Clinical Trials /

Immunotherapy for High Risk/Relapsed CD19+ Acute Lymphoblastic Leukaemia 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 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.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

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

    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

    Last Updated

    October 3, 2017