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.
Title
- Brief 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
- 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
Clinical Trial IDs
- ORG STUDY ID:
UCL/16/0530
- NCT ID:
NCT02935257
Conditions
- Leukemia, Lymphoblastic, Acute, Lymphoma
Interventions
Drug | Synonyms | Arms |
---|
CD19CAT-41BBZ CAR T-cells | | CD19CAT-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) 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.
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.
Trial Arms
Name | Type | Description | Interventions |
---|
CD19CAT-41BBZ CAR T-cells | Experimental | Treatment with the ATIMP: CD19CAT-41BBZ CAR T-cells | - CD19CAT-41BBZ CAR T-cells
|
Eligibility 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
Maximum Eligible Age: | N/A |
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: | 28 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
November 23, 2020