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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
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy for High Risk/Relapsed CD19+ Acute Lymphoblastic Leukaemia Using CAR T-cells to Target CD19
  • Official Title: Immunotherapy for High Risk/Relapsed CD19+ Acute Lymphoblastic Leukaemia

Clinical Trial IDs

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

Conditions

  • Leukemia, Lymphoblastic, Acute

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 to 65 years) with high risk, relapsed/refractory CD19+ B-ALL. The ATIMP for this study is cryopreserved autologous patient-derived T-cells transduced with a lentiviral vector to generate the CD19CAT-41BBZ CAR T-cells (referred to subsequently as 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 chemotherapy with cyclophosphamide 60mg/kg on Day -6 and fludarabine 30mg/m2 administered over 3 days (Day -5 to Day -3). The study is designed as an intra-patient dose escalation employing a total dose range (over 2 doses, Dose 1 and Dose 2) of between 5 x 106 CD19CAR T-cells and 1.1 x 109 CD19CAR T-cells. The study will evaluate ATIMP safety and efficacy and the duration of disease response in adults with high risk / relapsed CD19+ B-ALL. 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 5 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 to 65 years) with high
      risk, relapsed/refractory CD19+ B-ALL. The ATIMP for this study is cryopreserved autologous
      patient-derived T-cells transduced with a lentiviral vector to generate the CD19CAT-41BBZ CAR
      T-cells (referred to subsequently as 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 and fludarabine
      30mg/m2 administered over 3 days (Day -5 to Day -3).

      The study is designed as an intra-patient dose escalation employing a total dose range (over
      2 doses, Dose 1 and Dose 2) of between (minimum) 5 x 106 CD19CAR T-cells (plus 20% for
      thawing losses) and (maximum) 1.1 x 109 CD19CAR T-cells (plus 20% for thawing losses).

      The initial ATIMP dose administered is dependent upon B-ALL disease burden in the bone
      marrow. For patients with <20% marrow infiltration by B-ALL at baseline (screening), Dose 1a
      will be 1x108 CD19CAR T-cells and will be administered on Day 0 following LD. For those with
      ≥20% marrow infiltration by B-ALL, Dose 1b, administered on Day 0, will be 1x107 CD19CAR
      T-cells. This measure to prevent toxicity is in keeping with published data correlating
      severity of CRS with disease burden.

      Dose 1a* (BM blasts≤20%): 1x108 CD19CAR T-cells (plus 20% for thawing losses) Dose 1b* (BM
      blasts>20%): 1x107 CD19CAR T-cells (plus 20% for thawing losses) Dose 2* (all patients, in
      the absence of clinically severe CRS): dosing range between minimum dose of ≥5 x 106 CD19CAR
      T-cells (plus 20% for thawing losses) and maximum dose of ≤1x109 CD19CAR T-cells (plus 20%
      for thawing losses)

      *Minimum dose permitted on trial at all Dose levels is ≥5 x 106 CD19CAR T-cells (plus 20% for
      thawing losses) The study will evaluate ATIMP safety and efficacy and the duration of disease
      response in adults with high risk / relapsed CD19+ B-ALL. 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 5 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. Adults (age range 16 to 65 years) with high risk/relapsed histologically confirmed
             CD19+ B-ALL following standard therapy with measurable disease requiring salvage and
             in whom alternative therapies are deemed inappropriate by their treating physician.

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

          3. Written informed consent

        Exclusion Criteria:

          1. CD19 negative disease

          2. Overt CNS involvement (ie: patients with CNS2 with neurological symptoms or patients
             with CNS3)

          3. Isolated extramedullary disease

          4. Active hepatitis B, C or HIV infection

          5. Oxygen saturation ≤ 90% on air

          6. Bilirubin > 2 x upper limit of normal

          7. GFR>50ml/min

          8. Women who are pregnant or breast feeding

          9. Stem Cell Transplant patients only: active significant acute GVHD (overall Grade ≥ II,
             Seattle criteria) or moderate/severe chronic GVHD (NIH consensus criteria) requiring
             immunosuppressive therapy and/or systemic steroids

         10. Inability to tolerate leucapheresis

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

         12. Patients who have experienced significant neurotoxicity following blinatumomab

         13. Known allergy to albumin or DMSO

         14. Life expectancy <3months

         15. Arrythmias or significant cardiac disease and LVEF <40%

         16. Pre-existing neurological disorders (other than CNS involvement of underlying
             haematological malignancy)
      
Maximum Eligible Age:65 Years
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:30 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

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