<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/NCT03810339</url>
  </required_header>
  <id_info>
    <org_study_id>PPM</org_study_id>
    <nct_id>NCT03810339</nct_id>
  </id_info>
  <brief_title>Toripalimab as Monotherapy in Participants With POLE or POLD-1 Mutated and Non-MSI-H Advanced Solid Tumors</brief_title>
  <official_title>A Phase II Open Label Study of Toripalimab, a PD-1 Antibody, in Participants With POLE or POLD-1 Mutated and Non-MSI-H Advanced Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sun Yat-sen University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sun Yat-sen 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>
      The purpose of this study is to evaluate the response of toripalimab (JS001), a PD1 antibody,&#xD;
      in participants with POLE or POLD-mutated and non microsatellite instability (non-MSI-H)&#xD;
      advanced solid cancers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Immune checkpoint inhibitor (ICI) therapy including antibodies targeting PD-1/PD-L1 or CTLA-4&#xD;
      has greatly advanced the cancer treatments. Recent studies have identified several predictive&#xD;
      markers for ICI which includes microsatellite instability (MSI), PD-L1 expression and tumor&#xD;
      mutation burden (TMB). DNA polymerase epsilon (POLE) and delta (POLD) are in charge of DNA&#xD;
      replication as well as proofreading during DNA replication. Their germline or somatic&#xD;
      mutations can lead to DNA repair deficiencies and carcinogenesis. The investigators has found&#xD;
      that the POLE or POLD mutation causes an increased TMB in cancer patients and may lead to a&#xD;
      better survival to ICI. Therefore, the purpose of this study is to evaluate the efficacy of&#xD;
      toripalimab , a PD1 antibody, in participants with POLE or POLD-mutated and non&#xD;
      microsatellite instability high (non-MSI-H) advanced solid cancers. This is a Phase II, open&#xD;
      label, single arm study. Participants enrolled in this study received toripalimab 240mg,&#xD;
      every 3 weeks until disease progress or intolerable toxicity. Primary endpoints is ORR and&#xD;
      secondary endpoints are OS, PFS and safety.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 15, 2019</start_date>
  <completion_date type="Anticipated">January 15, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 15, 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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective Response Rates (ORR)</measure>
    <time_frame>up to 2 years</time_frame>
    <description>the ratio of patients whose efficiency evaluation is CR or PR</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>up to 2 years</time_frame>
    <description>defined as the period from the first dose of study treatment to loss of follow-up or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>up to 2 years</time_frame>
    <description>defined as the time from the first dose of study treatment to disease progression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events (AEs)</measure>
    <time_frame>up to 2 years</time_frame>
    <description>All treatment-related adverse events (AEs) were categorized according to the National Cancer Institute's Common Terminology Criteria for Adverse Events.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">35</enrollment>
  <condition>Solid Tumor</condition>
  <condition>Advanced Cancer</condition>
  <arm_group>
    <arm_group_label>Toripalimab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Toripalimab, 240mg, every 3 weeks until disease progress or intolerable toxicity</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Toripalimab</intervention_name>
    <description>Toripalimab, 240mg, every 3 weeks until disease progress or intolerable toxicity</description>
    <arm_group_label>Toripalimab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must provide written informed consent to participate&#xD;
&#xD;
          -  Adult aged between 18 and 75 years old&#xD;
&#xD;
          -  Participants with Histologically- or cytologically- proven advanced solid tumors and&#xD;
             not responding to standard therapy&#xD;
&#xD;
          -  MSS (microsatellite sability) or MSI-L (microsatellite instability-low) or pMMR status&#xD;
&#xD;
          -  Germline mutations or somatic mutations in POLE or POLD (synonymous mutation is&#xD;
             excluded)&#xD;
&#xD;
          -  Patients refuse any conventional chemotherapy or targeted therapy&#xD;
&#xD;
          -  Patients are willing to take biopsy of tumor tissue and take blood samples before&#xD;
             treatment (blood samples are also taken at each time of therapeutic evaluation)&#xD;
&#xD;
          -  Participants must have at least one measurable site of disease according to Response&#xD;
             Evaluation Criteria in Solid Tumors (RECIST) criteria. Lesions previously treated with&#xD;
             radiotherapy should not be regarded as target lesions unless there is a definite&#xD;
             progression of the lesion after radiotherapy.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1&#xD;
&#xD;
          -  Estimated life expectancy is greater than 3 months&#xD;
&#xD;
          -  Participants can provide more than 10 paraffin sections of tumor tissue&#xD;
&#xD;
          -  No history of radiotherapy or received non-targeted radiotherapy outside the target&#xD;
             lesions for this study more than 4 weeks ago before the first dose of study treatment&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x (5 x in&#xD;
             participants with liver metastasis) upper limit of normal (ULN)&#xD;
&#xD;
          -  Albumin ≥ 3 g/dL&#xD;
&#xD;
          -  Alkaline phosphatase ≤ 2.5 x ULN.&#xD;
&#xD;
          -  Serum bilirubin &lt;1.5 mg/dL&#xD;
&#xD;
          -  Creatinine ≤ ULN.&#xD;
&#xD;
          -  Absolute neutrophil count ≥ 1.5X10E9/L&#xD;
&#xD;
          -  Platelets ≥ 100 x 10E9/L&#xD;
&#xD;
          -  Hemoglobin ≥ 90 g/L&#xD;
&#xD;
          -  For females of childbearing potential (defined as &lt;2 years after last menstruation or&#xD;
             not surgically sterile), a negative serum pregnancy test must be performed within 21&#xD;
             days of the first dose of study treatment.&#xD;
&#xD;
          -  For females: agreement to contraception during the study treatment period and for at&#xD;
             least 28 days after the last dose of study treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with confirmed or suspected brain metastases&#xD;
&#xD;
          -  Patients with cancerous meningitis&#xD;
&#xD;
          -  Patients without germline mutations or somatic mutations in POLE and POLD&#xD;
&#xD;
          -  MSI-H (microsatellite instability-high) or dMMR&#xD;
&#xD;
          -  Prior treatment with PD-1 inhibitors, PD-L1 inhibitors or CTLA-4 inhibitors (or other&#xD;
             inhibitors in T cell co-stimulatory signals or checkpoint pathways)&#xD;
&#xD;
          -  Known history or evidence of cytotoxic drug therapy, biologic drug therapy (such as&#xD;
             monoclonal antibodies), immunotherapy (such as interleukin 2 or interferon), or other&#xD;
             investigational drugs therapy in the 4 weeks before the first dose of study treatment&#xD;
&#xD;
          -  Known history or evidence of significant immunodeficiency (including but not limited&#xD;
             to: interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation,&#xD;
             nephritis, hyperthyroidism and hypothyroidism; Patients with vitiligo or asthma&#xD;
             completely relieved can be included. Asthma that requires medical intervention cannot&#xD;
             be included)&#xD;
&#xD;
          -  Patients with a condition requiring systemic treatment with either corticosteroids (&gt;&#xD;
             10 mg daily prednisolone equivalent) or other immunosuppressive medications&#xD;
&#xD;
          -  Patients with active tuberculosis. Known history of antituberculosis drugs treatment&#xD;
             in 1 year before the first dose of study treatment&#xD;
&#xD;
          -  Administration of an anti-infection vaccine (e.g. influenza vaccine, chickenpox&#xD;
             vaccine) in the 4 weeks before the first dose of study treatment&#xD;
&#xD;
          -  Symptomatic heart failure, coronary heart disease (CHD), myocardial infarction in the&#xD;
             6 months before the first dose of study treatment&#xD;
&#xD;
          -  Known allergy to JS001 or its excipients&#xD;
&#xD;
          -  Pregnant or breastfeeding females&#xD;
&#xD;
          -  Other prior malignancy active within the previous 5 years except for non-melanoma skin&#xD;
             cancer&#xD;
&#xD;
          -  Persons without legal capacity&#xD;
&#xD;
          -  Positive test for HIV or AIDS&#xD;
&#xD;
          -  Positive test for HbsAg and HBV-DNA copy numbers (≥ 1000cps/ml)&#xD;
&#xD;
          -  Positive test for HCV&#xD;
&#xD;
          -  Any medical disorder or condition that, in the opinion of the investigator, may affect&#xD;
             the compliance or the signing of informed consent, etc.&#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>Rui-hua Xu, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sun Yat-sen University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Feng Wang, MD, PhD</last_name>
    <phone>+862087342635</phone>
    <email>wangfeng@sysucc.org.cn</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cancer center of Sun Yat-sen University</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Zhi-da Lv, BS</last_name>
      <phone>+862087342635</phone>
      <email>lvzd@sysucc.org.cn</email>
    </contact>
    <investigator>
      <last_name>Rui-hua Xu, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Feng Wang, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 17, 2019</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>June 24, 2023</last_update_submitted>
  <last_update_submitted_qc>June 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sun Yat-sen University</investigator_affiliation>
    <investigator_full_name>Ruihua Xu</investigator_full_name>
    <investigator_title>President and Professor</investigator_title>
  </responsible_party>
  <keyword>Immune checkpoint inhibitor</keyword>
  <keyword>POLE/POLD mutation</keyword>
  <keyword>non-MSI-H</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03810339
org study id: PPM
nct id: NCT03810339
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to evaluate the response of toripalimab (JS001), a PD1 antibody,
      in participants with POLE or POLD-mutated and non microsatellite instability (non-MSI-H)
      advanced solid cancers.
Immune checkpoint inhibitor (ICI) therapy including antibodies targeting PD-1/PD-L1 or CTLA-4
      has greatly advanced the cancer treatments. Recent studies have identified several predictive
      markers for ICI which includes microsatellite instability (MSI), PD-L1 expression and tumor
      mutation burden (TMB). DNA polymerase epsilon (POLE) and delta (POLD) are in charge of DNA
      replication as well as proofreading during DNA replication. Their germline or somatic
      mutations can lead to DNA repair deficiencies and carcinogenesis. The investigators has found
      that the POLE or POLD mutation causes an increased TMB in cancer patients and may lead to a
      better survival to ICI. Therefore, the purpose of this study is to evaluate the efficacy of
      toripalimab , a PD1 antibody, in participants with POLE or POLD-mutated and non
      microsatellite instability high (non-MSI-H) advanced solid cancers. This is a Phase II, open
      label, single arm study. Participants enrolled in this study received toripalimab 240mg,
      every 3 weeks until disease progress or intolerable toxicity. Primary endpoints is ORR and
      secondary endpoints are OS, PFS and safety.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response Rates (ORR)
time frame: up to 2 years
description: the ratio of patients whose efficiency evaluation is CR or PR
measure: Overall Survival (OS)
time frame: up to 2 years
description: defined as the period from the first dose of study treatment to loss of follow-up or death
measure: Progression free survival (PFS)
time frame: up to 2 years
description: defined as the time from the first dose of study treatment to disease progression
measure: Adverse Events (AEs)
time frame: up to 2 years
description: All treatment-related adverse events (AEs) were categorized according to the National Cancer Institute's Common Terminology Criteria for Adverse Events.
arm group label: Toripalimab
arm group type: Experimental
description: Toripalimab, 240mg, every 3 weeks until disease progress or intolerable toxicity
intervention type: Drug
intervention name: Toripalimab
description: Toripalimab, 240mg, every 3 weeks until disease progress or intolerable toxicity
arm group label: Toripalimab
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Rui-hua Xu, MD, PhD
role: Principal Investigator
affiliation: Sun Yat-sen University
last name: Feng Wang, MD, PhD
phone: +862087342635
email: wangfeng@sysucc.org.cn
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Sun Yat-sen University
investigator full name: Ruihua Xu
investigator title: President and Professor
mesh term: Neoplasms
sharing ipd: Undecided