Clinical Trials /

Immunotherapy Using CAR T-cells to Target CD19 for Relapsed/Refractory CD19+ Primary CNS Lymphoma

NCT04443829

Description:

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.

Related Conditions:
  • Primary Central Nervous System Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy Using CAR T-cells to Target CD19 for Relapsed/Refractory CD19+ Primary CNS Lymphoma
  • Official Title: Immunotherapy Using CAR T-cells to Target CD19 for Relapsed/Refractory CD19+ Primary Central Nervous System (CNS) Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: UCL/126892
  • NCT ID: NCT04443829

Conditions

  • Primary CNS Lymphoma

Interventions

DrugSynonymsArms
CD19CAR T-cellsCD19CAR T-cells

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
CD19CAR T-cellsExperimentalTreatment with the ATIMP: CD19CAR T-cells
  • CD19CAR T-cells

Eligibility Criteria

        Inclusion Criteria (Registration):

          1. Age ≥16

          2. Patients with a diagnosis of Primary CNS Lymphoma (PCNSL) with refractory or relapsed
             histologically confirmed CD19+ PCNSL following standard therapy requiring salvage in
             whom alternative therapies are deemed inappropriate by their treating physician

          3. Agreement to have a pregnancy test, use adequate contraception (if applicable)

          4. Written informed consent

        Exclusion Criteria (Registration):

          1. CD19 negative disease

          2. Evidence of secondary CNS lymphoma

          3. Prior allogeneic haematopoietic stem cell transplant

          4. Active hepatitis B, C or HIV infection

          5. Oxygen saturation ≤90% on air

          6. Bilirubin >2 x upper limit of normal

          7. Glomerular Filtration Rate (GFR) <50ml/min

          8. Women who are pregnant or breast feeding

          9. Inability to tolerate leucapheresis

         10. Karnofsky score <60% (ECOG 0-2 (appendix 3)

         11. Known allergy to albumin or Dimethyl sulfoxide (DMSO)

         12. Life expectancy <3months

         13. Arrhythmias or significant cardiac disease and left ventricular ejection fraction <40%

         14. Pre-existing neurological disorders (other than CNS involvement of underlying
             haematological malignancy)

         15. Any contraindications to PD-1 antibody Pembrolizumab

         16. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus)
             resulting in end organ injury or requiring systemic immunosuppression/systemic disease
             modifying agents within the last 24 months

         17. Evidence of active pneumonitis on chest computed tomography (CT) or positron emission
             tomography (PET)-CT scan at screening or history of drug-induced pneumonitis,
             idiopathic pulmonary fibrosis, organising pneumonia (e.g. bronchiolitis obliterans),
             or idiopathic pneumonitis. Prior radiation pneumonitis in the radiation field
             (fibrosis) is allowed (if >24 weeks since the event)

         18. Prior limited radiation therapy (e.g. radiation to bone metastasis for pain control)
             within 4 weeks of CAR T infusion or chest/mediastinal radiation within 24 weeks of CAR
             T infusion

        Exclusion criteria: for CD19CAR T-cell infusion ( Dose 1/i.v. and Dose 2/intraventricular):

          1. Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion

          2. Requirement for supplementary oxygen or active pulmonary infiltrates at the time of
             scheduled CD19CAR T-cell infusion

          3. Theme 2 only: absence of grade 3 or 4 Immune Effector Cell Associated Neurotoxicity
             (ICANS) following infusion of Dose 1
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicity evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP
Time Frame:28 days
Safety Issue:
Description:Toxicity following CD19CAR T-cell administration as evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP

Secondary Outcome Measures

Measure:Response at 1 and 3 months
Time Frame:From CD19CAR T-cells infusion to 1 and 3 months
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
Description:Overall Survival at 1 and 2 years after immunotherapy with CD19CAR T-cells infusion

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University College, London

Last Updated

June 19, 2020