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Immunotherapy for High Risk/Relapsed CD19+ Acute Lymphoblastic Leukaemia, B-cell Non-Hodgkin's Lymphoma (B-NHL) and Chronic Lymphocytic Leukaemia (CLL)/ Small Lymphocytic Lymphoma (SLL) Using CAR T-cells to Target CD19

NCT02935257

Description:

This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in adults (age ≥16) with (1) high risk, relapsed/refractory (r/r) CD19+ B-ALL; (2) r/r DLBCL; (3) r/r CLL/SLL and (4) r/r indolent B-NHL. The ATIMP for this study is cryopreserved autologous patient-derived T-cells transduced with the lentiviral pCCL.PGK.alpha.CD19CAT-41BBzeta vector, CD19CAT-41BBζ CAR T-cells (referred to sub-sequently as CD19CAR T-cells) which is classified as a gene therapy medicinal product. Patients will undergo an unstimulated leucapheresis for the generation of the ATIMP. The ATIMP will take approximately 15 days to generate. During this period, patients may receive "holding" chemotherapy as per institutional practice to maintain disease control. The study will evaluate ATIMP safety and efficacy and the duration of disease response in adults with high risk / relapsed CD19+ B-ALL, DLBCL, B-CLL/SLL and indolent B-NHL. Patients will receive pre-conditioning lymphodepleting chemotherapy with cyclophosphamide 60mg/kg on Day -6 and fludarabine 30mg/m2 administered over 3 days (Day -5 to Day -3). Patients with DLBCL only will also receive a single dose of pembrolizumab 200 mg at day -1. Patients recruited to ALLCAR19 will be treated with different dosing schedules, depending on their underlying disease. Patients with B-ALL and B-CLL/SLL are considered at high risk of CLL/CRES so receive split dosing, with the sec-ond dose only given in the absence of severe toxicity 9 days later. Please note CAR T-cell dosing in ALLCAR19 is flat i.e. not dependent on patient body weight or surface area. - Regimen A1: Patients with B-ALL with a baseline marrow blast% of ≤20% receive a split dose with a first dose of 100 x 106 CD19 CAR T-cells and a possible second dose of 310 x 106 CAR T-cells - Regimen A2: Patients with B-ALL with a baseline marrow blast% of >20% receive a split dose with a first dose of 10 x 106 CD19CAR T-cells and a possible second dose of 400 x 106 CAR T-cells - Regimen B: Patients with DLBCL receive a single dose of 200 x 106 CAR T-cells - Regimen C: Patients with CLL/SLL will receive a split dose with a first dose of 30 x 106 CD19 CAR T-cells and a possible second dose of 200 x 106 CD19 CAR T-cells. - Regimen D: Patients with indolent B-NHL receive a single dose of 200 x 106 CAR T-cells The study will evaluate ATIMP feasibility and safety of generating CD19CAR T-cells and for B-ALL patients only, efficacy and the duration of disease response to CD19CAR T-cells. 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 10 years post-CD19CAR T-cell infusion.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Transformed Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy for High Risk/Relapsed CD19+ Acute Lymphoblastic Leukaemia, B-cell Non-Hodgkin's Lymphoma (B-NHL) and Chronic Lymphocytic Leukaemia (CLL)/ Small Lymphocytic Lymphoma (SLL) Using CAR T-cells to Target CD19
  • Official Title: Immunotherapy for High Risk/Relapsed CD19+ Acute Lymphoblastic Leukaemia, B-cell Non-Hodgkin's Lymphoma (B-NHL) and Chronic Lymphocytic Leukaemia (CLL)/ Small Lymphocytic Lymphoma (SLL) Using CAR T-cells to Target CD19

Clinical Trial IDs

  • ORG STUDY ID: UCL/16/0530
  • NCT ID: NCT02935257

Conditions

  • Leukemia, Lymphoblastic, Acute, Lymphoma

Interventions

DrugSynonymsArms
CD19CAT-41BBZ CAR T-cellsCD19CAT-41BBZ CAR T-cells

Purpose

This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) in adults (age ≥16) with (1) high risk, relapsed/refractory (r/r) CD19+ B-ALL; (2) r/r DLBCL; (3) r/r CLL/SLL and (4) r/r indolent B-NHL. The ATIMP for this study is cryopreserved autologous patient-derived T-cells transduced with the lentiviral pCCL.PGK.alpha.CD19CAT-41BBzeta vector, CD19CAT-41BBζ CAR T-cells (referred to sub-sequently as CD19CAR T-cells) which is classified as a gene therapy medicinal product. Patients will undergo an unstimulated leucapheresis for the generation of the ATIMP. The ATIMP will take approximately 15 days to generate. During this period, patients may receive "holding" chemotherapy as per institutional practice to maintain disease control. The study will evaluate ATIMP safety and efficacy and the duration of disease response in adults with high risk / relapsed CD19+ B-ALL, DLBCL, B-CLL/SLL and indolent B-NHL. Patients will receive pre-conditioning lymphodepleting chemotherapy with cyclophosphamide 60mg/kg on Day -6 and fludarabine 30mg/m2 administered over 3 days (Day -5 to Day -3). Patients with DLBCL only will also receive a single dose of pembrolizumab 200 mg at day -1. Patients recruited to ALLCAR19 will be treated with different dosing schedules, depending on their underlying disease. Patients with B-ALL and B-CLL/SLL are considered at high risk of CLL/CRES so receive split dosing, with the sec-ond dose only given in the absence of severe toxicity 9 days later. Please note CAR T-cell dosing in ALLCAR19 is flat i.e. not dependent on patient body weight or surface area. - Regimen A1: Patients with B-ALL with a baseline marrow blast% of ≤20% receive a split dose with a first dose of 100 x 106 CD19 CAR T-cells and a possible second dose of 310 x 106 CAR T-cells - Regimen A2: Patients with B-ALL with a baseline marrow blast% of >20% receive a split dose with a first dose of 10 x 106 CD19CAR T-cells and a possible second dose of 400 x 106 CAR T-cells - Regimen B: Patients with DLBCL receive a single dose of 200 x 106 CAR T-cells - Regimen C: Patients with CLL/SLL will receive a split dose with a first dose of 30 x 106 CD19 CAR T-cells and a possible second dose of 200 x 106 CD19 CAR T-cells. - Regimen D: Patients with indolent B-NHL receive a single dose of 200 x 106 CAR T-cells The study will evaluate ATIMP feasibility and safety of generating CD19CAR T-cells and for B-ALL patients only, efficacy and the duration of disease response to CD19CAR T-cells. 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 10 years post-CD19CAR T-cell infusion.

Detailed Description

      This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced
      Therapy Investigational Medicinal Product (ATIMP) in adults (age ≥16) with (1) high risk,
      relapsed/refractory (r/r) CD19+ B-ALL; (2) r/r DLBCL; (3) r/r CLL/SLL and (4) r/r indolent
      B-NHL. The ATIMP for this study is cryopreserved autologous patient-derived T-cells
      transduced with the lentiviral pCCL.PGK.alpha.CD19CAT-41BBζ vector, CD19CAT-41BBζ CAR T-cells
      (referred to sub-sequently as CD19CAR T-cells) which is classified as a gene therapy
      medicinal product. Patients will undergo an unstimulated leucapheresis for the generation of
      the ATIMP. The ATIMP will take approximately 15 days to generate. During this period,
      patients may receive "holding" chemotherapy as per institutional practice to maintain disease
      control. The study will evaluate ATIMP safety and efficacy and the duration of disease
      response in adults with high risk / relapsed CD19+ B-ALL, DLBCL, B-CLL/SLL and indolent
      B-NHL.

      Patients will receive pre-conditioning lymphodepleting chemotherapy with cyclophosphamide
      60mg/kg on Day -6 and fludarabine 30mg/m2 administered over 3 days (Day -5 to Day -3).
      Patients with DLBCL only will also receive a single dose of pembrolizumab 200 mg at day -1.

      Patients recruited to ALLCAR19 will be treated with different dosing schedules, depending on
      their underlying disease. Patients with B-ALL and B-CLL/SLL are considered at high risk of
      CLL/CRES so receive split dosing, with the sec-ond dose only given in the absence of severe
      toxicity 9 days later. Please note CAR T-cell dosing in ALLCAR19 is flat i.e. not dependent
      on patient body weight or surface area.

        -  Regimen A1: Patients with B-ALL with a baseline marrow blast% of ≤20% receive a split
           dose with a first dose of 100 x 106 CD19 CAR T-cells and a possible second dose of 310 x
           106 CAR T-cells

        -  Regimen A2: Patients with B-ALL with a baseline marrow blast% of >20% receive a split
           dose with a first dose of 10 x 106 CD19CAR T-cells and a possible second dose of 400 x
           106 CAR T-cells

        -  Regimen B: Patients with DLBCL receive a single dose of 200 x 106 CAR T-cells

        -  Regimen C: Patients with CLL/SLL will receive a split dose with a first dose of 30 x 106
           CD19 CAR T-cells and a possible second dose of 200 x 106 CD19 CAR T-cells.

        -  Regimen D: Patients with indolent B-NHL receive a single dose of 200 x 106 CAR T-cells

      The study will evaluate ATIMP feasibility and safety of generating CD19CAR T-cells and for
      B-ALL patients only, efficacy and the duration of disease response to CD19CAR T-cells.

      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 10 years
      post-CD19CAR T-cell infusion.
    

Trial Arms

NameTypeDescriptionInterventions
CD19CAT-41BBZ CAR T-cellsExperimentalTreatment with the ATIMP: CD19CAT-41BBZ CAR T-cells
  • CD19CAT-41BBZ CAR T-cells

Eligibility Criteria

        Inclusion Criteria:

        1. Age ≥162. B-ALL: high risk or relapsed histologically confirmed CD19+ B-ALL following
        standard therapy requiring salvage in whom alternative therapies are deemed inappropriate
        by their treating physician Or DLBCL: relapsed/refractory DLBCL (incl. transformed FL but
        not Richter's transformation) following ≥2 prior lines of therapy including Rituximab and
        anthracycline Or CLL/SLL: relapsed/refractory CLL/SLL following ≥2 prior lines of therapy
        including Ibrutinib or other Bruton's Tyrosine Kinase (BTK) inhibitors Or Indolent B-NHL
        (either Follicular Lymphoma, Mantle Cell Lymphoma or Marginal Zone Lymhpoma) which is
        relapsed / refractory following ≥2 prior lines of therapy including Ritux-imab and
        anthracycline 3. Agreement to have a pregnancy test, use adequate contraception (if
        applicable) 4.Written informed consent

        Exclusion criteria for registration:

          1. CD19 negative disease

          2. B-ALL and CLL: overt CNS involvement (i.e.: patients with CNS2 with neurological
             symp-toms or patients with CNS3; appendix 2)

          3. B-NHL and CLL/SLL: primary or secondary CNS lymphoma

          4. Isolated extramedullary disease (B-ALL and CLL)

          5. Active hepatitis B, C or HIV infection

          6. Oxygen saturation ≤ 90% on air

          7. Bilirubin >2 x upper limit of normal

          8. GFR <50ml/min

          9. Women who are pregnant or breast feeding

         10. Stem Cell Transplant patients only: active significant acute GVHD (overall Grade ≥ II,
             Se-attle criteria) or moderate/severe chronic GVHD (NIH consensus criteria) requiring
             im-munosuppressive therapy and/or systemic steroids (see appendix 5)

         11. Inability to tolerate leucapheresis

         12. Karnofsky score <60% (see appendix 3)

         13. Patients who have experienced significant neurotoxicity following blinatumomab

         14. Known allergy to albumin or DMSO

         15. Life expectancy <3months

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

         17. Pre-existing neurological disorders (other than CNS involvement of underlying
             haemato-logical malignancy)

         18. DLBCL only:

               -  Any contraindications to PD-1 antibody Pembrolizumab

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

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

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

        Exclusion criteria: for CD19CAR T-cell infusion at Day 0 (all patients):

          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. Allogeneic transplant recipients with active significant acute GVHD overall grade ≥II
             or moderate/severe chronic GVHD requiring systemic steroids or other
             immunosuppres-sion at the time of scheduled CD19CAR T-cell infusion. Note: Such
             patients will be ex-cluded until the patient is GVHD free and off steroids

        Exclusion criteria: for supplementary CD19CAR T-cell infusion Day 9 (B-ALL and CLL/SLL
        pa-tients):

          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
             sched-uled CD19CAR T-cell infusion

          3. Grade 3-4 CRS and or grade 3-4 neurotoxicity following Day 0 CD19CAR T-cell dose

          4. Grade 1-2 neurotoxicity (if occurred) following Day 0 CD19CAR T-cell dose that has not
             fully resolved prior to proposed administration of 2nd CD19CAR T-cell dose

          5. Persisting Grade 2 CRS following Day 0 CD19CAR T-cell dose that has not resolved to ≤
             Grade 1 CRS prior to proposed administration of 2nd CD19CAR T-cell dose

          6. Allogeneic transplant recipients with active significant acute GVHD overall grade ≥II
             or moderate/severe chronic GVHD requiring systemic steroids or other immunosuppression
             at the time of scheduled CD19CAR T-cell infusion* *Note: Such patients will be
             excluded until the patient is GVHD free and off steroids
      
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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University College, London

Last Updated

November 23, 2020