<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/NCT03289455</url>
  </required_header>
  <id_info>
    <org_study_id>AUTO3-PA1</org_study_id>
    <secondary_id>2016-004680-39</secondary_id>
    <nct_id>NCT03289455</nct_id>
  </id_info>
  <brief_title>CD19 /22 CAR T Cells (AUTO3) for the Treatment of B Cell Acute Lymphoblastic Leukemia (ALL)</brief_title>
  <acronym>AMELIA</acronym>
  <official_title>A Single-Arm, Open-Label, Multi-Centre, Phase I/II Study Evaluating the Safety and Clinical Activity Of AUTO3, a CAR T Cell Treatment Targeting CD19 And CD22 in Paediatric And Young Adult Patients With Relapsed or Refractory B Cell Acute Lymphoblastic Leukaemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Autolus Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Autolus Limited</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>
      The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment&#xD;
      targeting CD19 and CD22 in paediatric or young adult patients with relapsed or refractory B&#xD;
      cell acute lymphoblastic leukaemia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will consist of 2 phases, a Phase I or dose escalation phase and a Phase II or&#xD;
      expansion phase. Paediatric or young adult patients with relapsed or refractory B cell ALL&#xD;
      will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis in&#xD;
      order to harvest T cells, which is the starting material for the manufacture of the&#xD;
      autologous CAR T product AUTO3 which is a CD19 and CD22 dual targeting CAR T cell product.&#xD;
      Following pre-conditioning by a chemotherapeutic regimen, the patient will receive AUTO3&#xD;
      intravenously as a single or split dose and will then enter a 24-month follow-up period.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 26, 2017</start_date>
  <completion_date type="Actual">May 18, 2020</completion_date>
  <primary_completion_date type="Actual">May 18, 2020</primary_completion_date>
  <phase>Phase 1/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>Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion</measure>
    <time_frame>Within 30 days (+/- 3 days) after the last dose of AUTO3.</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3</measure>
    <time_frame>Within 30 days (+/- 3 days) after the last dose of AUTO3.</time_frame>
    <description>DLT was defined as i) any new non-hematological adverse event (AE) of Grade 3 or higher toxicity using the NCI CTCAE (version 5.0), which was probably or definitely related to AUTO3 therapy, which occurred within the DLT evaluation period, and which failed to resolve to Grade 2 or better within 14 days, despite appropriate supportive measures; ii) Grade 4 cytokine release syndrome (CRS) or neurotoxicity, cerebral edema, or Grade 3 neurotoxicity (including cerebral edema) that lasted &gt;72 hours; iii) Grade &gt;3 disseminated intravascular coagulation; iv) Grade &gt;2 infusion reaction; v) Any other fatal event (Grade 5) or life-threatening event (Grade 4) that could not be managed with conventional supportive measures or which in the opinion of the Safety Evaluation Committee (SEC) necessitated dose reduction or other modification to trial treatment to avoid a similar hazard in future patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Patients Achieving Morphological Remission (Complete Response(CR) or Complete Response With Incomplete Count Recovery (CRi) and Minimal Residual Disease (MRD)-Negative Response in the Bone Marrow (PCR)).</measure>
    <time_frame>Within 30 days (+/- 3 days) post AUTO3 infusion</time_frame>
    <description>Morphological response evaluations were based on the response criteria for ALL according to the NCCN guidelines version 2.2014. Minimal residual disease-negative status was achieved if MRD was &lt;10^-4 (0.01%) by PCR amplification of individual rearrangements of Ig genes and/or flow cytometry MRD testing.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis</measure>
    <time_frame>Up to 8 weeks post leukapheresis</time_frame>
    <description>Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients screened).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-Free Survival (EFS) by Morphological Analysis</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Time from date of first AUTO3 infusion until the earliest of treatment failure (defined as not achieving CR/CRi post AUTO3 infusion / no response), morphological relapse, or death due to any cause, whichever occurred first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With CD19- and/or CD22-negative Relapse</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse-Free Survival (RFS) by Morphological Analysis</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Time from first achievement of morphological CR/CRi post AUTO3 treatment until the earliest of morphological relapse, or death due to any cause, whichever occurred first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 2 years after the last patient was infused</time_frame>
    <description>Calculated from the date of AUTO3 treatment to the date of death anytime post AUTO3 infusion. Patients who had not died were censored at the date of last contact.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Expansion of AUTO3 Following Adoptive Transfer</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Persistence of AUTO3 Following Adoptive Transfer</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Persistence of AUTO3 was measured by quantitative polymerase chain reaction (qPCR) and/or flow cytometry at a range of time points in the peripheral blood and the bone marrow.&#xD;
Persistence was defined as the timepoint in days of last detectable CAR T cell by qPCR or last assessment if zero copies per μg DNA (whichever occurred later) before morphological relapse (Tlast).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of B Cell Aplasia</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">23</enrollment>
  <condition>B Acute Lymphoblastic Leukemia</condition>
  <condition>Recurrent Childhood Acute Lymphoblastic Leukemia</condition>
  <condition>Refractory Childhood Acute Lymphoblastic Leukemia</condition>
  <condition>B-cell Acute Lymphoblastic Leukemia</condition>
  <arm_group>
    <arm_group_label>AUTO3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Paediatric patients with relapse or refractory B-cell ALL</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>AUTO3 (CD19/22 CAR T cells</intervention_name>
    <description>Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with 1 to 5.0 x 10⁶/kg CD19/CD22 Chimeric Antigen Receptor (CAR) positive T cells as a single or split dose.</description>
    <arm_group_label>AUTO3</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          1. Male or female patients aged 1-24 years with high risk (HR) relapsed/refractory&#xD;
             B-lineage ALL, AND:&#xD;
&#xD;
               1. Any bone marrow (BM) relapse or central nervous system (CNS) relapse with&#xD;
                  detectable BM disease after allogeneic stem cell transplant (SCT) and must be ≥6&#xD;
                  months from SCT at the time of AUTO3 infusion; OR,&#xD;
&#xD;
               2. HR first relapse; OR,&#xD;
&#xD;
               3. Standard risk relapse patients with HR cytogenetics; OR,&#xD;
&#xD;
               4. Second or greater relapse; OR,&#xD;
&#xD;
               5. BM minimal residual disease (MRD) ≥10-³ prior to planned SCT; OR,&#xD;
&#xD;
               6. Any on-treatment relapse in patients aged 16-24 years.&#xD;
&#xD;
                  (Phase II Only - Criteria in addition to those described above:)&#xD;
&#xD;
               7. Primary refractory disease; OR,&#xD;
&#xD;
               8. Patients with Philadelphia chromosome positive ALL are eligible if they are&#xD;
                  intolerant to or have failed 2 lines of tyrosine kinase inhibitor (TKI) therapy,&#xD;
                  or if TKI therapy is contraindicated; OR,&#xD;
&#xD;
               9. Isolated CNS relapse but with ≤CNS Grade 2 disease at time of enrolment.&#xD;
&#xD;
          2. Documentation of CD19 and or CD22 expression on leukaemic blasts in the BM, peripheral&#xD;
             blood, or cerebrospinal fluid within 3 months of screening.&#xD;
&#xD;
          3. Detectable disease in the BM at a level ≥10-⁴ (Phase I only).&#xD;
&#xD;
          4. Absolute lymphocyte count ≥0.5 x 10⁹/L.&#xD;
&#xD;
          5. Adequate renal, hepatic, pulmonary, and cardiac function.&#xD;
&#xD;
          6. Karnofsky (age ≥10 years) or Lansky (age &lt;10 years) score ≥50%.&#xD;
&#xD;
          7. Willing and able to give written, informed consent to the current study (patient&#xD;
             and/or parent or legal guardian).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Isolated extra-medullary disease relapse.&#xD;
&#xD;
          2. Active CNS involvement of ALL (CNS Grade 3 per National Comprehensive Cancer Network&#xD;
             guidelines).&#xD;
&#xD;
          3. Active infectious bacterial or viral disease requiring IV anti-microbials for&#xD;
             treatment.&#xD;
&#xD;
          4. Females who are pregnant or lactating.&#xD;
&#xD;
          5. Females of child-bearing potential and post pubertal male participants who are&#xD;
             unwilling to use highly effective methods of contraception for a period of 1 year&#xD;
             after the AUTO3 infusion.&#xD;
&#xD;
          6. Inability to tolerate leukapheresis.&#xD;
&#xD;
          7. Prior CD19 or CD22 targeted therapy with Grade 4 toxicity or ≥refractory Grade 3&#xD;
             cytokine release syndrome (CRS) or ≥Grade 3 drug related CNS toxicity.&#xD;
&#xD;
          8. Pre-existing significant neurological disorder.&#xD;
&#xD;
          9. Stem Cell Transplant patients only: active significant acute graft versus host disease&#xD;
             (GVHD) or moderate/severe chronic GVHD requiring systemic steroids or other&#xD;
             immunosuppressant within 4 weeks of enrolment.&#xD;
&#xD;
         10. The following medications are excluded:&#xD;
&#xD;
               1. Steroids: Therapeutic doses of steroids must be stopped &gt;72 hours prior to AUTO3&#xD;
                  infusion and leukapheresis. However, physiological replacement doses of steroids&#xD;
                  are allowed: &lt;12 mg/m2/day hydrocortisone or equivalent.&#xD;
&#xD;
               2. Allogeneic cellular therapy: Any donor lymphocyte infusions must be completed &gt;6&#xD;
                  weeks prior to AUTO3 infusion.&#xD;
&#xD;
               3. Graft versus host disease therapies: Any drug used for GVHD must be stopped &gt;4&#xD;
                  weeks prior to AUTO3 infusion.&#xD;
&#xD;
               4. Chemotherapy: Should be stopped 1 week prior to leukapheresis and 2 days prior to&#xD;
                  starting pre-conditioning chemotherapy.&#xD;
&#xD;
         11. Known allergy to albumin, dimethyl sulfoxide, cyclophosphamide or fludarabine.&#xD;
&#xD;
        For AUTO3 Infusion: Patients meeting any of the following exclusion criteria will not be&#xD;
        treated with AUTO3 or treatment will be delayed until they no longer meet these criteria:&#xD;
&#xD;
          1. Severe intercurrent infection.&#xD;
&#xD;
          2. Requirement for supplementary oxygen.&#xD;
&#xD;
          3. Allogeneic transplant recipients with active significant acute GVHD overall Grade ≥II&#xD;
             or moderate/severe chronic GVHD requiring systemic steroids.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>24 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Great Ormond Street Hospital for Children NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University College London Hospitals NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Manchester Children's Hospital</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>September 11, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 21, 2017</study_first_posted>
  <results_first_submitted>November 18, 2020</results_first_submitted>
  <results_first_submitted_qc>January 11, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">February 1, 2021</results_first_posted>
  <last_update_submitted>January 11, 2021</last_update_submitted>
  <last_update_submitted_qc>January 11, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Acute Lymphoblastic Leukaemia</keyword>
  <keyword>CD19 Positive</keyword>
  <keyword>CD22 Positive</keyword>
  <keyword>Relapsed Acute Lymphoblastic Leukaemia</keyword>
  <keyword>Refractory Acute Lymphoblastic Leukaemia</keyword>
  <keyword>AUTO3</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 10, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/55/NCT03289455/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 30, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/55/NCT03289455/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>23 patients were screened, 20 patients leukapheresed and 15 patients were pre-conditioned with cyclophosphamide and fludarabine and infused with AUTO3 at 3 different dose levels.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
        <group group_id="P2">
          <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
        <group group_id="P3">
          <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0">Completed = Received AUTO3 infusion and completed 24 months visit</participants>
                <participants group_id="P2" count="0">Completed = Received AUTO3 infusion and completed 24 months visit</participants>
                <participants group_id="P3" count="0">Completed = Received AUTO3 infusion and completed 24 months visit</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor decision due to covid19 restrictions</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>No CART persistence in MRD negativity. Patient proceeded with HSCT</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Progressive disease</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Patients infused with AUTO3</population>
      <group_list>
        <group group_id="B1">
          <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
        <group group_id="B2">
          <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
        <group group_id="B3">
          <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="4"/>
            <count group_id="B2" value="5"/>
            <count group_id="B3" value="6"/>
            <count group_id="B4" value="15"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Karnofsky/Lansky score</title>
          <description>The Karnofsky and Lansky scales are used to determine changes in daily activities for patients aged 10 to 24 years and &lt;10 years, respectively. The Karnofsky scale ranges from 0% (death) to 100% (normal, co complaints, no signs of disease) and the Lansky scale from 0% (unresponsive) to 100% (fully active, normal).</description>
          <units>percentage</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="95" lower_limit="80" upper_limit="100"/>
                    <measurement group_id="B2" value="90" lower_limit="80" upper_limit="100"/>
                    <measurement group_id="B3" value="100" lower_limit="90" upper_limit="100"/>
                    <measurement group_id="B4" value="90" lower_limit="80" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion</title>
        <time_frame>Within 30 days (+/- 3 days) after the last dose of AUTO3.</time_frame>
        <population>Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion</title>
          <population>Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="4"/>
                    <measurement group_id="O3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3</title>
        <description>DLT was defined as i) any new non-hematological adverse event (AE) of Grade 3 or higher toxicity using the NCI CTCAE (version 5.0), which was probably or definitely related to AUTO3 therapy, which occurred within the DLT evaluation period, and which failed to resolve to Grade 2 or better within 14 days, despite appropriate supportive measures; ii) Grade 4 cytokine release syndrome (CRS) or neurotoxicity, cerebral edema, or Grade 3 neurotoxicity (including cerebral edema) that lasted &gt;72 hours; iii) Grade &gt;3 disseminated intravascular coagulation; iv) Grade &gt;2 infusion reaction; v) Any other fatal event (Grade 5) or life-threatening event (Grade 4) that could not be managed with conventional supportive measures or which in the opinion of the Safety Evaluation Committee (SEC) necessitated dose reduction or other modification to trial treatment to avoid a similar hazard in future patients.</description>
        <time_frame>Within 30 days (+/- 3 days) after the last dose of AUTO3.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3</title>
          <description>DLT was defined as i) any new non-hematological adverse event (AE) of Grade 3 or higher toxicity using the NCI CTCAE (version 5.0), which was probably or definitely related to AUTO3 therapy, which occurred within the DLT evaluation period, and which failed to resolve to Grade 2 or better within 14 days, despite appropriate supportive measures; ii) Grade 4 cytokine release syndrome (CRS) or neurotoxicity, cerebral edema, or Grade 3 neurotoxicity (including cerebral edema) that lasted &gt;72 hours; iii) Grade &gt;3 disseminated intravascular coagulation; iv) Grade &gt;2 infusion reaction; v) Any other fatal event (Grade 5) or life-threatening event (Grade 4) that could not be managed with conventional supportive measures or which in the opinion of the Safety Evaluation Committee (SEC) necessitated dose reduction or other modification to trial treatment to avoid a similar hazard in future patients.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Patients Achieving Morphological Remission (Complete Response(CR) or Complete Response With Incomplete Count Recovery (CRi) and Minimal Residual Disease (MRD)-Negative Response in the Bone Marrow (PCR)).</title>
        <description>Morphological response evaluations were based on the response criteria for ALL according to the NCCN guidelines version 2.2014. Minimal residual disease-negative status was achieved if MRD was &lt;10^-4 (0.01%) by PCR amplification of individual rearrangements of Ig genes and/or flow cytometry MRD testing.</description>
        <time_frame>Within 30 days (+/- 3 days) post AUTO3 infusion</time_frame>
        <population>Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set).</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Achieving Morphological Remission (Complete Response(CR) or Complete Response With Incomplete Count Recovery (CRi) and Minimal Residual Disease (MRD)-Negative Response in the Bone Marrow (PCR)).</title>
          <description>Morphological response evaluations were based on the response criteria for ALL according to the NCCN guidelines version 2.2014. Minimal residual disease-negative status was achieved if MRD was &lt;10^-4 (0.01%) by PCR amplification of individual rearrangements of Ig genes and/or flow cytometry MRD testing.</description>
          <population>Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis</title>
        <description>Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients screened).</description>
        <time_frame>Up to 8 weeks post leukapheresis</time_frame>
        <population>Patients who underwent leukapheresis. This outcome is measured before patients received infusion with AUTO3. Therefore, no split by dose cohort can be provided.</population>
        <group_list>
          <group group_id="O1">
            <title>AUTO3</title>
            <description>Pediatric and young adult patients with relapsed or refractory B cell ALL</description>
          </group>
        </group_list>
        <measure>
          <title>Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis</title>
          <description>Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients screened).</description>
          <population>Patients who underwent leukapheresis. This outcome is measured before patients received infusion with AUTO3. Therefore, no split by dose cohort can be provided.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Event-Free Survival (EFS) by Morphological Analysis</title>
        <description>Time from date of first AUTO3 infusion until the earliest of treatment failure (defined as not achieving CR/CRi post AUTO3 infusion / no response), morphological relapse, or death due to any cause, whichever occurred first.</description>
        <time_frame>Up to 2 years</time_frame>
        <population>Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Event-Free Survival (EFS) by Morphological Analysis</title>
          <description>Time from date of first AUTO3 infusion until the earliest of treatment failure (defined as not achieving CR/CRi post AUTO3 infusion / no response), morphological relapse, or death due to any cause, whichever occurred first.</description>
          <population>Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.48" lower_limit="0.03" upper_limit="NA">Upper limit of the confidence interval was not reached</measurement>
                    <measurement group_id="O2" value="12.42" lower_limit="3.94" upper_limit="NA">Upper limit of the confidence interval was not reached</measurement>
                    <measurement group_id="O3" value="2.79" lower_limit="0.03" upper_limit="NA">Upper limit of the confidence interval was not reached</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With CD19- and/or CD22-negative Relapse</title>
        <time_frame>Up to 2 years</time_frame>
        <population>Patients who received at least 1 (complete or partial dose) of AUTO3 and had morphological relapses</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With CD19- and/or CD22-negative Relapse</title>
          <population>Patients who received at least 1 (complete or partial dose) of AUTO3 and had morphological relapses</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Relapse-Free Survival (RFS) by Morphological Analysis</title>
        <description>Time from first achievement of morphological CR/CRi post AUTO3 treatment until the earliest of morphological relapse, or death due to any cause, whichever occurred first.</description>
        <time_frame>Up to 2 years</time_frame>
        <population>Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Relapse-Free Survival (RFS) by Morphological Analysis</title>
          <description>Time from first achievement of morphological CR/CRi post AUTO3 treatment until the earliest of morphological relapse, or death due to any cause, whichever occurred first.</description>
          <population>Patients who received at least 1 (complete or partial) dose of AUTO3 (infused set)</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.09" lower_limit="2.56" upper_limit="NA">Upper limit of the confidence interval was not reached</measurement>
                    <measurement group_id="O2" value="11.50" lower_limit="3.02" upper_limit="NA">Upper limit of the confidence interval was not reached</measurement>
                    <measurement group_id="O3" value="3.98" lower_limit="1.87" upper_limit="NA">Upper limit of the confidence interval was not reached</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>Calculated from the date of AUTO3 treatment to the date of death anytime post AUTO3 infusion. Patients who had not died were censored at the date of last contact.</description>
        <time_frame>Up to 2 years after the last patient was infused</time_frame>
        <population>Patients who received at least 1 (complete or partial) dose of AUTO3</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>Calculated from the date of AUTO3 treatment to the date of death anytime post AUTO3 infusion. Patients who had not died were censored at the date of last contact.</description>
          <population>Patients who received at least 1 (complete or partial) dose of AUTO3</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.17" lower_limit="2.30" upper_limit="NA">The upper limit of the confidence interval was not reached</measurement>
                    <measurement group_id="O2" value="25.20" lower_limit="4.34" upper_limit="NA">The upper limit of the confidence interval was not reached</measurement>
                    <measurement group_id="O3" value="NA" lower_limit="4.07" upper_limit="NA">The median was not estimable. The upper limit of the confidence interval was not reached</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Expansion of AUTO3 Following Adoptive Transfer</title>
        <description>Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion</description>
        <time_frame>Up to 2 years</time_frame>
        <population>Patients who received at least 1 (complete or partial) dose of AUTO3 and had evaluable cellular kinetics data (who had at least 1 cellular kinetics concentration post AUTO3 infusion above the lower limit of quantitation) (cellular kinetics analysis set)</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Expansion of AUTO3 Following Adoptive Transfer</title>
          <description>Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion</description>
          <population>Patients who received at least 1 (complete or partial) dose of AUTO3 and had evaluable cellular kinetics data (who had at least 1 cellular kinetics concentration post AUTO3 infusion above the lower limit of quantitation) (cellular kinetics analysis set)</population>
          <units>vector copies/ug DNA</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10240" lower_limit="5690" upper_limit="37000"/>
                    <measurement group_id="O2" value="102000" lower_limit="34800" upper_limit="127000"/>
                    <measurement group_id="O3" value="79800" lower_limit="13200" upper_limit="104000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Persistence of AUTO3 Following Adoptive Transfer</title>
        <description>Persistence of AUTO3 was measured by quantitative polymerase chain reaction (qPCR) and/or flow cytometry at a range of time points in the peripheral blood and the bone marrow.&#xD;
Persistence was defined as the timepoint in days of last detectable CAR T cell by qPCR or last assessment if zero copies per μg DNA (whichever occurred later) before morphological relapse (Tlast).</description>
        <time_frame>Up to 2 years</time_frame>
        <population>Patients who received at least 1 (complete or partial) dose of AUTO3 and had evaluable cellular kinetics data (who had at least 1 cellular kinetics concentration post AUTO3 infusion above the lower limit of quantitation) (cellular kinetics analysis set)</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Persistence of AUTO3 Following Adoptive Transfer</title>
          <description>Persistence of AUTO3 was measured by quantitative polymerase chain reaction (qPCR) and/or flow cytometry at a range of time points in the peripheral blood and the bone marrow.&#xD;
Persistence was defined as the timepoint in days of last detectable CAR T cell by qPCR or last assessment if zero copies per μg DNA (whichever occurred later) before morphological relapse (Tlast).</description>
          <population>Patients who received at least 1 (complete or partial) dose of AUTO3 and had evaluable cellular kinetics data (who had at least 1 cellular kinetics concentration post AUTO3 infusion above the lower limit of quantitation) (cellular kinetics analysis set)</population>
          <units>days</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.7" lower_limit="19.8" upper_limit="256.8"/>
                    <measurement group_id="O2" value="343.7" lower_limit="62.7" upper_limit="538.9"/>
                    <measurement group_id="O3" value="24.3" lower_limit="18.8" upper_limit="570.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of B Cell Aplasia</title>
        <description>Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood</description>
        <time_frame>Up to 2 years</time_frame>
        <population>Patients who received at least 1 (complete or partial) dose of the pre-conditioning regimen (safety set)</population>
        <group_list>
          <group group_id="O1">
            <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O2">
            <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
          <group group_id="O3">
            <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
            <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of B Cell Aplasia</title>
          <description>Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood</description>
          <population>Patients who received at least 1 (complete or partial) dose of the pre-conditioning regimen (safety set)</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">B cell aplasia from the database was inconclusive because the total lymphocytes from the peripheral blood analyzed by flow cytometry were not collected systematically</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">B cell aplasia from the database was inconclusive because the total lymphocytes from the peripheral blood analyzed by flow cytometry were not collected systematically</measurement>
                    <measurement group_id="O3" value="NA" lower_limit="NA" upper_limit="NA">B cell aplasia from the database was inconclusive because the total lymphocytes from the peripheral blood analyzed by flow cytometry were not collected systematically</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From AUTO3 infusion (Day 0) until the end of study (2 years after last patient dosed) or withdrawal, whichever occurred first</time_frame>
      <group_list>
        <group group_id="E1">
          <title>1x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>Patients assigned in this Cohort received actual doses of 0.3 to 2x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
        <group group_id="E2">
          <title>3x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>All patients assigned in this Cohort received actual doses of 3x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
        <group group_id="E3">
          <title>5x10^6 CD19/CD22 CAR-positive T Cells/kg</title>
          <description>Patients assigned in this Cohort received actual doses of 4.3 to 5x10^6 CD19/CD22 CAR-positive T cells</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (23.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (23.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Anal haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Haematochezia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lip dry</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="9" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E3" events="16" subjects_affected="5" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Catheter bacteraemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Device related infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Enterococcal infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Folliculitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gingival abscess</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Infectious pleural effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Parvovirus infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Staphylococcal infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Limb injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Procedural pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Soft tissue injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Human herpes virus 6 serology positive</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="24" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="6" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Staphylococcus test positive</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gout</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypophosphataemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Aphasia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Hallucination</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Dysuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Painful respiration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rash erythematous</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rash papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Early completion of the study leading to small numbers of patients analyzed from the Phase I part of the study.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Clinical Project Manager</name_or_title>
      <organization>Autolus Ltd</organization>
      <phone>+44 1483 920748</phone>
      <email>clinicaltrials@autolus.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03289455
org study id: AUTO3-PA1
secondary id: 2016-004680-39
nct id: NCT03289455
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to test the safety and efficacy of AUTO3, a CAR T cell treatment
      targeting CD19 and CD22 in paediatric or young adult patients with relapsed or refractory B
      cell acute lymphoblastic leukaemia.
The study will consist of 2 phases, a Phase I or dose escalation phase and a Phase II or
      expansion phase. Paediatric or young adult patients with relapsed or refractory B cell ALL
      will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis in
      order to harvest T cells, which is the starting material for the manufacture of the
      autologous CAR T product AUTO3 which is a CD19 and CD22 dual targeting CAR T cell product.
      Following pre-conditioning by a chemotherapeutic regimen, the patient will receive AUTO3
      intravenously as a single or split dose and will then enter a 24-month follow-up period.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Patients With Grade 3-5 Toxicities Occurring Within the Dose Limiting Toxicity (DLT) Period of AUTO3 Infusion
time frame: Within 30 days (+/- 3 days) after the last dose of AUTO3.
measure: Number of Patients With Dose Limiting Toxicity (DLT) of AUTO3
time frame: Within 30 days (+/- 3 days) after the last dose of AUTO3.
description: DLT was defined as i) any new non-hematological adverse event (AE) of Grade 3 or higher toxicity using the NCI CTCAE (version 5.0), which was probably or definitely related to AUTO3 therapy, which occurred within the DLT evaluation period, and which failed to resolve to Grade 2 or better within 14 days, despite appropriate supportive measures; ii) Grade 4 cytokine release syndrome (CRS) or neurotoxicity, cerebral edema, or Grade 3 neurotoxicity (including cerebral edema) that lasted >72 hours; iii) Grade >3 disseminated intravascular coagulation; iv) Grade >2 infusion reaction; v) Any other fatal event (Grade 5) or life-threatening event (Grade 4) that could not be managed with conventional supportive measures or which in the opinion of the Safety Evaluation Committee (SEC) necessitated dose reduction or other modification to trial treatment to avoid a similar hazard in future patients.
measure: Number of Patients Achieving Morphological Remission (Complete Response(CR) or Complete Response With Incomplete Count Recovery (CRi) and Minimal Residual Disease (MRD)-Negative Response in the Bone Marrow (PCR)).
time frame: Within 30 days (+/- 3 days) post AUTO3 infusion
description: Morphological response evaluations were based on the response criteria for ALL according to the NCCN guidelines version 2.2014. Minimal residual disease-negative status was achieved if MRD was <10^-4 (0.01%) by PCR amplification of individual rearrangements of Ig genes and/or flow cytometry MRD testing.
measure: Feasibility of Generating AUTO3: Number of Patients' Cells Successfully Manufactured as a Proportion of the Number of Patients Undergoing Leukapheresis
time frame: Up to 8 weeks post leukapheresis
description: Feasibility of product generation was examined by assessing the number of AUTO3 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients screened).
measure: Event-Free Survival (EFS) by Morphological Analysis
time frame: Up to 2 years
description: Time from date of first AUTO3 infusion until the earliest of treatment failure (defined as not achieving CR/CRi post AUTO3 infusion / no response), morphological relapse, or death due to any cause, whichever occurred first.
measure: Number of Patients With CD19- and/or CD22-negative Relapse
time frame: Up to 2 years
measure: Relapse-Free Survival (RFS) by Morphological Analysis
time frame: Up to 2 years
description: Time from first achievement of morphological CR/CRi post AUTO3 treatment until the earliest of morphological relapse, or death due to any cause, whichever occurred first.
measure: Overall Survival (OS)
time frame: Up to 2 years after the last patient was infused
description: Calculated from the date of AUTO3 treatment to the date of death anytime post AUTO3 infusion. Patients who had not died were censored at the date of last contact.
measure: Expansion of AUTO3 Following Adoptive Transfer
time frame: Up to 2 years
description: Expansion of AUTO3 was measured as the median peak (Cmax) of transgene levels in the peripheral blood after AUTO3 infusion
measure: Persistence of AUTO3 Following Adoptive Transfer
time frame: Up to 2 years
description: Persistence of AUTO3 was measured by quantitative polymerase chain reaction (qPCR) and/or flow cytometry at a range of time points in the peripheral blood and the bone marrow.
Persistence was defined as the timepoint in days of last detectable CAR T cell by qPCR or last assessment if zero copies per μg DNA (whichever occurred later) before morphological relapse (Tlast).
measure: Duration of B Cell Aplasia
time frame: Up to 2 years
description: Depletion of circulating B cells assessed by flow cytometry at a range of time points in the peripheral blood
arm group label: AUTO3
arm group type: Experimental
description: Paediatric patients with relapse or refractory B-cell ALL
intervention type: Biological
intervention name: AUTO3 (CD19/22 CAR T cells
description: Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with 1 to 5.0 x 10⁶/kg CD19/CD22 Chimeric Antigen Receptor (CAR) positive T cells as a single or split dose.
arm group label: AUTO3
criteria: 
gender: All
minimum age: 1 Year
maximum age: 24 Years
healthy volunteers: No
facility: 
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Precursor Cell Lymphoblastic Leukemia-Lymphoma
mesh term: Leukemia, Lymphoid
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Early completion of the study leading to small numbers of patients analyzed from the Phase I part of the study.
point of contact: 