<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/NCT03298828</url>
  </required_header>
  <id_info>
    <org_study_id>TMMU-CAR-001</org_study_id>
    <nct_id>NCT03298828</nct_id>
  </id_info>
  <brief_title>CD19 CAR and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma</brief_title>
  <official_title>CD19 Chimeric Antigen Receptor (CAR) and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Third Military Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Third Military Medical 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 safety, efficacy and blood kinetics of&#xD;
      autologous T cells genetically modified to express CD19 Chimeric Antigen Receptor and PD-1&#xD;
      knockout engineered T cells in patients with relapsed or refractory B-Cell Non-Hodgkin&#xD;
      Lymphoma and Leukaemia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced&#xD;
      Therapy Investigational Medicinal Product named CD19 Chimeric Antigen Receptor (CAR) and PD-1&#xD;
      knock out engineered T-cells (CD19 CAR and PD-1 knock out engineered T-cells) in children and&#xD;
      adults (age &lt;70 years) with high risk, relapsed CD19+ haematological malignancies (Acute&#xD;
      Lymphoblastic Leukemia and Burkitt's lymphoma). Following informed consent and registration&#xD;
      to the trial, patients will undergo an unstimulated leukapheresis for the generation of the&#xD;
      CD19 CAR T-cells. Patients will receive the CD19 CAR and PD-1 knock out engineered T-cells&#xD;
      following lymphodepleting chemotherapy. The study will evaluate the safety, efficacy and&#xD;
      duration of response of the CD19 CAR and PD-1 knock out engineered T-cells in children with&#xD;
      high risk relapsed CD19+ malignancies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">November 2017</start_date>
  <completion_date type="Anticipated">October 2022</completion_date>
  <primary_completion_date type="Anticipated">October 2020</primary_completion_date>
  <phase>Phase 1</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>Molecular remission</measure>
    <time_frame>1 month</time_frame>
    <description>Efficacy will be assessed by determining Minimal Residual Disease in the bone marrow aspirate using immunoglobulin heavy chain (IgH) quantitative polymerase chain reaction (qPCR) and/or Next Generation Sequencing in all patients. The proportion of patients achieving molecular remission at 1 month post CD19 CAR and PD-1 Knockout Engineered T-cell infusion will be determined.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Long term molecular remission</measure>
    <time_frame>2 years</time_frame>
    <description>Number of patients in molecular remission without further therapy at 2 years</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells</measure>
    <time_frame>2 years</time_frame>
    <description>Persistence and frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells in the peripheral blood by flow cytometry and qPCR analyses.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of hypogammaglobulinaemia</measure>
    <time_frame>2 years</time_frame>
    <description>Incidence and duration of hypogammaglobulinaemia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse rate</measure>
    <time_frame>10 years</time_frame>
    <description>Relapse rate monitored during interventional phase and long term follow up for a total of 10 years post cell infusion. Number of patients who relapsed can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>10 years</time_frame>
    <description>Overall survival is monitored during interventional phase and long term follow up for 10 years post-CD19 CAR and PD-1 Knockout Engineered T-cell infusion. Number of patients alive can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Acute Lymphoblastic Leukemia</condition>
  <condition>Burkitt Lymphoma</condition>
  <arm_group>
    <arm_group_label>CD19 CAR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR T-cells.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CD19 CAR and PD-1 knock out</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR and PD-1 knock out engineered T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR and PD-1 knock out engineered T-cells.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CD19 CAR and PD-1 knock out engineered T-cells</intervention_name>
    <description>A single dose of 1 x 10^6/kg CD19 CAR transduced and PD-1 knock out engineered T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.</description>
    <arm_group_label>CD19 CAR and PD-1 knock out</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CD19 CAR T-cells</intervention_name>
    <description>A single dose of 1 x 10^6/kg CD19 CAR transduced T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.</description>
    <arm_group_label>CD19 CAR</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1.Children and adults (age 70 years or younger) with high risk/relapsed CD19+&#xD;
             haematological malignancy:&#xD;
&#xD;
               1. Resistant disease (&gt;25% blasts) at end of UKALL 2011 or equivalent induction&#xD;
&#xD;
               2. ALL with persistent high level MRD at 2nd time point of frontline national&#xD;
                  protocol (currently &gt; 5 x 10-3 at week 14 UKALL2011 or equivalent)&#xD;
&#xD;
               3. High risk infant ALL (age &lt; 6 months at diagnosis with MLL gene rearrangement and&#xD;
                  either presenting white cell count &gt; 300 x 109/L or poor steroid early response&#xD;
                  (i.e circulating blast count &gt;1x109/L following 7 day steroid pre- phase of&#xD;
                  Interfant 06)&#xD;
&#xD;
               4. Intermediate risk infant ALL with MRD &gt; 10-3 at end of Interfant06 induction&#xD;
&#xD;
               5. Very early (&lt; 18 months from diagnosis) bone marrow or extramedullary relapse of&#xD;
                  acute lymphoblastic leukaemia (ALL)&#xD;
&#xD;
               6. Early (within 6 months of finishing therapy) bone marrow, or combined&#xD;
                  extramedullary relapse of ALL with bone marrow minimal residual disease (MRD) &gt;&#xD;
                  10-3 at end of re-induction&#xD;
&#xD;
               7. Any on therapy relapse of ALL in patients age 16-70&#xD;
&#xD;
               8. Any relapse of infant ALL&#xD;
&#xD;
               9. ALL post ≥ 2nd relapse&#xD;
&#xD;
              10. Any refractory relapse of ALL&#xD;
&#xD;
              11. ALL with MRD &gt;10-4 prior to planned stem cell transplant&#xD;
&#xD;
              12. Any relapse of ALL eligible for stem cell transplant but no available HLA matched&#xD;
                  donor or other contraindication to transplant&#xD;
&#xD;
              13. Any relapse of ALL after stem cell transplant&#xD;
&#xD;
              14. Any relapse of Burkitt's or other CD19+ lymphoma&#xD;
&#xD;
          -  2.Agreement to have a pregnancy test, use adequate contraception (if applicable)&#xD;
&#xD;
          -  3.Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Exclusion Criteria for registration:&#xD;
&#xD;
               1. CD19 negative disease&#xD;
&#xD;
               2. Active hepatitis B, C or HIV infection&#xD;
&#xD;
               3. Oxygen saturation ≤ 90% on air&#xD;
&#xD;
               4. Bilirubin &gt; 3 x upper limit of normal&#xD;
&#xD;
               5. Creatinine &gt; 3 x upper limit of normal&#xD;
&#xD;
               6. Women who are pregnant or lactating&#xD;
&#xD;
               7. Stem Cell Transplant patients only: active acute graft-versus-host disease (GVHD)&#xD;
                  overall Grade ≥ II (Seattle criteria) or moderate/severe chronic GVHD (NIH&#xD;
                  consensus criteria) requiring systemic steroids&#xD;
&#xD;
               8. Inability to tolerate leucapheresis&#xD;
&#xD;
               9. Karnofsky (age ≥ 10 years) or Lansky (age &lt; 10) score ≤ 50%&#xD;
&#xD;
          -  Exclusion criteria for CD19CAR T-cell infusion:&#xD;
&#xD;
               1. Severe intercurrent infection at the time of scheduled CD19 CAR and PD-1 Knockout&#xD;
                  Engineered T Cells infusion&#xD;
&#xD;
               2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time&#xD;
                  of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion&#xD;
&#xD;
               3. Allogeneic transplant recipients with active acute GVHD overall grade &gt;2 or&#xD;
                  moderate/severe chronic GVHD requiring systemic steroids at the time of scheduled&#xD;
                  CD19 CAR and PD-1 Knockout Engineered T Cells infusion&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Xiaoyun Shang, Dr.</last_name>
    <phone>+8618580607020</phone>
    <email>shangxiaoyun@gmail.com</email>
  </overall_contact>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>July 24, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 2, 2017</study_first_posted>
  <last_update_submitted>September 26, 2017</last_update_submitted>
  <last_update_submitted_qc>September 26, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 2, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Third Military Medical University</investigator_affiliation>
    <investigator_full_name>Xiaoyun Shang</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Burkitt Lymphoma</mesh_term>
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</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/NCT03298828
org study id: TMMU-CAR-001
nct id: NCT03298828
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to evaluate the safety, efficacy and blood kinetics of
      autologous T cells genetically modified to express CD19 Chimeric Antigen Receptor and PD-1
      knockout engineered T cells in patients with relapsed or refractory B-Cell Non-Hodgkin
      Lymphoma and Leukaemia.
This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced
      Therapy Investigational Medicinal Product named CD19 Chimeric Antigen Receptor (CAR) and PD-1
      knock out engineered T-cells (CD19 CAR and PD-1 knock out engineered T-cells) in children and
      adults (age <70 years) with high risk, relapsed CD19+ haematological malignancies (Acute
      Lymphoblastic Leukemia and Burkitt's lymphoma). Following informed consent and registration
      to the trial, patients will undergo an unstimulated leukapheresis for the generation of the
      CD19 CAR T-cells. Patients will receive the CD19 CAR and PD-1 knock out engineered T-cells
      following lymphodepleting chemotherapy. The study will evaluate the safety, efficacy and
      duration of response of the CD19 CAR and PD-1 knock out engineered T-cells in children with
      high risk relapsed CD19+ malignancies.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Molecular remission
time frame: 1 month
description: Efficacy will be assessed by determining Minimal Residual Disease in the bone marrow aspirate using immunoglobulin heavy chain (IgH) quantitative polymerase chain reaction (qPCR) and/or Next Generation Sequencing in all patients. The proportion of patients achieving molecular remission at 1 month post CD19 CAR and PD-1 Knockout Engineered T-cell infusion will be determined.
measure: Long term molecular remission
time frame: 2 years
description: Number of patients in molecular remission without further therapy at 2 years
measure: Frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells
time frame: 2 years
description: Persistence and frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells in the peripheral blood by flow cytometry and qPCR analyses.
measure: Incidence of hypogammaglobulinaemia
time frame: 2 years
description: Incidence and duration of hypogammaglobulinaemia.
measure: Relapse rate
time frame: 10 years
description: Relapse rate monitored during interventional phase and long term follow up for a total of 10 years post cell infusion. Number of patients who relapsed can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).
measure: Overall Survival
time frame: 10 years
description: Overall survival is monitored during interventional phase and long term follow up for 10 years post-CD19 CAR and PD-1 Knockout Engineered T-cell infusion. Number of patients alive can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).
arm group label: CD19 CAR
arm group type: Experimental
description: Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR T-cells.
arm group label: CD19 CAR and PD-1 knock out
arm group type: Experimental
description: Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR and PD-1 knock out engineered T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR and PD-1 knock out engineered T-cells.
intervention type: Biological
intervention name: CD19 CAR and PD-1 knock out engineered T-cells
description: A single dose of 1 x 10^6/kg CD19 CAR transduced and PD-1 knock out engineered T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.
arm group label: CD19 CAR and PD-1 knock out
intervention type: Biological
intervention name: CD19 CAR T-cells
description: A single dose of 1 x 10^6/kg CD19 CAR transduced T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.
arm group label: CD19 CAR
criteria: 
gender: All
minimum age: N/A
maximum age: 70 Years
healthy volunteers: No
last name: Xiaoyun Shang, Dr.
phone: +8618580607020
email: shangxiaoyun@gmail.com
responsible party type: Principal Investigator
investigator affiliation: Third Military Medical University
investigator full name: Xiaoyun Shang
investigator title: Principal Investigator
mesh term: Burkitt Lymphoma
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
sharing ipd: Undecided