<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/NCT04489862</url>
  </required_header>
  <id_info>
    <org_study_id>BZDS1901</org_study_id>
    <nct_id>NCT04489862</nct_id>
  </id_info>
  <brief_title>αPD1-MSLN-CAR T Cells for the Treatment of MSLN-positive Advanced Solid Tumors</brief_title>
  <official_title>An Exploratory Study of MSLN-CAR T Cells Secreting PD-1 Nanobodies for the Treatment of MSLN-positive Advanced Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wuhan Union Hospital, China</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Shanghai Cell Therapy Group Co.,Ltd</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Wuhan Union Hospital, China</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 is a single arm, open-label, dose escalation clinical study to evaluate the safety and&#xD;
      tolerability of autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T&#xD;
      cells secreting PD-1 nanobodies (αPD1-MSLN-CAR T cells) in patients with solid tumors.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 13, 2020</start_date>
  <completion_date type="Anticipated">December 2022</completion_date>
  <primary_completion_date type="Anticipated">June 2022</primary_completion_date>
  <phase>Early Phase 1</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>Dose-limiting toxicity （DLT）</measure>
    <time_frame>After 28 days of single infusion</time_frame>
    <description>Safety</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum tolerated dose (MTD)</measure>
    <time_frame>After 28 days of single infusion</time_frame>
    <description>Tolerability</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>Month 12</time_frame>
    <description>Clinical response will be assessed by RECIST 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Month 12</time_frame>
    <description>PFS of patients receiving αPD1-MSLN-CAR T cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Month 12</time_frame>
    <description>OS of patients receiving αPD1-MSLN-CAR T cells.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Plasma Concentration (Cmax)</measure>
    <time_frame>Month 12</time_frame>
    <description>Pharmacokinetics (PK</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamics (PD)</measure>
    <time_frame>Day 28</time_frame>
    <description>PD of IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IFN-γ, TNF-α and MCP1 will be analysed after CAR T cell infusion</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Non-small-cell Lung Cancer</condition>
  <condition>Mesothelioma</condition>
  <arm_group>
    <arm_group_label>CAR T cells therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The safety and efficacy of αPD1-MSLN-CAR T cells will be assessed in a standard 3+3 dose escalation approach. Four doses of CAR T cells will be evaluated in this study: 1×10^5 CAR+ T cells/kg, 3×10^5 CAR+ T cells/kg, 1×10^6 CAR+ T cells/kg, and 3×10^6 CAR+ T cells/kg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>αPD1-MSLN-CAR T cells</intervention_name>
    <description>Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of αPD1-MSLN-CAR T cells. During αPD1-MSLN-CAR T cells production, subjects will receive cyclophosphamide for the purpose of lymphocytes depletion，Cyclophosphamide 300 mg/m2/day IV infusion on days -5, -4 and -3. After lymphodepletion, subjects will receive one dose treatment with αPD1-MSLN-CAR T cells by intravenous (IV) injection. The initial dose of 1×10^5 CAR+ T cells/kg will be infused on day 0.</description>
    <arm_group_label>CAR T cells therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have a histological or cytological diagnosis of advanced solid tumors,&#xD;
             such as non-small-cell lung cancer and mesothelioma；&#xD;
&#xD;
          -  Patients must have failed established standard medical anti-cancer therapies；&#xD;
&#xD;
          -  Greater than or equal to 18 years of age and less than or equal to 70 years of age on&#xD;
             day of signing informed consent；&#xD;
&#xD;
          -  Life expectancy &gt;3 months；&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1；&#xD;
&#xD;
          -  Subjects must meet blood coagulation parameters and have adequate venous peripheral&#xD;
             access for apheresis. Patients must also have adequate mononuclear cells for CAR T&#xD;
             cell manufacturing；&#xD;
&#xD;
          -  Staining of MSLN must be greater than 50% of the cells in the tumor tissue and with&#xD;
             apparent expression in the membrane. PD-L1 expression must be positive. Tissue&#xD;
             obtained for the biopsy must be ≤1 year prior to enrollment for screening, not have&#xD;
             been previously irradiated or exposed to chemotherapy. If unavailable, new tissue&#xD;
             material from a recently obtained surgical or diagnostic biopsy is mandatory for this&#xD;
             trial；&#xD;
&#xD;
          -  Satisfactory organ and bone marrow function as defined by the following:&#xD;
&#xD;
               1. Adequate bone marrow function in the opinion of the Investigator for&#xD;
                  lymphocyte-depleting chemotherapy: absolute neutrophil count must be greater than&#xD;
                  ≥ 1.5×109/L, lymphocyte count must be greater than ≥ 0.5×109/L, platelets must be&#xD;
                  greater than ≥ 90×109/L, hemoglobin must be greater than ≥ 90g/L without&#xD;
                  transfusion within 7 days or dependency on EPO;&#xD;
&#xD;
               2. Total bilirubin must be less than or equal to two times (≤2.0x) the institutional&#xD;
                  normal upper limit; transaminases, serum alanine aminotransferase (ALT) or&#xD;
                  aspartate aminotransferase (AST), must be less than or equal to 2.5 times (≤2.5x)&#xD;
                  the institutional normal upper limit (≤2.5x if there is hepatic metastasis);&#xD;
&#xD;
               3. Creatinine must be less than or equal to one and one half times (≤ 1.5x) the&#xD;
                  institutional normal upper limit or eGFR ≥ 60ml/min/1.73m^2&#xD;
                  [eGFR=186×（age）-0.203×SCr-1.154（mg/dl）,for female the eGFR shoud be timed by&#xD;
                  0.742];&#xD;
&#xD;
               4. International normalized ratio (INR) or the PT is not greater than one and one&#xD;
                  half times (≤ 1.5) the upper limit of normal;&#xD;
&#xD;
               5. Lung function: ≤ CTCAE grade 1 dyspnea and SaO2≥ 91%&#xD;
&#xD;
               6. Cardiac function: cardiac ejection fraction (LVEF) must be greater than fifty&#xD;
                  percent (≥50%) by echocardiogram or MUGA one month before enrollment.&#xD;
&#xD;
          -  Subjects must have measureable disease as defined by RECIST 1.1 criteria;&#xD;
&#xD;
          -  Subjects sufficiently understand the trial and willingly sign the informed consent;&#xD;
&#xD;
          -  For concurrent medication:&#xD;
&#xD;
               1. Systemic therapeutic corticosteroids must be stopped 72 hours before CAR-T&#xD;
                  infusion. However, patients using physiologic replacement doses of&#xD;
                  corticosteroids, or its equivalent, will be considered eligible;&#xD;
&#xD;
               2. Immunosuppressive therapy must be stopped within four (4) weeks prior to&#xD;
                  enrollment;&#xD;
&#xD;
          -  Male and Female subjects agree to use approved contraceptive methods (e.g. birth&#xD;
             control pills, barrier device, intrauterine device, abstinence) during the study and&#xD;
             for at least 12 months following the last dose of the study cell infusion and until no&#xD;
             CAR-T cells can be detected after two consecutive PCR tests.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior therapy with targeted therapy or cell therapy against MSLN；&#xD;
&#xD;
          -  Prior therapy with any gene therapy (including CAR-T cell therapy) or any T cell&#xD;
             therapy home and abroad；&#xD;
&#xD;
          -  Active bacteria, viral or fungal infection, and not contained after anti-infective&#xD;
             therapy (positive results in the blood ≤72 hours before infusion);&#xD;
&#xD;
          -  Patient is positive for Syphilis, Human Immunodeficiency Virus (HIV) , active&#xD;
             Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected);&#xD;
&#xD;
          -  Patient has a medical condition such as autoimmune disease or organ transplantation&#xD;
             that requires chronic systemic steroid therapy or requires any other form of&#xD;
             immunosuppressive medication;&#xD;
&#xD;
          -  History of severe cardiac or pulmonary disease, including hypertension that cannot be&#xD;
             controlled by medication, and any of the conditions occurred within the past 6 months:&#xD;
             congestive heart failure (New York Heart Association functional classification ≥3),&#xD;
             cardiac angioplasty and stents, myocardial infarction, unstable angina, or other&#xD;
             clinically significant heart disease；&#xD;
&#xD;
          -  Detectable clinically relevant central nervous system (CNS) metastases and/or&#xD;
             pathology such as epilepsy/seizure, brain Ischemia/ hemorrhage, dementia, cerebellar&#xD;
             disease, or autoimmune disease affecting central nervous system；&#xD;
&#xD;
          -  Patient has a history or current evidence of any condition such as neurotic,&#xD;
             psychiatric, immune, metabolic and infectious disease, on any therapy, or laboratory&#xD;
             abnormality that might confound the results of the study, interfere with the patient's&#xD;
             participation for the full duration of the study, or is not in the best interest of&#xD;
             the patient to participate, in the opinion of the treating Investigator；&#xD;
&#xD;
          -  Patient has a known history of a hematologic malignancy, or of another malignant&#xD;
             primary solid tumor concurrently, with the exception of :&#xD;
&#xD;
               1. Patients with in situ cervical cancer or breast cancer with no evidence of&#xD;
                  disease for ≥ 3 years after curative treatments;&#xD;
&#xD;
               2. Patients who underwent successful definitive resection of in situ cancer with no&#xD;
                  evidence of disease for ≥5 years;&#xD;
&#xD;
          -  Has had chemotherapy, radioactive, small molecules, biological cancer therapy,&#xD;
             immunotherapy or other investigational drugs within 4 weeks prior to the initiation of&#xD;
             the study；&#xD;
&#xD;
          -  Pregnant or breastfeeding women;&#xD;
&#xD;
          -  Investigators think that patient has a history or current evidence of any condition,&#xD;
             therapy, or laboratory abnormality that might confound the results of the study,&#xD;
             interfere with the patient's participation for the full duration of the study and&#xD;
             cooperation with the requirements of the trial, uncontrolled medical, psychological,&#xD;
             familial, sociological, or geographical conditions, or is not in the best interest of&#xD;
             the patient to participate.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xiaorong Dong</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wuhan Union Hospital, China</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lu Wen</last_name>
    <phone>027-85872859</phone>
    <email>wenlu2808@126.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Xiaoli Lu</last_name>
    <phone>027-85872859</phone>
    <email>52548791@qq.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology</name>
      <address>
        <city>Wuhan</city>
        <state>Hubei</state>
        <zip>430000</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lu Wen</last_name>
      <phone>027-85872589</phone>
      <email>wenlu2808@126.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 21, 2020</study_first_submitted>
  <study_first_submitted_qc>July 27, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 28, 2020</study_first_posted>
  <last_update_submitted>July 27, 2020</last_update_submitted>
  <last_update_submitted_qc>July 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 28, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Wuhan Union Hospital, China</investigator_affiliation>
    <investigator_full_name>Xiaorong Dong</investigator_full_name>
    <investigator_title>Director</investigator_title>
  </responsible_party>
  <keyword>MSLN-CAR T</keyword>
  <keyword>PD-1 nanobodies</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mesothelioma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT04489862
org study id: BZDS1901
nct id: NCT04489862
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a single arm, open-label, dose escalation clinical study to evaluate the safety and
      tolerability of autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T
      cells secreting PD-1 nanobodies (αPD1-MSLN-CAR T cells) in patients with solid tumors.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose-limiting toxicity （DLT）
time frame: After 28 days of single infusion
description: Safety
measure: Maximum tolerated dose (MTD)
time frame: After 28 days of single infusion
description: Tolerability
measure: Objective response rate (ORR)
time frame: Month 12
description: Clinical response will be assessed by RECIST 1.1.
measure: Progression-free survival (PFS)
time frame: Month 12
description: PFS of patients receiving αPD1-MSLN-CAR T cells
measure: Overall survival (OS)
time frame: Month 12
description: OS of patients receiving αPD1-MSLN-CAR T cells.
measure: Peak Plasma Concentration (Cmax)
time frame: Month 12
description: Pharmacokinetics (PK
measure: Pharmacodynamics (PD)
time frame: Day 28
description: PD of IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IFN-γ, TNF-α and MCP1 will be analysed after CAR T cell infusion
arm group label: CAR T cells therapy
arm group type: Experimental
description: The safety and efficacy of αPD1-MSLN-CAR T cells will be assessed in a standard 3+3 dose escalation approach. Four doses of CAR T cells will be evaluated in this study: 1×10^5 CAR+ T cells/kg, 3×10^5 CAR+ T cells/kg, 1×10^6 CAR+ T cells/kg, and 3×10^6 CAR+ T cells/kg.
intervention type: Biological
intervention name: αPD1-MSLN-CAR T cells
description: Subjects will undergo leukapheresis to isolate peripheral blood mononuclear cells (PBMCs) for the production of αPD1-MSLN-CAR T cells. During αPD1-MSLN-CAR T cells production, subjects will receive cyclophosphamide for the purpose of lymphocytes depletion，Cyclophosphamide 300 mg/m2/day IV infusion on days -5, -4 and -3. After lymphodepletion, subjects will receive one dose treatment with αPD1-MSLN-CAR T cells by intravenous (IV) injection. The initial dose of 1×10^5 CAR+ T cells/kg will be infused on day 0.
arm group label: CAR T cells therapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Xiaorong Dong
role: Principal Investigator
affiliation: Wuhan Union Hospital, China
last name: Lu Wen
phone: 027-85872859
email: wenlu2808@126.com
last name: Xiaoli Lu
phone: 027-85872859
email: 52548791@qq.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Wuhan Union Hospital, China
investigator full name: Xiaorong Dong
investigator title: Director
mesh term: Mesothelioma
sharing ipd: No