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 |
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Recruitment Status :
Recruiting
First Posted : October 17, 2016
Last Update Posted : September 19, 2022
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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 FL and (5) r/r MCL. 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 subsequently 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, FL and MCL.
Recruitment into the ALL cohort has been completed and no further patients with ALL are being treated on the study.
Patients 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 are 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 second dose only given in the absence of severe toxicity 9 days later. 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 10^6 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 10^6 CD19CAR T-cells and a possible second dose of 400 x 10^6 CAR T-cells
- Regimen B: Patients with DLBCL receive a single dose of 200 x 10^6 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 10^6 CD19 CAR T-cells.
- Regimen D: Patients with FL and MCL receive a single dose of 200 x 10^6 CAR T-cells
The study evaluates 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, 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 |
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, (4) r/r FL and (5) r/r MCL. 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 take approximately 15 days to generate. During this period, patients may receive "holding" chemotherapy as per institutional practice to maintain disease control. The study evaluates ATIMP safety and efficacy and the duration of disease response in adults with high risk / relapsed CD19+ B-ALL, DLBCL, B-CLL/SLL, FL and MCL.
The ALL and FL cohorts are now completed and no further patients with ALL or FL are treated on the study.
Patients receive 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 also receive a single dose of pembrolizumab 200 mg at day -1.
Patients recruited to ALLCAR19 are 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 second dose only given in the absence of severe toxicity 9 days later. 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 10^6 CD19 CAR T-cells and a possible second dose of 310 x 10^6 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 10^6 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 10^6 CAR T-cells
- Regimen C: Patients with CLL/SLL will receive a split dose with a first dose of 30 x 10^6 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 10^6 CAR T-cells
The study evaluates 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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 60 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 : | December 2024 |
| Estimated Study Completion Date : | December 2033 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: CD19CAT-41BBZ CAR T-cells
Treatment with the ATIMP: CD19CAT-41BBZ CAR T-cells
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Biological: CD19CAT-41BBZ CAR T-cells
Infusion with CD19CAT-41BBZ CAR T-cells |
- 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.
- 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.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 16 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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 Follicular Lymphoma which is relapsed / refractory following ≥2 prior lines of therapy Or Mantle Cell Lymphoma which is relapsed / refractory following ≥2 prior lines of therapy 3. Agreement to have a pregnancy test, use adequate contraception (if applicable) 4.Written informed consent
Exclusion criteria for registration:
- CD19 negative disease
- B-ALL and CLL: overt CNS involvement (i.e.: patients with CNS2 with neurological symp-toms or patients with CNS3; appendix 2)
- DLBCL, FL, MCL and CLL/SLL: primary or secondary CNS lymphoma
- Isolated extramedullary disease (B-ALL and CLL)
- Active hepatitis B, C or HIV infection
- Oxygen saturation ≤ 90% on air
- Bilirubin >2 x upper limit of normal
- GFR <50ml/min
- Women who are pregnant or breast feeding
- Stem Cell Transplant patients only: active significant acute GVHD (overall Grade ≥ II, Seattle criteria) or moderate/severe chronic GVHD (NIH consensus criteria) requiring im-munosuppressive therapy and/or systemic steroids
- Inability to tolerate leucapheresis
- Karnofsky score <60% (see appendix 3)
- Patients who have experienced significant neurotoxicity following blinatumomab
- Known allergy to albumin or DMSO
- Life expectancy <3months
- Significant cardiac disease, left ventricular ejection fraction <40% and uncontrolled cardiac arrhythmias (patients with rate-controlled atrial fibrillation are not excluded)
- Pre-existing neurological disorders (other than CNS involvement of underlying haemato-logical malignancy)
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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)
- Chest/mediastinal radiation within 24 weeks of CAR T-cellinfusion
Exclusion criteria: for CD19CAR T-cell infusion at Day 0 (all patients):
- Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion
- Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19CAR T-cell infusion
- 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 patients):
- Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion
- Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19CAR T-cell infusion
- Grade 3-4 CRS and or grade 3-4 neurotoxicity following Day 0 CD19CAR T-cell dose
- 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
- 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
- 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
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
| Contact: ALLCAR19 Trial Coordinator | 02076799860 | ctc.allcar19@ucl.ac.uk |
| United Kingdom | |
| University College London Hospital | Recruiting |
| London, United Kingdom | |
| Contact: Prof. Karl Peggs | |
| Principal Investigator: Prof. Karl Peggs | |
| Study Chair: | Karl Peggs | University College London Hospitals |
| 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: | September 19, 2022 |
| Last Verified: | September 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| 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 |
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Lymphoma Leukemia Lymphoma, Non-Hodgkin Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid 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 |