<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/NCT03287817</url>
  </required_header>
  <id_info>
    <org_study_id>AUTO3-DB1</org_study_id>
    <secondary_id>2016-004682-11</secondary_id>
    <nct_id>NCT03287817</nct_id>
  </id_info>
  <brief_title>CD19/22 CAR T Cells (AUTO3) for the Treatment of Diffuse Large B Cell Lymphoma</brief_title>
  <acronym>ALEXANDER</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 With Anti PD1 Antibody in Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma</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>Yes</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 followed by limited duration of anti-PD1 antibody in patients with&#xD;
      DLBCL&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will consist of 2 phases, a Phase I or dose escalation and expansion phase, and a&#xD;
      Phase II. Patients with relapsed or refractory DLBCL will be enrolled in both phases of the&#xD;
      study. Eligible patients will undergo leukapheresis in order to harvest T cells, which is the&#xD;
      starting material for the manufacture of the autologous CAR T product AUTO3 which is a CD19&#xD;
      and CD22 dual targeting CAR T cell product. Following pre-conditioning by a chemotherapeutic&#xD;
      regimen, the patient will receive AUTO 3 intravenously as a single dose and in addition a&#xD;
      limited duration of treatment with an anti-PD1 antibody (either as part of the&#xD;
      pre-conditioning regimen or consolidation). Patients will then enter a 36-month follow-up&#xD;
      period.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 5, 2017</start_date>
  <completion_date type="Anticipated">November 2024</completion_date>
  <primary_completion_date type="Anticipated">November 2024</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>
    <intervention_model_description>A dose escalation and expansion phase (Phase I) followed by Phase II</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Phase I Escalation - Safety (incidence of Grade 3-5 toxicities) and identification of recommended Phase II dose and schedule.</measure>
    <time_frame>Within 75 days of AUTO3 infusion</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase I Expansion - Safety (incidence of Grade 3-5 toxicities) in the outpatient / ambulatory care setting</measure>
    <time_frame>Within 75 days of AUTO3 infusion</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II - Overall response rate as per Lugano criteria</measure>
    <time_frame>Up to 2 years</time_frame>
  </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>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete response rate, as per Lugano criteria.</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR).</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS).</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS).</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">73</enrollment>
  <condition>Diffuse Large B Cell Lymphoma</condition>
  <condition>Relapsed Diffuse Large B-Cell Lymphoma</condition>
  <condition>Refractory Diffuse Large B-Cell Lymphoma</condition>
  <condition>DLBCL</condition>
  <arm_group>
    <arm_group_label>AUTO3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient with relapsed or refractory DLBCL</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>AUTO3</intervention_name>
    <description>Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with doses from 50 x 10⁶ to 900 x 10⁶ CD19/ CD22 Chimeric Antigen Receptor (CAR) positive T cells followed by limited duration of anti-PD1 antibody (pembrolizumab).</description>
    <arm_group_label>AUTO3</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female, aged ≥18 years.&#xD;
&#xD;
          2. Willing and able to give written, informed consent.&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.&#xD;
&#xD;
          4. Histologically confirmed DLBCL and large B cell lymphoma (at last relapse) subsets,&#xD;
             including:&#xD;
&#xD;
             Phase I and Phase II Cohort 1:&#xD;
&#xD;
               1. DLBCL, not otherwise specified (NOS), per World Health Organisation&#xD;
                  classification and DLBCL with MYC and BCL2 and/or BCL6 rearrangements&#xD;
                  (double/triple hit).&#xD;
&#xD;
               2. Transformed DLBCL from FL.&#xD;
&#xD;
               3. High-grade B cell lymphoma with MYC expression (excluding Burkitt's lymphoma)&#xD;
&#xD;
                  Phase I and Phase II Cohort 2:&#xD;
&#xD;
               4. Transformed DLBCL from other indolent lymphomas (excluding Richter's&#xD;
                  transformation).&#xD;
&#xD;
               5. Primary mediastinal large B cell lymphoma.&#xD;
&#xD;
          5. Chemotherapy-refractory disease, defined as one or more of the following:&#xD;
&#xD;
               1. Stable disease (≤12 months) or progressive disease as best response to most&#xD;
                  recent chemotherapy containing regimen. Refractory disease after frontline&#xD;
                  chemo-immunotherapy is allowed.&#xD;
&#xD;
               2. Disease progression or recurrence in ≤12 months of prior autologous&#xD;
                  haematopoietic stem cells transplantation (ASCT).&#xD;
&#xD;
             OR&#xD;
&#xD;
          6. Relapse after ≥two lines of therapy or after ASCT. At a minimum:&#xD;
&#xD;
               1. Patients must have received rituximab or another anti-CD20 monoclonal antibody&#xD;
                  (unless Investigator determines that tumour is CD20-negative) and an&#xD;
                  anthracycline-containing chemotherapy regimen.&#xD;
&#xD;
               2. Patients must have either failed ASCT, or be ineligible for or not consenting to&#xD;
                  ASCT.&#xD;
&#xD;
               3. Patients with transformed DLBCL must have received at least one line of therapy&#xD;
                  after transformation to DLBCL.&#xD;
&#xD;
          7. PET-positive disease per Lugano classification.&#xD;
&#xD;
          8. For females of childbearing potential, a negative serum or urine pregnancy test must&#xD;
             be documented at screening, prior to pre-conditioning and confirmed before receiving&#xD;
             the first dose of study treatment.&#xD;
&#xD;
             For females who are not postmenopausal or surgically sterile, highly effective methods&#xD;
             of contraception must be used during the treatment period and for at least 12 months&#xD;
             after the last dose of study treatment.&#xD;
&#xD;
          9. For males, it must be agreed that that two acceptable methods of contraception are&#xD;
             used.&#xD;
&#xD;
         10. Adequate renal, hepatic, pulmonary, and cardiac function defined as:&#xD;
&#xD;
               1. Creatinine clearance ≥40 cc/min.&#xD;
&#xD;
               2. Serum alanine aminotransferase / aspartate aminotransferase ≤2.5 x ULN.&#xD;
&#xD;
               3. Total bilirubin ≤1.5 x ULN, except in subjects with Gilbert's syndrome.&#xD;
&#xD;
               4. LVEF ≥50% (by ECHO or MUGA) unless the institutional lower limit of normal is&#xD;
                  lower.&#xD;
&#xD;
               5. Baseline oxygen saturation &gt;92% on room air and ≤Grade 1 dyspnoea.&#xD;
&#xD;
         11. Patient has adequate BM function without requiring ongoing blood product or&#xD;
             granulocyte-colony stimulating factor support and meets the following criteria:&#xD;
&#xD;
               1. Absolute neutrophil count ≥1.0 × 109/L.&#xD;
&#xD;
               2. Absolute lymphocyte count ≥0.3 × 109/L (at enrolment and prior to leukapheresis).&#xD;
&#xD;
               3. Haemoglobin ≥80 g/L.&#xD;
&#xD;
               4. Platelets ≥75 × 109/L&#xD;
&#xD;
         12. No contra-indications for leukapheresis.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior allogeneic haematopoietic stem cell transplant.&#xD;
&#xD;
          2. Females who are pregnant or lactating.&#xD;
&#xD;
          3. History or presence of clinically relevant CNS pathology such as epilepsy, paresis,&#xD;
             aphasia, stroke within prior 3 months, severe brain injuries, dementia, Parkinson's&#xD;
             disease, cerebellar disease, organic brain syndrome, uncontrolled mental illness, or&#xD;
             psychosis.&#xD;
&#xD;
          4. Patients with active CNS involvement by malignancy. Patients with history of CNS&#xD;
             involvement with malignancy may be eligible if CNS disease has been effectively&#xD;
             treated and provided treatment was at least 4 weeks prior to enrolment (at least 8&#xD;
             weeks prior to AUTO3 infusion).&#xD;
&#xD;
          5. Clinically significant, uncontrolled heart disease or a recent (within 12 months)&#xD;
             cardiac event.&#xD;
&#xD;
               1. Uncontrolled cardiac arrhythmia (patients with rate-controlled atrial&#xD;
                  fibrillation are not excluded).&#xD;
&#xD;
               2. Evidence of pericardial effusion&#xD;
&#xD;
          6. Patients with a history (within 3 months) or evidence of deep vein thrombosis or&#xD;
             pulmonary embolism requiring ongoing therapeutic anticoagulation at the time of&#xD;
             pre-conditioning.&#xD;
&#xD;
          7. Patients with active gastrointestinal bleeding.&#xD;
&#xD;
          8. Patients with any major surgical intervention in the last 3 months.&#xD;
&#xD;
          9. Active bacterial, viral or fungal infection requiring systemic treatment. Active or&#xD;
             latent hepatitis B infection or hepatitis C infection. Testing positive for human&#xD;
             immunodeficiency virus, human T cell lymphotropic virus (HTLV1 and 2) or syphilis.&#xD;
&#xD;
         10. History of autoimmune disease resulting in end organ injury or requiring systemic&#xD;
             immunosuppression/systemic disease modifying agents within the last 24 months.&#xD;
&#xD;
         11. Patients with a known history or prior diagnosis of optic neuritis or other&#xD;
             immunologic or inflammatory disease affecting the CNS.&#xD;
&#xD;
         12. Evidence of active pneumonitis on chest computed tomography (CT) scan at screening or&#xD;
             history of drug-induced pneumonitis, idiopathic pulmonary fibrosis, organising&#xD;
             pneumonia, or idiopathic pneumonitis.&#xD;
&#xD;
         13. History of other malignant neoplasms unless disease free for at least 24 months&#xD;
             (carcinoma in situ, non-melanoma skin cancer, breast or prostate cancer on hormonal&#xD;
             therapy allowed).&#xD;
&#xD;
         14. Prior treatment with PD1, PD-L1, or cytotoxic T lymphocyte-associated&#xD;
             protein-4-targeted therapy, or tumour necrosis factor (TNF) receptor superfamily&#xD;
             agonists within 6 weeks prior to AUTO3 infusion.&#xD;
&#xD;
         15. Prior treatment with investigational or approved gene therapy or cell therapy products&#xD;
             until a dose level has treated at least three patients and has been declared safe.&#xD;
&#xD;
         16. Prior CD19 or CD22 targeted therapy.&#xD;
&#xD;
         17. The following medications are excluded:&#xD;
&#xD;
               1. Steroids: Therapeutic doses of corticosteroids within 7 days of leukapheresis or&#xD;
                  72 hours prior to AUTO3 administration. However, physiological replacement,&#xD;
                  topical, and inhaled steroids are permitted.&#xD;
&#xD;
               2. Immunosuppression: Immunosuppressive medication must be stopped ≥2 weeks prior to&#xD;
                  leukapheresis or AUTO3 infusion.&#xD;
&#xD;
               3. Cytotoxic chemotherapies within 2 weeks of AUTO3 infusion and 1 week prior to&#xD;
                  leukapheresis (2 weeks for lymphodepleting chemotherapy).&#xD;
&#xD;
               4. Antibody therapy use including anti-CD20 therapy within 2 weeks prior to AUTO3&#xD;
                  infusion, or 5 half-lives of the respective antibody, whichever is shorter.&#xD;
&#xD;
               5. Granulocyte-colony stimulating factor less than 10 days prior to leukapheresis.&#xD;
&#xD;
               6. Live vaccine ≤4 weeks prior to enrolment.&#xD;
&#xD;
               7. Prophylactic intrathecal therapy: Methotrexate within 4 weeks and other&#xD;
                  intrathecal chemotherapy (e.g. Ara-C) within 2 weeks prior to starting&#xD;
                  pre-conditioning chemotherapy.&#xD;
&#xD;
         18. Prior limited radiation therapy within 4 weeks of AUTO3 infusion or within 24 weeks&#xD;
             for definitive radiation to chest.&#xD;
&#xD;
         19. Research participants receiving any other investigational agents, or concurrent&#xD;
             biological, chemotherapy, or radiation therapy.&#xD;
&#xD;
         20. Known allergy to albumin, dimethyl sulphoxide (DMSO), cyclophosphamide or fludarabine,&#xD;
             pembrolizumab or tocilizumab.&#xD;
&#xD;
         21. Any contraindications to receive anti-PD1 antibody pembrolizumab will be excluded from&#xD;
             cohorts requiring administration of pembrolizumab.&#xD;
&#xD;
         22. Patients, who in the opinion of the Investigator, may not be able to understand or&#xD;
             comply with the safety monitoring requirements of the study.&#xD;
&#xD;
         23. Any other condition that in the Investigator's opinion would make the patient&#xD;
             unsuitable for the clinical trial.&#xD;
&#xD;
             Phase I outpatient cohort:&#xD;
&#xD;
         24. Subjects who do not have caregiver support (in line with institutional outpatient&#xD;
             transplant guidelines) for outpatient/ambulatory care setting.&#xD;
&#xD;
         25. Subjects who are staying greater than 60 minutes (or whatever is permissible per&#xD;
             institutional outpatient transplant guidelines) from the clinical trial site at the&#xD;
             time of treatment.&#xD;
&#xD;
        For AUTO3 Infusion: Patients meeting any of the following exclusion criteria must not be&#xD;
        treated with AUTO3 or have treatment delayed until they no longer meet these criteria:&#xD;
&#xD;
          1. Severe intercurrent infection.&#xD;
&#xD;
          2. Requirement for supplementary oxygen or active pulmonary infiltrates.&#xD;
&#xD;
          3. Clinical deterioration of organ function (renal and hepatic) exceeding the criteria&#xD;
             set at study entry.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>City of Hope Hospital</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Colorado Blood Cancer Institute at Presbyterian/St. Luke's Medical Center/Sarah Cannon Research Institute</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80218</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sylvester Comprehensive Cancer Center / University of Miami</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siteman Cancer Center / Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>TriStar Centennial Medical Center /Sarah Cannon Research Institute</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St David's South Austin Medical Center /Sarah Cannon Research Institute</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78704</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Beatson West of Scotland Cancer Centre / Queen Elizabeth University Hospital</name>
      <address>
        <city>Glasgow</city>
        <zip>G12 0YN</zip>
        <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>Manchester University NHS Foundation Trust</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust</name>
      <address>
        <city>Newcastle upon Tyne</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Netherlands</country>
  </removed_countries>
  <verification_date>October 2022</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 19, 2017</study_first_posted>
  <last_update_submitted>October 19, 2022</last_update_submitted>
  <last_update_submitted_qc>October 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diffuse Large B Cell Lymphoma</keyword>
  <keyword>Relapsed Diffuse Large B Cell Lymphoma</keyword>
  <keyword>Refractory Diffuse Large B Cell Lymphoma</keyword>
  <keyword>AUTO3</keyword>
  <keyword>PD-1</keyword>
  <keyword>Anti PD-1 antibody</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Lymphoma, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Large B-Cell, Diffuse</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03287817
org study id: AUTO3-DB1
secondary id: 2016-004682-11
nct id: NCT03287817
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
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 followed by limited duration of anti-PD1 antibody in patients with
      DLBCL
The study will consist of 2 phases, a Phase I or dose escalation and expansion phase, and a
      Phase II. Patients with relapsed or refractory DLBCL 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 AUTO 3 intravenously as a single dose and in addition a
      limited duration of treatment with an anti-PD1 antibody (either as part of the
      pre-conditioning regimen or consolidation). Patients will then enter a 36-month follow-up
      period.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: A dose escalation and expansion phase (Phase I) followed by Phase II
primary purpose: Treatment
masking: None (Open Label)
measure: Phase I Escalation - Safety (incidence of Grade 3-5 toxicities) and identification of recommended Phase II dose and schedule.
time frame: Within 75 days of AUTO3 infusion
measure: Phase I Expansion - Safety (incidence of Grade 3-5 toxicities) in the outpatient / ambulatory care setting
time frame: Within 75 days of AUTO3 infusion
measure: Phase II - Overall response rate as per Lugano criteria
time frame: Up to 2 years
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.
measure: Complete response rate, as per Lugano criteria.
time frame: Up to 2 years
measure: Duration of response (DOR).
time frame: Up to 2 years
measure: Progression-free survival (PFS).
time frame: Up to 2 years
measure: Overall survival (OS).
time frame: Up to 2 years
arm group label: AUTO3
arm group type: Experimental
description: Patient with relapsed or refractory DLBCL
intervention type: Biological
intervention name: AUTO3
description: Following preconditioning with chemotherapy (cyclophosphamide and fludarabine) patients will be treated with doses from 50 x 10⁶ to 900 x 10⁶ CD19/ CD22 Chimeric Antigen Receptor (CAR) positive T cells followed by limited duration of anti-PD1 antibody (pembrolizumab).
arm group label: AUTO3
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United Kingdom
country: United States
country: Netherlands
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, B-Cell
mesh term: Lymphoma, Large B-Cell, Diffuse