<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/NCT04443829</url>
  </required_header>
  <id_info>
    <org_study_id>UCL/126892</org_study_id>
    <nct_id>NCT04443829</nct_id>
  </id_info>
  <brief_title>Immunotherapy Using CAR T-cells to Target CD19 for Relapsed/Refractory CD19+ Primary CNS Lymphoma</brief_title>
  <acronym>CAROUSEL</acronym>
  <official_title>Immunotherapy Using CAR T-cells to Target CD19 for Relapsed/Refractory CD19+ Primary Central Nervous System (CNS) Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University College, London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University College, London</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 CAROUSEL Trial is a single-centre, non-randomised, open label Phase I clinical trial of&#xD;
      an Advanced Therapy Investigational Medicinal Product (ATIMP) in adults (age ≥16) with&#xD;
      relapsed/refractory Primary CNS Lymphoma.&#xD;
&#xD;
      The study will evaluate the feasibility of generating the ATIMP, the safety of administering&#xD;
      CD19CAR T-cell therapy and how effectively CD19CAR T-cells engraft, expand and persist&#xD;
      following administration in patients with relapsed/refractory primary CNS lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The CAROUSEL Trial is a single-centre, non-randomised, open label Phase I clinical trial of&#xD;
      an Advanced Therapy Investigational Medicinal Product (ATIMP) in adults (age ≥16) with&#xD;
      relapsed/refractory Primary CNS Lymphoma. The ATIMP for this study is cryopreserved&#xD;
      autologous patient-derived T-cells transduced with CD19CAR vector to generate CD19CAR&#xD;
      T-cells.&#xD;
&#xD;
      Patients will undergo an unstimulated leucapheresis for the generation of the ATIMP which&#xD;
      will take approximately 15 days to generate. During this period, patients may receive&#xD;
      &quot;holding&quot; chemotherapy as per institutional practice to maintain disease control. Patients&#xD;
      will receive pre-conditioning lymphodepleting (LD) chemotherapy with cyclophosphamide 60mg/kg&#xD;
      on Day -6, fludarabine 30mg/m2 administered over 3 days (Day -5 to Day -3) and pembrolizumab&#xD;
      200mg on Day -1.&#xD;
&#xD;
      All patients will be treated on Theme 1 of the study with 250 x 10^6 CD19 CAR T-cells i.v.&#xD;
      following LD chemotherapy as described above. Patients with response of Stable Disease (SD)&#xD;
      or Progressive Disease (PD) at Day 28 (or frank relapse beyond Day 28) and in the absence of&#xD;
      severe toxicity related to the ATIMP, will be potentially eligible for Theme 2 of the study&#xD;
      where they can receive Dose 2, a single dose of 25 x 10^6 CD19CAR T-cells intraventricularly&#xD;
      via an Ommaya reservoir following LD chemotherapy as described above.&#xD;
&#xD;
      The study will evaluate the feasibility of generating the ATIMP, the safety of administering&#xD;
      CD19CAR T-cell therapy and how effectively CD19CAR T-cells engraft, expand and persist&#xD;
      following administration in patients with relapsed/refractory primary CNS lymphoma.&#xD;
&#xD;
      Following infusion of CD19CAR T-cell therapy patients will be monitored for between 2-4 weeks&#xD;
      as an inpatient. Following discharge, patients will enter the interventional follow up phase&#xD;
      and be followed up for 2 years. Patients will be seen monthly for the first 6 months, then 6&#xD;
      weekly to 12 months and then 3 monthly until 2 years post CD19CAR T-cell infusion.&#xD;
&#xD;
      If patients relapse within the first 2 years post CD19CAR T-cell infusion they will come off&#xD;
      the interventional follow up and will be followed up annually until the end of trial is&#xD;
      declared.&#xD;
&#xD;
      After completing the interventional phase of the study all patients, irrespective of whether&#xD;
      they progressed or responded to treatment, will enter long term follow up until the end of&#xD;
      trial is declared.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 23, 2021</start_date>
  <completion_date type="Anticipated">December 2032</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Toxicity evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP</measure>
    <time_frame>28 days</time_frame>
    <description>Toxicity following CD19CAR T-cell administration as evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Feasibility of manufacturing CD19CAR T-cells evaluated by the number of therapeutic products generated</measure>
    <time_frame>28 days</time_frame>
    <description>Feasibility of adequate leucapheresis collection and generation of CD19CAR T-cells as evaluated by the number of therapeutic products generated.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response at 1 and 3 months</measure>
    <time_frame>From CD19CAR T-cells infusion to 1 and 3 months</time_frame>
    <description>Proportion of patients achieving a Complete Response (CR) or Partial Response (PR) at 1 and 3 months post CD19CAR T-cells infusion: Theme 1 (i.v.) and Theme 2 (intraventricular)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of circulating CD19CAR T-cells in peripheral blood</measure>
    <time_frame>From CD19CAR T-cells infusion up to 2 years post CD19CAR T-cells infusion</time_frame>
    <description>Frequency of circulating CD19CAR T-cells in peripheral blood as assessed by flow cytometry and qPCR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of B-cell aplasia</measure>
    <time_frame>From CD19CAR T-cells infusion up to 2 years post CD19CAR T-cells infusion</time_frame>
    <description>Incidence of B-cell aplasia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse rate at 1 and 2 years</measure>
    <time_frame>At 1 year and 2 years after CD19CAR T-cells infusion</time_frame>
    <description>Proportion of patients who have relapsed at 1 and 2 years after CD19CAR T-cells infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) at 1 and 2 years</measure>
    <time_frame>At 1 year and 2 years after CD19CAR T-cells infusion</time_frame>
    <description>Progression Free Survival at 1 and 2 years after CD19CAR T-cells infusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) at 1 and 2 years</measure>
    <time_frame>At 1 year and 2 years after CD19CAR T-cells infusion</time_frame>
    <description>Overall Survival at 1 and 2 years after immunotherapy with CD19CAR T-cells infusion</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Primary CNS Lymphoma</condition>
  <arm_group>
    <arm_group_label>CD19CAR T-cells</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment with the ATIMP: CD19CAR T-cells</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CD19CAR T-cells</intervention_name>
    <description>Infusion with: CD19CAR T-cells</description>
    <arm_group_label>CD19CAR T-cells</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥16&#xD;
&#xD;
          2. Patients with a histologically confirmed Diffuse Large B-Cell Lymphoma (DLBCL)&#xD;
             confined to the CNS (Primary CNS Lymphoma (PCNSL))&#xD;
&#xD;
          3. Relapsed* or refractory CD19+ PCNSL, defined as disease progression following&#xD;
             CR/CRu/PR, or failure to achieve PR, after one or more lines of a high-dose&#xD;
             methotrexate-containing protocol *Histological confirmation by re-biopsy at relapse is&#xD;
             recommended if feasible. However, patients will be eligible without re-biopsy provided&#xD;
             the initial diagnostic material is available and current MRI imaging features are&#xD;
             consistent with PCNSL by neuroradiology review.&#xD;
&#xD;
          4. Measurable disease on contrast-enhanced MRI&#xD;
&#xD;
          5. Unsuitable for alternative salvage therapies as determined by their treating physician&#xD;
&#xD;
          6. Agreement to have a pregnancy test, use highly effective contraception (if applicable)&#xD;
&#xD;
          7. Written informed consent** ** Some patients with PCNSL may be incapable of providing&#xD;
             their own consent due to the neurological effects of their disease. In these cases a&#xD;
             legal representative may be sought to provide consent'.&#xD;
&#xD;
        Exclusion Criteria (Registration):&#xD;
&#xD;
          1. CD19 negative disease&#xD;
&#xD;
          2. Evidence of secondary CNS lymphoma&#xD;
&#xD;
          3. Prior allogeneic haematopoietic stem cell transplant&#xD;
&#xD;
          4. Active hepatitis B, C or HIV infection&#xD;
&#xD;
          5. Oxygen saturation ≤90% on air&#xD;
&#xD;
          6. Bilirubin &gt;2 x upper limit of normal&#xD;
&#xD;
          7. Glomerular Filtration Rate (GFR) &lt;50ml/min&#xD;
&#xD;
          8. Women who are pregnant or breast feeding&#xD;
&#xD;
          9. Inability to tolerate leucapheresis&#xD;
&#xD;
         10. ECOG 3-4&#xD;
&#xD;
         11. Known allergy to albumin or Dimethyl sulfoxide (DMSO)&#xD;
&#xD;
         12. Life expectancy &lt;3months&#xD;
&#xD;
         13. Arrhythmias or significant cardiac disease and left ventricular ejection fraction &lt;40%&#xD;
&#xD;
         14. Pre-existing neurological disorders (other than CNS involvement of underlying&#xD;
             haematological malignancy)&#xD;
&#xD;
         15. Any contraindications to PD-1 antibody Pembrolizumab&#xD;
&#xD;
         16. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus)&#xD;
             resulting in end organ injury or requiring systemic immunosuppression/systemic disease&#xD;
             modifying agents within the last 24 months&#xD;
&#xD;
         17. Evidence of active pneumonitis on chest computed tomography (CT) or positron emission&#xD;
             tomography (PET)-CT scan at screening or history of drug-induced pneumonitis,&#xD;
             idiopathic pulmonary fibrosis, organising pneumonia (e.g. bronchiolitis obliterans),&#xD;
             or idiopathic pneumonitis. Prior radiation pneumonitis in the radiation field&#xD;
             (fibrosis) is allowed (if &gt;24 weeks since the event)&#xD;
&#xD;
        Exclusion criteria: for CD19CAR T-cell infusion ( Dose 1/i.v. and Dose 2/intraventricular):&#xD;
&#xD;
          1. Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion&#xD;
&#xD;
          2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of&#xD;
             scheduled CD19CAR T-cell infusion&#xD;
&#xD;
          3. Theme 2 only:&#xD;
&#xD;
               1. presence of grade 3 or 4 ICANS casually related to the ATIMP following infusion&#xD;
                  of Dose 1&#xD;
&#xD;
               2. grade 1-2 neurotoxicity (if occurred) following Theme 1 dosing (Dose 1/i.v&#xD;
                  CD19CAR Tcell dose) that has not fully resolved prior to proposed administration&#xD;
                  of 2nd CD19CAR T-cell infusion (Dose /intraventricular) for theme 2&#xD;
&#xD;
               3. grade 3-4 CRS following infusion of Dose 1&#xD;
&#xD;
               4. persisting grade 2 CRS following Theme 1 dosing (Dose 1/i.v CD19CAR T-cell dose)&#xD;
                  that has not resolved to ≤ grade 1 CRS prior to proposed administration of 2nd&#xD;
                  CD19CAR Tcell infusion (Dose 2/intraventricular) for theme 2&#xD;
&#xD;
               5. pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Claire Roddie</last_name>
    <role>Study Chair</role>
    <affiliation>University College London Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University College London Hospital</name>
      <address>
        <city>London</city>
        <zip>WC1E6BT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>June 21, 2023</last_update_submitted>
  <last_update_submitted_qc>June 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04443829
org study id: UCL/126892
nct id: NCT04443829
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The CAROUSEL Trial is a single-centre, non-randomised, open label Phase I clinical trial of
      an Advanced Therapy Investigational Medicinal Product (ATIMP) in adults (age ≥16) with
      relapsed/refractory Primary CNS Lymphoma.

      The study will evaluate the feasibility of generating the ATIMP, the safety of administering
      CD19CAR T-cell therapy and how effectively CD19CAR T-cells engraft, expand and persist
      following administration in patients with relapsed/refractory primary CNS lymphoma.
The CAROUSEL Trial is a single-centre, non-randomised, open label Phase I clinical trial of
      an Advanced Therapy Investigational Medicinal Product (ATIMP) in adults (age ≥16) with
      relapsed/refractory Primary CNS Lymphoma. The ATIMP for this study is cryopreserved
      autologous patient-derived T-cells transduced with CD19CAR vector to generate CD19CAR
      T-cells.

      Patients will undergo an unstimulated leucapheresis for the generation of the ATIMP which
      will take approximately 15 days to generate. During this period, patients may receive
      "holding" chemotherapy as per institutional practice to maintain disease control. Patients
      will receive pre-conditioning lymphodepleting (LD) chemotherapy with cyclophosphamide 60mg/kg
      on Day -6, fludarabine 30mg/m2 administered over 3 days (Day -5 to Day -3) and pembrolizumab
      200mg on Day -1.

      All patients will be treated on Theme 1 of the study with 250 x 10^6 CD19 CAR T-cells i.v.
      following LD chemotherapy as described above. Patients with response of Stable Disease (SD)
      or Progressive Disease (PD) at Day 28 (or frank relapse beyond Day 28) and in the absence of
      severe toxicity related to the ATIMP, will be potentially eligible for Theme 2 of the study
      where they can receive Dose 2, a single dose of 25 x 10^6 CD19CAR T-cells intraventricularly
      via an Ommaya reservoir following LD chemotherapy as described above.

      The study will evaluate the feasibility of generating the ATIMP, the safety of administering
      CD19CAR T-cell therapy and how effectively CD19CAR T-cells engraft, expand and persist
      following administration in patients with relapsed/refractory primary CNS lymphoma.

      Following infusion of CD19CAR T-cell therapy patients will be monitored for between 2-4 weeks
      as an inpatient. Following discharge, patients will enter the interventional follow up phase
      and be followed up for 2 years. Patients will be seen monthly for the first 6 months, then 6
      weekly to 12 months and then 3 monthly until 2 years post CD19CAR T-cell infusion.

      If patients relapse within the first 2 years post CD19CAR T-cell infusion they will come off
      the interventional follow up and will be followed up annually until the end of trial is
      declared.

      After completing the interventional phase of the study all patients, irrespective of whether
      they progressed or responded to treatment, will enter long term follow up until the end of
      trial is declared.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Toxicity evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP
time frame: 28 days
description: Toxicity following CD19CAR T-cell administration as evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP
measure: Feasibility of manufacturing CD19CAR T-cells evaluated by the number of therapeutic products generated
time frame: 28 days
description: Feasibility of adequate leucapheresis collection and generation of CD19CAR T-cells as evaluated by the number of therapeutic products generated.
measure: Response at 1 and 3 months
time frame: From CD19CAR T-cells infusion to 1 and 3 months
description: Proportion of patients achieving a Complete Response (CR) or Partial Response (PR) at 1 and 3 months post CD19CAR T-cells infusion: Theme 1 (i.v.) and Theme 2 (intraventricular)
measure: Frequency of circulating CD19CAR T-cells in peripheral blood
time frame: From CD19CAR T-cells infusion up to 2 years post CD19CAR T-cells infusion
description: Frequency of circulating CD19CAR T-cells in peripheral blood as assessed by flow cytometry and qPCR
measure: Incidence of B-cell aplasia
time frame: From CD19CAR T-cells infusion up to 2 years post CD19CAR T-cells infusion
description: Incidence of B-cell aplasia
measure: Relapse rate at 1 and 2 years
time frame: At 1 year and 2 years after CD19CAR T-cells infusion
description: Proportion of patients who have relapsed at 1 and 2 years after CD19CAR T-cells infusion
measure: Progression Free Survival (PFS) at 1 and 2 years
time frame: At 1 year and 2 years after CD19CAR T-cells infusion
description: Progression Free Survival at 1 and 2 years after CD19CAR T-cells infusion
measure: Overall Survival (OS) at 1 and 2 years
time frame: At 1 year and 2 years after CD19CAR T-cells infusion
description: Overall Survival at 1 and 2 years after immunotherapy with CD19CAR T-cells infusion
arm group label: CD19CAR T-cells
arm group type: Experimental
description: Treatment with the ATIMP: CD19CAR T-cells
intervention type: Biological
intervention name: CD19CAR T-cells
description: Infusion with: CD19CAR T-cells
arm group label: CD19CAR T-cells
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
last name: Claire Roddie
role: Study Chair
affiliation: University College London Hospital
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Lymphoma
sharing ipd: No