ALLCAR19: 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

Sponsor

University College, London (Other)

Overall Status

Recruiting

CT.gov ID

NCT02935257

Collaborator

(none)

Enrollment

Location

Arm

181.1

Anticipated Duration (Months)

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

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.

Study Design

Study Type:

Interventional

Anticipated 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 :

Sep 29, 2017

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Nov 1, 2032

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Toxicity evaluated by the incidence of grade 3-5 toxicity causally related to the ATIMP [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 [30 days]
Feasibility of adequate leucapheresis collection and generation of CAR19 T cells as evaluated by the number of therapeutic products generated.

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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:

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)
B-NHL 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, Se-attle criteria) or moderate/severe chronic GVHD (NIH consensus criteria) requiring im-munosuppressive therapy and/or systemic steroids (see appendix 5)
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
Arrhythmias or significant cardiac disease and left ventricular ejection fraction <40%
Pre-existing neurological disorders (other than CNS involvement of underlying haemato-logical malignancy)
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):

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 pa-tients):

Severe intercurrent infection at the time of scheduled CD19CAR T-cell infusion
Requirement for supplementary oxygen or active pulmonary infiltrates at the time of sched-uled 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