renal injury [creatinine clearance rate≤50 ml/min (according to&#xD;
             Cockroft &amp; Gault equation)], or Scr&gt;ULN.&#xD;
&#xD;
         15. allergic to any drug in this study.&#xD;
&#xD;
         16. history of allogeneic stem cell transplantation or organ transplantation.&#xD;
&#xD;
         17. use of steroids (dosage&gt;10mg/d prednisone) or other systemic immune suppressive&#xD;
             therapy in 14 days before recruitment, except patients treated with regimens below: a.&#xD;
             steroids for hormone replacement (dosage&gt;10mg/d prednisone); b. steroids for local&#xD;
             application with little systemic absorption; c. short -term (≤ 7 days) steroids for&#xD;
             preventing allergy or vomiting.&#xD;
&#xD;
         18. vaccinated with live vaccine in 4 weeks before recruitment.&#xD;
&#xD;
         19. receiving immune (interleukin, interferon, thymin) treatment or treatment of other&#xD;
             trials in 28 days before recruitment.&#xD;
&#xD;
         20. receiving palliative radiation in 14 days before recruitment.&#xD;
&#xD;
         21. history of anti PD-1, PD-L1, PD-L2 or any other specific T cell co-stimulation or&#xD;
             checkpoint pathway targeted treatment.&#xD;
&#xD;
         22. receiving operation in 28 days before recruitment, only if the operation is a&#xD;
             minimally invasive one e.g. PICC.&#xD;
&#xD;
         23. for patients with uncontrolled epilepsy, CNS diseases or history of mental disorder,&#xD;
             researchers should evaluate whether their diseases will impede their signing of&#xD;
             informed consent or compliance of treatment.&#xD;
&#xD;
         24. existing of potential situation which will impede drug administration or affect&#xD;
             toxicity analysis or alcohol/ drug abuse.&#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>Tianshu Liu, Doctor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shanghai Zhongshan Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Tianshu Liu, Doctor</last_name>
    <phone>+861368 1973 996</phone>
    <email>liu.tianshu@zs-hospital.sh.cn</email>
  </overall_contact>
  <location>
    <facility>
      <name>Zhongshan Hospital Affiliated to Fudan University</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <zip>200032</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tianshu Liu, Doctor</last_name>
      <email>liu.tianshu@zs-hospital.sh.cn</email>
    </contact>
    <investigator>
      <last_name>Yiyi Yu, master</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 4, 2019</study_first_submitted>
  <study_first_submitted_qc>January 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>January 4, 2019</last_update_submitted>
  <last_update_submitted_qc>January 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Shanghai Zhongshan Hospital</investigator_affiliation>
    <investigator_full_name>Tianshu Liu</investigator_full_name>
    <investigator_title>Doctor</investigator_title>
  </responsible_party>
  <keyword>Advanced Biliary Tract Cancer</keyword>
  <keyword>PD-1 antibody(Toripalimab)</keyword>
  <keyword>first-line chemotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Biliary Tract Neoplasms</mesh_term>
  </condition_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/NCT03796429
org study id: JS001-ZS-BC001
nct id: NCT03796429
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
1. Target population: patients with advanced biliary tract cancer (including gallbladder
           carcinoma, intrahepatic and extrahepatic cholangiocarcinoma) .

        2. Primary objective: progression free survival (PFS)/ overall survival (OS) of first-line
           chemotherapy plus PD-1 antibody (Toripalimab) in patients with advanced biliary tract
           cancer.

      Secondary objectives:

        1. objective response rate (ORR) of first-line chemotherapy plus PD-1 antibody
           (Toripalimab)

        2. safety of first-line chemotherapy plus PD-1 antibody (Toripalimab)

      3.Trial design: This is a monocenter, single arm, phase II study to evaluate the efficacy and
      safety of first-line chemotherapy plus PD-1 antibody (Toripalimab) in patients with advanced
      advanced biliary tract cancer.

      4.Treatment plan: Patients will be given treatment as below once recruited: PD-1 antibody
      Toripalimab（240mg, iv, q3w），combined with GS regimen(gemcitabine 1000mg／m2 ，d1,d8 + S1
      40-60mg bid*14d，Q21d).

      The treatment will be continued until emerging of disease progression or intolerable adverse
      effects (The upper time limit for treatment is 2 years).

      5.Number of subjects: 40 patients. Number of centers: 1 sites ( Fudan University Affiliated
      Zhongshan Hospital).
Backgrounds:

      Toripalimab (JS-001) is a PD-1 antibody developed by Shanghai Jun Shi Biomedical technology
      Co. Ltd. Nowadays, eighteen clinical trials of this drug have been conducted in patients with
      different types of advanced malignant tumor. Until now, Toripalimab has exhibited favorable
      safety in recruited patients. Incidence rate of SAE is 14.7%. JS001-Ib-CRP-1.0 is a phase
      Ib/II basket trial, aiming at evaluating safety and efficacy of JS001 in treating advanced
      gastric adenocarcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma and head
      and neck squamous cell carcinoma.The interim analyses results of 161 patients show that the
      ORR is 22.4%.

      Now, the standard chemotherapies regimen for advanced biliary tract cancer include
      gemcitabine, platinum and fluorouracil; Considering the synergistic effect of chemotherapy
      and immune therapy, we choose GS regimen (gemcitabine+S1) to combine Toripalimab.

      We will shut down the study in advance, if unpredicted SAE or low efficacy occur.

      Patients with abnormal autoimmune status, unfavorable body function, factors impeding drug
      taking, absorption and metabolism will be excluded. Study participants with disease
      progression or severe/ intolerant toxicity during treatment will withdraw the study.

      Hyper-progressive disease is defined as 1) progression 2) more than doubled growth rate 3)
      tumor volume increase >50% in 2 months after initialing the treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: progression free survival (PFS) of GS regimen plus PD-1 antibody (Toripalimab)
time frame: 36 months after the last subject participating in
description: PFS is defined as time interval from recruitment to tumor progression or censoring. Tumor progression is defined as below: 1) relapse of primary lesion 2) emerging of new lesion 3) distant metastasis 4) death of any reason 5)tumor progression according to RESIST 1.1 on CT/MRI.
measure: overall survival (OS) of GS regimen plus PD-1 antibody (Toripalimab)
time frame: 36 months after the last subject participating in
description: OS is defined as time interval from recruitment to all-caused death or censoring.
measure: objective response rate (ORR) of GS regimen plus PD-1 antibody (Toripalimab)
time frame: 36 months after the last subject participating in
description: rate of patients with complete remission (CR) or partial remission (PR) based on RESIST1.1. ORR was evaluated by chest, abdominal & pelvic CT/MRI. Evaluation will be conducted every 6 weeks during treatment, and every 0.5 year after all treatments.
measure: safety of GS regimen plus PD-1 antibody (Toripalimab)
time frame: 1 month after the last date of treatment
description: Adverse events (AE) of chemotherapy will be graded and documented according to NCI-CTC AE v4.03 from the beginning of treatment to 1 months after the last date of treatment. Documentary will include severity, lasting period and occurrence time. Main AEs include vomiting, diarrhea, anemia, leukopenia, thrombocytopenia, hand-foot syndrome, immune related adverse events (including interstitial lung disease, AST/ALT elevations, hypothyroidism and hyperthyroidism,etc) and hyper-progressive tumor.
arm group label: GS+Toripalimab
arm group type: Experimental
intervention type: Drug
intervention name: GS+Toripalimab
description: Patients will be given treatment as below once recruited: PD-1 antibody Toripalimab（240mg, iv, q3w），combined with GS regimen(gemcitabine 1000mg／m2 ，d1,d8 + S1 40-60mg bid*14d，Q21d).
The treatment will be continued until emerging of disease progression or intolerable adverse effects (The upper time limit for treatment is 2 years).
arm group label: GS+Toripalimab
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Tianshu Liu, Doctor
role: Principal Investigator
affiliation: Shanghai Zhongshan Hospital
last name: Tianshu Liu, Doctor
phone: +861368 1973 996
email: liu.tianshu@zs-hospital.sh.cn
facility: 
status: Recruiting
contact: 
investigator: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Shanghai Zhongshan Hospital
investigator full name: Tianshu Liu
investigator title: Doctor
mesh term: Biliary Tract Neoplasms