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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 (ALLCAR19)

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ClinicalTrials.gov Identifier: NCT02935257
Recruitment Status : Recruiting
First Posted : October 17, 2016
Last Update Posted : November 23, 2020
Sponsor:
Information provided by (Responsible Party):
University College, London

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Leukemia, Lymphoblastic, Acute, Lymphoma Biological: CD19CAT-41BBZ CAR T-cells Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 29, 2017
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : November 2032


Arm Intervention/treatment
Experimental: CD19CAT-41BBZ CAR T-cells
Treatment with the ATIMP: CD19CAT-41BBZ CAR T-cells
Biological: CD19CAT-41BBZ CAR T-cells
Infusion with CD19CAT-41BBZ CAR T-cells




Primary Outcome Measures :
  1. Toxicity evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP [ Time Frame: 28 days ]
    Toxicity following CD19CAR T-cell administration as evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP.

  2. Feasibility of manufacturing CD19CAR T-cells evaluated by the number of therapeutic products generated [ Time Frame: 30 days ]
    Feasibility of adequate leucapheresis collection and generation of CAR19 T cells as evaluated by the number of therapeutic products generated.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02935257


Contacts
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Contact: ALLCAR19 Trial Coordinator 02076799860 ctc.allcar19@ucl.ac.uk

Locations
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United Kingdom
University College London Hospital Recruiting
London, United Kingdom
Contact: Prof. Karl Peggs         
Principal Investigator: Prof. Karl Peggs         
Sponsors and Collaborators
University College, London
Investigators
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Study Chair: Karl Peggs University College London Hospitals
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT02935257    
Other Study ID Numbers: UCL/16/0530
First Posted: October 17, 2016    Key Record Dates
Last Update Posted: November 23, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Leukemia, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases