<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/NCT04486872</url>
  </required_header>
  <id_info>
    <org_study_id>A-02 POC-01</org_study_id>
    <nct_id>NCT04486872</nct_id>
  </id_info>
  <brief_title>An Exploratory Clinical Trial of Autologous Humanized Anti-cluster of Differentiation Antigen 19/20(CD19/CD20) Dual Specific CAR-T Cells Injection</brief_title>
  <official_title>A Single-arm, Open-label, Dose Escalation Study to Explore Safety, Efficacy and Pharmacokinetics of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells in Adult Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>First Affiliated Hospital of Zhejiang University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>First Affiliated Hospital of 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 is a single-arm, open-label, dose escalation, phase I study, aiming to evaluate the&#xD;
      safety and efficacy of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific Chimeric&#xD;
      Antigen Receptor (CAR) T-cells in patient with relapsed or refractory diffuse B cell&#xD;
      lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      CD19 CAR-T cell therapy has made breakthroughs in the treatment of B cell lymphoma and&#xD;
      leukemia, but 30% of patients still have antigen escape, which may be related to variants in&#xD;
      tumor cells and the expansion of CD19-negative tumor cells after treatment with CD19 CAR-T&#xD;
      cells. CD19/CD20 bispecific CAR-T cell targeting multiple antigens can attack tumor cells&#xD;
      while overcoming tumor antigen escape caused by a single target, maximizing efficacy and&#xD;
      duration of treatment, and can also solve the problem of uneven distribution or low&#xD;
      expression of single target on the tumor surface.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 25, 2020</start_date>
  <completion_date type="Anticipated">June 25, 2022</completion_date>
  <primary_completion_date type="Anticipated">May 11, 2022</primary_completion_date>
  <phase>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>The types and Incidence of adverse events</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of overall response</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Time from the first occurrence of CR (complete response) or PR (partial response) to the first diagnosis of PD (progressive disease)or recurrence.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Time from randomization to death due to any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Time from enrollment to tumor progression or death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>The proportion of CR (complete response) and PR (partial response).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Duration of response is defined as the time from the date of first occurrence of CR (complete response) or PR (partial response) to the date of the first documented PD (progressive disease) or death due to any cause.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Diffuse Large B Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>anti-CD19 and anti-CD20 dual specific CAR-T Cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Autologous humanized anti-CD19 and anti-CD20 dual specific CAR-T Cells</intervention_name>
    <description>Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells injection. Within 3 to 5 days after the pretreatment, the subjects received a single A-02 reinfusion, the infusion dose of each group of subjects 1.00 × 10^6/kg, 3.00 × 10^6/kg or 5.00 × 10^6/kg (if applicable), it is recommended to complete the infusion within 30 min after cell recovery.</description>
    <arm_group_label>anti-CD19 and anti-CD20 dual specific CAR-T Cells</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The subject or her/his legally guardian(s) must sign the informed consent form&#xD;
             approved by the Institutional Ethics Committee (IEC) prior to any screening&#xD;
             procedures;&#xD;
&#xD;
          2. Subjects aged 18 years or older with relapsed or refractory DLBCL (including primary&#xD;
             mediastinal large B-cell lymphoma and transformed follicular lymphoma), of which&#xD;
             refractory is defined as:&#xD;
&#xD;
               -  Have no response to the recent treatment including:&#xD;
&#xD;
                    -  The best response to the treatment regimen is progressive disease (PD) ,or;&#xD;
&#xD;
                    -  stable disease(SD) which maintained less than 6 months after the last&#xD;
                       treatment, or;&#xD;
&#xD;
               -  not suitable for autologous hematopoietic stem cell transplantation (ASCT), or&#xD;
                  ASCT refractory, including:&#xD;
&#xD;
                    -  progressive disease after ASCT or relapse within 12 months (relapse must be&#xD;
                       confirmed by biopsy), or;&#xD;
&#xD;
                    -  If remedial treatment is given after ASCT, the subject must have no response&#xD;
                       or relapse after the last treatment.&#xD;
&#xD;
          3. Subjects who have previously received ≥2 lines treatment, and at least including:&#xD;
&#xD;
               -  Anti-CD20 monoclonal antibody(rituximab), unless the CD20 negative;&#xD;
&#xD;
               -  A chemotherapy regimen containing anthracyclines;&#xD;
&#xD;
               -  The DLBCL patients who transformed from follicular lymphoma must have previously&#xD;
                  received chemotherapy for follicular lymphoma and have developed&#xD;
                  chemotherapy-refractory diseases after transform to DLBCL.&#xD;
&#xD;
          4. Confirmation for either CD19 or CD20 positivity using immunohistochemistry or flow&#xD;
             cytometry(accepting the previous results from the a third-level grade A hospitals&#xD;
             before the collection of peripheral blood mononuclear cells or peripheral blood. For&#xD;
             CD20 positive only, the investigator needs to determine whether the treatment&#xD;
             benefit);&#xD;
&#xD;
          5. According to the preliminary assessment of Hodgkin's lymphoma and non-Hodgkin's&#xD;
             lymphoma, staging and response assessment recommendations (2014 version), there is at&#xD;
             least one measurable lesion at baseline;&#xD;
&#xD;
          6. If the subject has received a single target in the past, such as CD19-CAR cell&#xD;
             therapy, it must be confirmed that the disease has progressed or relapsed after&#xD;
             treatment and is at least 1 month from the planned single collection period&#xD;
&#xD;
          7. Life expectancy ≥12 weeks;&#xD;
&#xD;
          8. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at&#xD;
             screening;&#xD;
&#xD;
          9. Adequate organ function:&#xD;
&#xD;
               -  Renal function defined as:&#xD;
&#xD;
                    -  A serum creatinine of ≤1.5 × Upper Limit of Normal(ULN), or;&#xD;
&#xD;
                    -  Estimated Glomerular Filtration Rate (eGFR) ≥60&#xD;
                       ml/min/1.73m2；[eGFR=186×（age）-0.203×SCr-1.154（mg/dl）， female ×0.742 on the&#xD;
                       basis of the calculation results]；&#xD;
&#xD;
               -  Liver function defined as:&#xD;
&#xD;
                    -  Alanine aminotransferase (ALT)≤ 5 × Upper Limit of Normal(ULN) for age, and;&#xD;
&#xD;
                    -  Total bilirubin ≤ 2.0 mg/dl with the exception of patients with&#xD;
                       Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome&#xD;
                       may be included if their total bilirubin is ≤ 3.0 × ULN and direct bilirubin&#xD;
                       ≤ 1.5 × ULN.&#xD;
&#xD;
               -  Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and&#xD;
                  blood oxygen saturation &gt; 91% on room air;&#xD;
&#xD;
         10. Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by&#xD;
             echocardiogram or Multigated Radionuclide Angiography (MUGA);&#xD;
&#xD;
         11. Adequate bone marrow reserve without transfusions defined as:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt;1×10^9 /L；&#xD;
&#xD;
               -  Absolute lymphocyte count (ALC) ≥0.3×10^9 /L；&#xD;
&#xD;
               -  Platelets ≥50×10^9 /L;&#xD;
&#xD;
               -  Hemoglobin &gt; 8.0 g/dl;&#xD;
&#xD;
         12. Subjects who use the following drugs should meet the following criteria:&#xD;
&#xD;
               -  Steroids: Therapeutic doses of steroids must be stopped 2 weeks prior to A-02&#xD;
                  infusion. However, the following physiological replacement doses of steroids are&#xD;
                  allowed: &lt; 6 - 12 mg/m2/day hydrocortisone or equivalent;&#xD;
&#xD;
               -  Immunosuppression: Any immunosuppressive medication must be stopped ≥ 4 weeks&#xD;
                  prior to sign the informed consent form;&#xD;
&#xD;
               -  Anti-proliferative therapy other than pretreatment chemotherapy within 2 weeks of&#xD;
                  A-02 infusion;&#xD;
&#xD;
               -  CD20 antibody-related treatment must be discontinued within 4 weeks of A-02&#xD;
                  infusion or 5 half-lives (whichever is longer);&#xD;
&#xD;
               -  CNS disease prophylaxis must be stopped &gt; 1 week prior to A-02 infusion (e.g.&#xD;
                  intrathecal methotrexate);&#xD;
&#xD;
         13. The investigator judged that the subject recovered from the toxicity of the previous&#xD;
             anti-tumor treatment to grade 1 or below (except for special grade 2 or below toxicity&#xD;
             that cannot be recovered in a short period of time, such as hair loss), suitable for&#xD;
             pretreatment. Chemotherapy and treatment of CAR-T cells;&#xD;
&#xD;
         14. Women of child-bearing potential and all male subjects must agree to use highly&#xD;
             effective methods of contraception for at least 12 months following A-02 infusion and&#xD;
             until CAR-T cells are no longer present by Polymerase chain reaction(PCR) on two&#xD;
             consecutive tests.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Subjects who meet any of the following criteria will not be enrolled:&#xD;
&#xD;
          1. Subjects who have received any CD19/CD20 dual-target cell therapy products before&#xD;
             signing the informed consent form;&#xD;
&#xD;
          2. Subjects with detectable cerebrospinal fluid malignant cells or brain metastases, or&#xD;
             with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma;&#xD;
&#xD;
          3. Subjects with current or previous history of central nervous system disease, such as&#xD;
             seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any&#xD;
             autoimmune disease involving the central nervous system;&#xD;
&#xD;
          4. Subjects who have previously received allogeneic hematopoietic stem cell&#xD;
             transplantation (HSCT); or suitable and consenting to Autologous hematopoietic stem&#xD;
             cell transplantation (ASCT);&#xD;
&#xD;
          5. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of A-02 infusion;&#xD;
&#xD;
          6. Investigational medicinal product within the last 30 days prior to sign the informed&#xD;
             consent form;&#xD;
&#xD;
          7. Subjects with active hepatitis B（defined as hepatitis B surface antigen positive, or&#xD;
             hepatitis B core antibody positive with hepatitis B virus DNA detection value &gt; 1000&#xD;
             copies/ml）or hepatitis C(HCV RNA positive);&#xD;
&#xD;
          8. Subjects positive for HIV antibody or treponema pallidum antibody;&#xD;
&#xD;
          9. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood&#xD;
             culture positive ≤ 72 hours prior to A-02 infusion);&#xD;
&#xD;
         10. Unstable angina and/or myocardial infarction within 6 months prior to sign the&#xD;
             informed consent form;&#xD;
&#xD;
         11. Previous or concurrent malignancy with the following exceptions:&#xD;
&#xD;
               -  Adequately treated basal cell or squamous cell carcinoma (adequate wound healing&#xD;
                  is required prior to sign the informed consent form);&#xD;
&#xD;
               -  In situ carcinoma of the cervix or breast, treated curatively and without&#xD;
                  evidence of recurrence for at least 3 years prior to sign the informed consent&#xD;
                  form;&#xD;
&#xD;
               -  A primary malignancy which has been completely resected and in complete remission&#xD;
                  for ≥ 5 years;&#xD;
&#xD;
         12. Pregnant or nursing women (women of childbearing age were tested positive for&#xD;
             pregnancy during screening period);&#xD;
&#xD;
         13. Subjects with active neurological auto immune or inflammatory disorders (e.g. Guillain&#xD;
             Barre Syndrome, Amyotrophic Lateral Sclerosis);&#xD;
&#xD;
         14. Other conditions that the investigator thinks he/she should not be included in this&#xD;
             clinical trial, such as poor compliance.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Jie Jin, Prof</last_name>
    <phone>13505716779</phone>
    <email>jiej0503@163.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jianzhong Shentu, Prof</last_name>
    <phone>13957111817</phone>
    <email>stjz@zju.edu.cn</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>First Affiliated Hospital of Zhejiang University</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <zip>310009</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jie Jin, Prof</last_name>
      <phone>13505716779</phone>
      <email>jiej0503@163.com</email>
    </contact>
    <contact_backup>
      <last_name>Jianzhong Shentu, Prof</last_name>
      <phone>13957111817</phone>
      <email>stjz@zju.edu.cn</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>July 17, 2020</study_first_submitted>
  <study_first_submitted_qc>July 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>August 25, 2020</last_update_submitted>
  <last_update_submitted_qc>August 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>First Affiliated Hospital of Zhejiang University</investigator_affiliation>
    <investigator_full_name>shentu jianzhong</investigator_full_name>
    <investigator_title>Prof</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</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/NCT04486872
org study id: A-02 POC-01
nct id: NCT04486872
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a single-arm, open-label, dose escalation, phase I study, aiming to evaluate the
      safety and efficacy of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific Chimeric
      Antigen Receptor (CAR) T-cells in patient with relapsed or refractory diffuse B cell
      lymphoma.
CD19 CAR-T cell therapy has made breakthroughs in the treatment of B cell lymphoma and
      leukemia, but 30% of patients still have antigen escape, which may be related to variants in
      tumor cells and the expansion of CD19-negative tumor cells after treatment with CD19 CAR-T
      cells. CD19/CD20 bispecific CAR-T cell targeting multiple antigens can attack tumor cells
      while overcoming tumor antigen escape caused by a single target, maximizing efficacy and
      duration of treatment, and can also solve the problem of uneven distribution or low
      expression of single target on the tumor surface.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The types and Incidence of adverse events
time frame: Up to 12 months
description: Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.
measure: Duration of overall response
time frame: Up to 12 months
description: Time from the first occurrence of CR (complete response) or PR (partial response) to the first diagnosis of PD (progressive disease)or recurrence.
measure: Overall survival
time frame: Up to 12 months
description: Time from randomization to death due to any cause
measure: Progression-free survival
time frame: Up to 12 months
description: Time from enrollment to tumor progression or death.
measure: Objective response rate
time frame: Up to 12 months
description: The proportion of CR (complete response) and PR (partial response).
measure: Duration of response
time frame: Up to 12 months
description: Duration of response is defined as the time from the date of first occurrence of CR (complete response) or PR (partial response) to the date of the first documented PD (progressive disease) or death due to any cause.
arm group label: anti-CD19 and anti-CD20 dual specific CAR-T Cells
arm group type: Experimental
intervention type: Biological
intervention name: Autologous humanized anti-CD19 and anti-CD20 dual specific CAR-T Cells
description: Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells injection. Within 3 to 5 days after the pretreatment, the subjects received a single A-02 reinfusion, the infusion dose of each group of subjects 1.00 × 10^6/kg, 3.00 × 10^6/kg or 5.00 × 10^6/kg (if applicable), it is recommended to complete the infusion within 30 min after cell recovery.
arm group label: anti-CD19 and anti-CD20 dual specific CAR-T Cells
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jie Jin, Prof
phone: 13505716779
email: jiej0503@163.com
last name: Jianzhong Shentu, Prof
phone: 13957111817
email: stjz@zju.edu.cn
facility: 
status: Recruiting
contact: 
contact backup: 
country: China
responsible party type: Principal Investigator
investigator affiliation: First Affiliated Hospital of Zhejiang University
investigator full name: shentu jianzhong
investigator title: Prof
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse
sharing ipd: No