CD45RA-depleted CD19-CAR T Cell Consolidation After TCRαβ+/CD19 B Cell-depleted Haploidentical Hematopoietic Cell Transplantation for Relapsed/Refractory CD19+ ALL and Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- To assess the safety of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies.
研究概览
简要总结
The purpose of this study is to learn more about newer methods of transplanting blood cells donated by a partially matched family member to children with high-risk CD19 positive leukemia ALL.
Primary Objective:
- To assess the safety and feasibility of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies.
Secondary Objectives:
- To estimate 1-year post-transplant overall survival, event-free survival, and GVHD-free relapse-free survival (GRFS).
- To estimate cumulative incidence of engraftment, acute and chronic GVHD, and immune-related adverse events, including CRS and ICANS.
详细描述
This is a Phase I study evaluating the addback of CD19-CAR(Mem) T cells after TCRαβ+/CD19 B cell depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies.
Donors that meet eligibility criteria will be consented to undergo two separate collections: 1) G-CSF mobilized stem cell graft via apheresis for progenitor cell infusion and 2) Non-mobilized peripheral blood mononuclear cells (PBMC) via apheresis for subsequent CAR T-cell manufacturing and DLI if needed.
Patients that meet eligibility criteria to receive therapy will be consented to proceed on study. Treatment will include a conditioning chemotherapy preparative regimen followed by infusion of TCRαβ/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product, as well as collection of correlative samples.
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 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age less than or equal to 21 years
- •High risk hematologic malignancy where allogeneic transplantation is the current standard of care. This includes (but is not limited to):
- •High risk CD19+ B cell ALL in CR1 or CR2
- •Any CD19+ B-cell ALL in CR3 or subsequent
- •If prior CNS leukemia, it must be treated and in CNS CR
- •Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%
- •Creatinine clearance (CrCl) or glomerular filtration rate (GFR) ≥ 50 ml/min/1.73m2
- •Forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing
- •Karnofsky or Lansky (age dependent) performance score ≥ 50 (See APPENDIX A)
- •Bilirubin ≤ 3 times the upper limit of normal for age
- •Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age
- •At least single haplotype matched (≥ 4 of 8) family member
- •At least 18 years of age
- •HIV negative
- •If sexually active, agreement to use birth control until 2 weeks after completion of the mobilization and apheresis procedure
- •Regarding donation eligibility, is identified as either:
- •Completed the process of donor eligibility determination as outlined in 21 CFR 1271 and agency guidance; OR
- •Does not meet 21 CFR 1271 eligibility requirements, but has a declaration of urgent medical need completed by the principal investigator or physician sub-investigator per 21 CFR 1271
排除标准
- •Has a suitable HLA-identical sibling or suitable 12/12 (HLA-A, B, C, DRB1, DQB1, and DPB1) HLA-matched unrelated donor available in an appropriate time frame
- •Any other active malignancy other than the one for which this HCT is indicated
- •Received a prior allogeneic HCT at any time
- •Pregnant, if female is of childbearing potential, negative test must be confirmed by serum or urine pregnancy test within 14 days prior to enrollment
- •If sexually active, agreement to use birth control until 6 months after T cell infusion
- •Breast feeding
- •Any severe current uncontrolled bacterial, fungal or viral infection
- •Pregnant, negative test must be confirmed by serum or urine pregnancy test within 14 days prior to enrollment if female
- •If female, breast feeding
研究组 & 干预措施
HAPALL Treatment
Patients receive a conditioning regimen that will comprise of ATG, Fludarabine, Cyclophosphamide. Melphalan and Thiotepa. Following the conditioning regimen, patients receive infusion of TCRαβ+/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product,
Cells for infusion are prepared using the CliniMACS system.
干预措施: Fludarabine (Drug)
HAPALL Treatment
Patients receive a conditioning regimen that will comprise of ATG, Fludarabine, Cyclophosphamide. Melphalan and Thiotepa. Following the conditioning regimen, patients receive infusion of TCRαβ+/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product,
Cells for infusion are prepared using the CliniMACS system.
干预措施: Melphalan (Drug)
HAPALL Treatment
Patients receive a conditioning regimen that will comprise of ATG, Fludarabine, Cyclophosphamide. Melphalan and Thiotepa. Following the conditioning regimen, patients receive infusion of TCRαβ+/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product,
Cells for infusion are prepared using the CliniMACS system.
干预措施: CliniMACS System (Device)
HAPALL Treatment
Patients receive a conditioning regimen that will comprise of ATG, Fludarabine, Cyclophosphamide. Melphalan and Thiotepa. Following the conditioning regimen, patients receive infusion of TCRαβ+/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product,
Cells for infusion are prepared using the CliniMACS system.
干预措施: Cyclophosphamide (Drug)
HAPALL Treatment
Patients receive a conditioning regimen that will comprise of ATG, Fludarabine, Cyclophosphamide. Melphalan and Thiotepa. Following the conditioning regimen, patients receive infusion of TCRαβ+/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product,
Cells for infusion are prepared using the CliniMACS system.
干预措施: Mesna (Drug)
HAPALL Treatment
Patients receive a conditioning regimen that will comprise of ATG, Fludarabine, Cyclophosphamide. Melphalan and Thiotepa. Following the conditioning regimen, patients receive infusion of TCRαβ+/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product,
Cells for infusion are prepared using the CliniMACS system.
干预措施: Anti-Thymocyte Globulin (Rabbit) (Drug)
HAPALL Treatment
Patients receive a conditioning regimen that will comprise of ATG, Fludarabine, Cyclophosphamide. Melphalan and Thiotepa. Following the conditioning regimen, patients receive infusion of TCRαβ+/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product,
Cells for infusion are prepared using the CliniMACS system.
干预措施: Thiotepa (Drug)
HAPALL Treatment
Patients receive a conditioning regimen that will comprise of ATG, Fludarabine, Cyclophosphamide. Melphalan and Thiotepa. Following the conditioning regimen, patients receive infusion of TCRαβ+/CD19 B cell depleted progenitor cell infusion on day 0. Then as early as day + 14 patients will receive the previously manufactured CD19-CAR(Mem) T cell product. Patients will then be monitored for safety and efficacy of the infused CAR T-cell product,
Cells for infusion are prepared using the CliniMACS system.
干预措施: Filgrastim (Drug)
结局指标
主要结局
To assess the safety of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies.
时间窗: This will be assessed 100 days post-HCT
The primary analysis will compute the sample proportions and corresponding binomial exact 95% confidence intervals among evaluable patients for the following toxicities (separately for each toxicity) within 100 days post-HCT: 1) Severe aGVHD defined as Grade 3-4 aGVHD 2) Severe CRS defined as Grade 4 CRS that does not resolve to grade 3 or lower within 72 hours of onset 3) Severe ICANS defined as Grade 4 ICANS that does not resolve to grade 3 or lower within 72 hours of onset 4) TRM defined as death without prior relapse or disease progression within 100 days post-HCT 5) Other toxicity data will also be reported for a complete safety assessment of the study regimen.
To assess the feasibility of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies.
时间窗: This will be assessed in the first 60 days post-HCT
this will be measured by the failure to receive CD19-CAR(Mem) T cells among patients who received HCT. The number of patients who fail to receive addback will be reported as the proportion who were unable to receive addback within 60 days post-HCT
次要结局
- Estimate cumulative incidence of immune-related adverse events(This will be assessed in the first 1 years post-HCT)
- Estimate 1-year post-transplant relapse free survival(This will be assessed in the first 3 years post-HCT)
- Estimate cumulative incidence of platelet engraftment(This will be assessed in the first 100 days post-HCT)
- Estimate cumulative incidence of neutrophil engraftment(This will be assessed in the first 30 days post-HCT)
- Estimate cumulative incidence of acute and chronic GVHD(This will be assessed in the first 3 years post-HCT)
- To assess the feasibility of combining CD19-CAR(Mem) T cells after TCRαβ+/CD19 depleted haploidentical donor transplantation for pediatric patients with relapsed/refractory CD19+ B-cell malignancies.(This will be assessed in the first 60 days post-HCT)