CD19 CAR and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate the safety, efficacy and blood kinetics of autologous T cells genetically modified to express CD19 Chimeric Antigen Receptor and PD-1 knockout engineered T cells in patients with relapsed or refractory B-Cell Non-Hodgkin Lymphoma and Leukaemia.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This is a multi-centre, non-randomised, open label Phase I clinical trial of an Advanced Therapy Investigational Medicinal Product named CD19 Chimeric Antigen Receptor (CAR) and PD-1 knock out engineered T-cells (CD19 CAR and PD-1 knock out engineered T-cells) in children and adults (age <70 years) with high risk, relapsed CD19+ haematological malignancies (Acute Lymphoblastic Leukemia and Burkitt's lymphoma). Following informed consent and registration to the trial, patients will undergo an unstimulated leukapheresis for the generation of the CD19 CAR T-cells. Patients will receive the CD19 CAR and PD-1 knock out engineered T-cells following lymphodepleting chemotherapy. The study will evaluate the safety, efficacy and duration of response of the CD19 CAR and PD-1 knock out engineered T-cells in children with high risk relapsed CD19+ malignancies.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CD19 CAR Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR T-cells. |
Biological: CD19 CAR T-cells
A single dose of 1 x 10^6/kg CD19 CAR transduced T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.
|
| Experimental: CD19 CAR and PD-1 knock out Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19 CAR and PD-1 knock out engineered T-cells. Patients will receive lymphodepletion with fludarabine and cyclophosphamide prior to infusion of the CD19 CAR and PD-1 knock out engineered T-cells. |
Biological: CD19 CAR and PD-1 knock out engineered T-cells
A single dose of 1 x 10^6/kg CD19 CAR transduced and PD-1 knock out engineered T-cells will be given as an intravenous injection through a Hickman line or PICC line(peripherally inserted central catheter) on day 0.
|
Outcome Measures
Primary Outcome Measures
- Molecular remission [1 month]
Efficacy will be assessed by determining Minimal Residual Disease in the bone marrow aspirate using immunoglobulin heavy chain (IgH) quantitative polymerase chain reaction (qPCR) and/or Next Generation Sequencing in all patients. The proportion of patients achieving molecular remission at 1 month post CD19 CAR and PD-1 Knockout Engineered T-cell infusion will be determined.
Secondary Outcome Measures
- Long term molecular remission [2 years]
Number of patients in molecular remission without further therapy at 2 years
- Frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells [2 years]
Persistence and frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells in the peripheral blood by flow cytometry and qPCR analyses.
- Incidence of hypogammaglobulinaemia [2 years]
Incidence and duration of hypogammaglobulinaemia.
- Relapse rate [10 years]
Relapse rate monitored during interventional phase and long term follow up for a total of 10 years post cell infusion. Number of patients who relapsed can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).
- Overall Survival [10 years]
Overall survival is monitored during interventional phase and long term follow up for 10 years post-CD19 CAR and PD-1 Knockout Engineered T-cell infusion. Number of patients alive can be summarized as a percentage (for all patients registered to the trial, and also only for those who received the cell infusion).
Eligibility Criteria
Criteria
Inclusion Criteria:
- 1.Children and adults (age 70 years or younger) with high risk/relapsed CD19+ haematological malignancy:
-
Resistant disease (>25% blasts) at end of UKALL 2011 or equivalent induction
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ALL with persistent high level MRD at 2nd time point of frontline national protocol (currently > 5 x 10-3 at week 14 UKALL2011 or equivalent)
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High risk infant ALL (age < 6 months at diagnosis with MLL gene rearrangement and either presenting white cell count > 300 x 109/L or poor steroid early response (i.e circulating blast count >1x109/L following 7 day steroid pre- phase of Interfant 06)
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Intermediate risk infant ALL with MRD > 10-3 at end of Interfant06 induction
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Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse of acute lymphoblastic leukaemia (ALL)
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Early (within 6 months of finishing therapy) bone marrow, or combined extramedullary relapse of ALL with bone marrow minimal residual disease (MRD) > 10-3 at end of re-induction
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Any on therapy relapse of ALL in patients age 16-70
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Any relapse of infant ALL
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ALL post ≥ 2nd relapse
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Any refractory relapse of ALL
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ALL with MRD >10-4 prior to planned stem cell transplant
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Any relapse of ALL eligible for stem cell transplant but no available HLA matched donor or other contraindication to transplant
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Any relapse of ALL after stem cell transplant
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Any relapse of Burkitt's or other CD19+ lymphoma
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2.Agreement to have a pregnancy test, use adequate contraception (if applicable)
-
3.Written informed consent
Exclusion Criteria:
- Exclusion Criteria for registration:
-
CD19 negative disease
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Active hepatitis B, C or HIV infection
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Oxygen saturation ≤ 90% on air
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Bilirubin > 3 x upper limit of normal
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Creatinine > 3 x upper limit of normal
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Women who are pregnant or lactating
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Stem Cell Transplant patients only: active acute graft-versus-host disease (GVHD) overall Grade ≥ II (Seattle criteria) or moderate/severe chronic GVHD (NIH consensus criteria) requiring systemic steroids
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Inability to tolerate leucapheresis
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Karnofsky (age ≥ 10 years) or Lansky (age < 10) score ≤ 50%
- Exclusion criteria for CD19CAR T-cell infusion:
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Severe intercurrent infection at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
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Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
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Allogeneic transplant recipients with active acute GVHD overall grade >2 or moderate/severe chronic GVHD requiring systemic steroids at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Third Military Medical University
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TMMU-CAR-001