CD19 Chimeric Antigen Receptor (CAR) and PD-1 Knockout Engineered T Cells for CD19 Positive Malignant B-cell Derived Leukemia and Lymphoma
试验速览
- 阶段
- 1 期
- 入组人数
- 30
- 主要终点
- Molecular remission
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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)
- •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)
- •Intermediate risk infant ALL with MRD > 10-3 at end of Interfant06 induction
- •Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse of acute lymphoblastic leukaemia (ALL)
- •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
- •Any on therapy relapse of ALL in patients age 16-70
- •Any relapse of infant ALL
- •ALL post ≥ 2nd relapse
- •Any refractory relapse of ALL
- •ALL with MRD >10-4 prior to planned stem cell transplant
- •Any relapse of ALL eligible for stem cell transplant but no available HLA matched donor or other contraindication to transplant
- •Any relapse of ALL after stem cell transplant
- •Any relapse of Burkitt's or other CD19+ lymphoma
- •2.Agreement to have a pregnancy test, use adequate contraception (if applicable)
- •3.Written informed consent
排除标准
- •Exclusion Criteria for registration:
- •CD19 negative disease
- •Active hepatitis B, C or HIV infection
- •Oxygen saturation ≤ 90% on air
- •Bilirubin > 3 x upper limit of normal
- •Creatinine > 3 x upper limit of normal
- •Women who are pregnant or lactating
- •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
- •Inability to tolerate leucapheresis
- •Karnofsky (age ≥ 10 years) or Lansky (age < 10) score ≤ 50%
- •Exclusion criteria for CD19CAR T-cell infusion:
- •Severe intercurrent infection at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
- •Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19 CAR and PD-1 Knockout Engineered T Cells infusion
- •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
研究组 & 干预措施
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.
干预措施: CD19 CAR T-cells (Biological)
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.
干预措施: CD19 CAR and PD-1 knock out engineered T-cells (Biological)
结局指标
主要结局
Molecular remission
时间窗: 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.
次要结局
- Long term molecular remission(2 years)
- Frequency of circulating CD19 CAR and PD-1 Knockout Engineered T-cells(2 years)
- Relapse rate(10 years)
- Overall Survival(10 years)
- Incidence of hypogammaglobulinaemia(2 years)
研究者
Xiaoyun Shang
Principal Investigator
Third Military Medical University