A Phase I Study Evaluating Allogeneic Memory T Cells Engineered to Express Chimeric Antigen Receptors Specific for CD19 for the Treatment of Pediatric and Young Adult Patients ≤ 21 Years of Age With Relapsed or Refractory CD19-Positive Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose of allogeneic, CD19-CAR.CD45RA-negative cells
研究概览
简要总结
This is a Phase I clinical study evaluating the safety and maximum tolerated dose of a novel CAR T-cell product: allogeneic memory (CD45RA- negative) T-cells expressing a CD19-specific CAR 41BBz (CD19-CAR.CD45RA- negative T-cells) for the treatment of patients ≤ 21 years old with relapsed and/ or refractory CD19-positive leukemia.
Primary Objective
To determine the maximum tolerated dose (MTD) and characterize the safety profile and dose-limiting toxicities (DLTs) of treatment with allogeneic CD19-CAR.CD45RA-negative T-cells in pediatric, adolescent and young adult patients ≤ 21 years of age, with relapsed and/or refractory CD19-positive leukemia.
Secondary Objectives
- To evaluate the anti-leukemic activity of allogeneic CD19-CAR.CD45RA-negative T-cells.
- To determine rates and severity of graft-versus-host-disease (GVHD) after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells.
Exploratory Objectives
- To study the expansion, persistence and phenotype of allogeneic CD19-CAR.CD45RA-negative T-cells.
- To characterize the cytokine profile in the peripheral blood and CSF after treatment with allogeneic CD19-CAR.CD45RA-negative T-cells.
- To assess whether allogeneic CD19-CAR.CD45RA-negative T-cells acquire functional versus exhaustion-associated epigenetic programs.
- To determine immune reconstitution post treatment, and the clonal structure and endogenous repertoire of allogeneic CD19-CAR.CD45RA-negative T-cells and relate inferred specificity to CAR response profiles.
- To characterize incidence and mechanisms of relapse post-therapy with allogeneic CD19-CAR.CD45RA-negative T-cells.
详细描述
This is a Phase I dose escalation study using a 3+3 study design. Two groups of patients will be evaluated in this study: group A - patients have received a prior stem cell transplant from their CAR T-cell donor; group B - patients have not received a prior stem cell transplant from their CAR T-cell donor. There will be up to 30 participants per group and a donor/ family member for each patient.
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研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eligibility Criteria for Donors: Apheresis and Manufacturing
- •Age ≥ 18 years old
- •At least single haplotype matched (≥ 3/6) family member
- •HIV negative
- •For females of child bearing age: Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment AND Not lactating with intent to breastfeed
- •Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance. *For Cohort A only, an ineligible donor may be used under urgent medical need if the reason for ineligibility was previously present at time of transplant determination.
- •For Cohort A only, identified recipient with relapsed and/or refractory CD19-positive leukemia
- •For Cohort B only, iIdentified recipient with relapsed and/or refractory CD19-positive leukemia who is not suitable to receive autologous CD19-CAR T-cell therapy as defined by the following:
- •Relapsed and/or refractory disease despite prior treatment with autologous CD19- CAR T-cell therapy
- •History of prior autologous leukapheresis failure
- •History of prior autologous CAR T-cell manufacturing failure
- •Unable to undergo autologous leukapheresis in the opinion of the study PI(s): examples may include - patient small size/low weight, inadequate T-cell counts, rapidly progressive leukemia, clinical status not amenable to apheresis
- •Eligibility Criteria for Patients: Pre-Treatment Evaluation*
- •MEMCAR19 recipient candidate ≤<21 years old with rRelapsed and/or refractory CD19-positive leukemia.
- •*Due to potential scheduling challenges, all recipients may not be offered the Pre-Treatment Evaluation consent. This will not be counted as a deviation.
- •Eligibility Criteria for Patients:Treatment
- •Age ≤ 21 years old
- •Relapsed and/or refractory CD19-positive leukemia*:
- •Refractory disease (defined as any of the following):
- •Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission
- •Refractory disease despite salvage therapy
- •Relapsed disease (defined as any of the following):
- •2nd or greater relapse
- •Any relapse after allogeneic hematopoietic cell transplantation (HCT)
- •1st relapse if patient requires an allogeneic HCT as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for HCT
- •CD19-positivity confirmed within 2 months and after receipt of any CD19-directed therapy
- •Patient cohorts:
- •Cohort A: patient has previously received a HCT from the selected CAR T-cell donor
- •Cohort B - patient has NOT previously received a HCT from the selected CAR T-cell donor.
- •For Cohort B only, not suitable to receive autologous CD19-CAR T-cell therapy as defined above in Criteria: Eligibility Criteria for Donors: Apheresis and Manufacturing
- •Detectable medullary CD19-positive leukemia
- •Estimated life expectancy of ≥ 8 weeks
- •Karnofsky or Lansky performance score ≥ 50
- •No CNS-3 disease or any level of detectable leukemia in CNS with associated neurologic symptoms
- •If history of allogeneic HCT (regardless of donor type), prior to planned CAR T-cell infusion, must meet the following criteria:
- •≥ 3 months from HCT
- •have recovered from prior HCT therapy
- •have no evidence of active GVHD within prior 2 months
- •have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned CAR T-cell infusion
- •Adequate cardiac function: left ventricular ejection fraction ≥ 40% or shortening fraction ≥ 25% (function may be supported by pharmacologic therapy)
- •EKG without evidence of clinically significant arrhythmia
- •Adequate renal function: creatinine clearance or radioisotope GFR 50 ml/min/1.73m2 (GFR 40 ml/min/1.73m2 if < 2 years of age)
- •Adequate pulmonary function: forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing
- •Total bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age
- •No history of HIV infection
- •No evidence of severe, uncontrolled bacterial, viral or fungal infection
- •Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
- •For females of child bearing age:
- •Not pregnant with negative serum or urine pregnancy test ≤ 7 days prior to enrollment AND Not lactating with intent to breastfeed
- 另有 5 项未显示
排除标准
- 未提供
研究组 & 干预措施
Group A
Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
干预措施: Leukapheresis (Procedure)
Group A
Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
干预措施: CliniMACS (Device)
Group B
Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.
干预措施: CD19-CAR(Mem) T-cells (Biological)
Group A
Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
干预措施: CD19-CAR(Mem) T-cells (Biological)
Group A
Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
干预措施: Cyclophosphamide (Drug)
Group B
Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.
干预措施: Leukapheresis (Procedure)
Group B
Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.
干预措施: CliniMACS (Device)
Group A
Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
干预措施: Mesna (Drug)
Group B
Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.
干预措施: Mesna (Drug)
Group A
Participants in group A have received a prior stem cell transplant from their CAR T-cell donor.
干预措施: Fludarabine (Drug)
Group B
Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.
干预措施: Cyclophosphamide (Drug)
Group B
Participants in group B have not received a prior stem cell transplant from their CAR T-cell donor.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Maximum tolerated dose of allogeneic, CD19-CAR.CD45RA-negative cells
时间窗: 4 weeks after CAR T-cell infusion
This phase I study includes dose escalation/de-escalation based on dose limiting toxicity (DLT) assessment to determine the maximum tolerated dose (MTD) of allogeneic, CD19-CAR.CD45RA-negative cells.
次要结局
未报告次要终点