Immunotherapy With CD19+CD22 CAR Redirected T-cells for High Risk/Relapsed Paediatric CD19+ and CD22+ Acute Lymphoblastic Leukaemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 3
- 主要终点
- Incidence of dose limiting toxicity (DLT) following CD19+CD22 CAR T-cell infusion
研究概览
简要总结
This study aims to evaluate the safety, efficacy and duration of response of CD19+CD22 Chimeric Antigen Receptor (CAR) redirected autologous T-cells in children with high risk, relapsed CD19+ and CD22+ acute lymphoblastic 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+CD22 Chimeric Antigen Receptor (CAR) T-cells (CD19+CD22 CAR T-cells) in children and young adults (age <24 years) with high risk, relapsed CD19+ and CD22+ acute lymphoblastic leukaemia. Following informed consent and registration to the trial, patients will undergo an unstimulated leukapheresis for the generation of the CD19+CD22 CAR T-cells. Patients will receive the CD19+CD22CAR T-cells following lymphodepleting chemotherapy and total body irradiation. The study will evaluate the safety, efficacy and duration of response of the CD19+CD22 CAR T-cells in children with high risk relapsed CD19+ and CD22+ acute lymphoblastic leukaemia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 24 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Children and young adults (age 24 years or younger) with high risk/relapsed CD19+ and CD22+ acute lymphoblastic leukaemia with:
- •Resistant disease (>5% blasts) at end of ALLTogether-1 protocol or equivalent induction
- •ALL with persisting high level MRD at 2nd time point of frontline national protocol (currently MRD >10-4 at week 9 ALLTogether-1 Protocol or equivalent).
- •High risk infant ALL (age < 6 months at diagnosis with MLL gene rearrangement and either presenting white cell count > 300 x 10^9/L or poor steroid early response (i.e. circulating blast count >1x10^9/L following 7 day steroid pre-phase of induction as per national guidelines or equivalent)
- •Any patient with t(17,19) TCF3-HLF rearrangement
- •High risk 1st relapse (defined as very early (relapse within 18 months of diagnosis) and early relapses (any patient relapsing on therapy or within 6 months of completing treatment) and any relapse with high risk genetics, namely (KMT2A (MLL) rearrangements, low hypodiploidy/near haploidy, t(17;19)(q22;p13)/TCF3-HLF, iAMP21 and t(1;19)(q21;p13)/TCF3- PBX1, t(9;22)(34.1 q11.2)/BCR-ABL1
- •Any on therapy relapse in patients age 16-24
- •Any relapse of infant ALL
- •ALL post ≥ 2nd relapse
- •Any refractory relapse of ALL (defined as > 1% blasts by flow cytometry after a at least 1 cycle of standard chemotherapy)
- •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 as long as planned time of CD19+CD22CAR T cell infusion is > 4 months post-transplant
- •Early (defined as < 6 months post-infusion) loss of B cell aplasia or any CD19+CD22+ relapse following CD19CAR T cell therapy with Tisagenlecleucel
- •Note patients with isolated CNS relapse meeting one or more of the criteria above are eligible for the study
- •Agreement to have a pregnancy test, use adequate contraception (if applicable)
- •Written informed consent
排除标准
- •Exclusion Criteria for registration:
- •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 breastfeeding
- •Stem Cell Transplant patients only: active significant (overall Grade ≥ II, Seattle criteria) acute GVHD 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%
- •Pre-existing significant neurological disorder (other than CNS involvement of underlying haematological malignancy)
- •CD19 negative or CD22 negative disease
- •Exclusion criteria for CD19+CD22CAR T-cell infusion:
- •Severe intercurrent infection at the time of scheduled CD19+CD22 CAR T-cell infusion
- •Requirement for supplementary oxygen or active pulmonary infiltrates at the time of scheduled CD19+CD22 CAR T-cell infusion
- •Allogeneic transplant recipients with active significant acute GVHD overall grade ≥II or moderate/severe chronic GVHD requiring systemic steroids at the time of scheduled CD19+CD22 CAR T-cell infusion. Note: Such patients will be excluded until the patient is GVHD free and off steroids
研究组 & 干预措施
CD19+CD22 CAR T-cells
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
干预措施: Leukapheresis (Procedure)
CD19+CD22 CAR T-cells
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
干预措施: Total Body Irradiation (TBI) (Radiation)
CD19+CD22 CAR T-cells
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
干预措施: Lymphodepletion with Cyclophosphamide (Drug)
CD19+CD22 CAR T-cells
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
干预措施: CD19+CD22 CAR T-cells (Biological)
CD19+CD22 CAR T-cells
Patients meeting the eligibility criteria will have leukapheresis to isolate the blood immune cells used to manufacture the CD19+CD22CAR T-cells. Patients will receive lymphodepletion with low dose total body irradiation, fludarabine and cyclophosphamide prior to infusion of the CD19+CD22CAR T-cells.
干预措施: Lymphodepletion with Fludarabine (Drug)
结局指标
主要结局
Incidence of dose limiting toxicity (DLT) following CD19+CD22 CAR T-cell infusion
时间窗: 28 days
The incidence of dose limiting toxicity (DLT) occurring within 28 days of CD19+CD22CAR T-cell infusion.
Molecular remission
时间窗: 28 days
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 28 days post CD19+CD22CAR T-cell infusion will be determined.
次要结局
- Incidence of Hypogammaglobulinaemia(2 years)
- Feasibility of Generation of CD19+CD22 CAR T-cells(Day 28)
- Long-Term Molecular Remission(2 years)
- Duration of Response(15 years)
- Molecular Remission(3 months)
- Incidence of B Aplasia(2 years)
- Relapse rate(2 years)
- Frequency of Circulating CD19+CD22 CAR T-cells(2 years)
- Safety and Tolerability of the CAR T-cells(15 years)
- Overall Survival (OS)(2 years)