Phase 1b/2a Trial of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) From an HLA-partially Matched Related or Unrelated Donor After TCRαβ+ T-cell/CD19+ B-cell Depletion for Patients Who Will Receive a Kidney Transplant (KT) From the Same HSCT/KT Donor
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Number of patients who are able to discontinue immunosuppression post-KT
研究概览
简要总结
This is a single center, non-randomized, non-controlled open-label phase 1b/2a trial of performing sequential αβdepleted-HSCT and KT in patients requiring KT to prevent kidney rejection post-KT, in the absence of any post-KT immunosuppression, to abrogate the need for lifelong immunosuppression, the risk of chronic rejection and, ultimately, the need for repeated transplantation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Anticipated need for kidney transplant due to:
- •a. Underlying genetic/immunologic disease the following conditions i. SIOD ii. FSGS iii. Cystinosis iv. SLE v. Membranoproliferative glomerulonephritis vi. Renal vasculitis characterized by positivity of the presence of ANCA vii. Other genetic diseases leading to kidney disease requiring KT Or b. Patients who have rejected a previous KT regardless of the underlying disease
- •Chronic kidney disease (CKD) stage 3 or greater
- •Steroids < 0.5 mg/Kg/day
- •The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB1
- •Lansky/Karnofsky score > 50; the Karnofsky Scale will be used in subjects ≥ 16 years of age, and the Lansky Scale will be used for those < 16 years of age.
- •Able to give informed consent or have an LAR available to provide consent
- •Male and female subjects of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression, and if the subject experiences any cGvHD
排除标准
- •Pregnant or lactating females.
- •Greater than Grade II aGvHD or severe, unmanaged extensive cGvHD due to a previous allograft at the time of inclusion
- •Dysfunction of liver (ALT/AST > 10 times upper normal value, or direct bilirubin > 3 times upper normal value), unmanageable dysfunction of renal function while undergoing dialysis
- •Severe cardiovascular disease at the time of evaluation unresponsive to nutritional and dialytic support (left ventricular ejection fraction < 40%), or clinical or echocardiographic evidence of severe diastolic dysfunction
- •Current active infectious disease. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
- •Serious concurrent uncontrolled medical disorders except for primary disease leading to chronic kidney disease
- •Lack of patient/parent/guardian informed consent
- •Any severe concurrent disease which, in the judgement of the investigator would place the patient at increased risk during participation in the study
研究组 & 干预措施
Cohort 1b: Conditioning Regimen A
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Cyclophosphamide 1200 mg/Kg (Drug)
Cohort 1b: Conditioning Regimen A
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Fludarabine (Drug)
Cohort 1b: Conditioning Regimen A
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Total Body Irradiation (Radiation)
Cohort 2a: Conditioning Regimen A
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: ATG (Drug)
Cohort 1b: Conditioning Regimen A
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: ATG (Drug)
Cohort 1b: Conditioning Regimen A
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Rituximab (Drug)
Cohort 1b: Conditioning Regimen A
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System (Device)
Cohort 1b: Conditioning Regimen A
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen A (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Kidney Transplant (Procedure)
Cohort 2a: Conditioning Regimen A
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Cyclophosphamide 1200 mg/Kg (Drug)
Cohort 2a: Conditioning Regimen A
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Fludarabine (Drug)
Cohort 2a: Conditioning Regimen A
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Total Body Irradiation (Radiation)
Cohort 2a: Conditioning Regimen A
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Rituximab (Drug)
Cohort 2a: Conditioning Regimen A
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System (Device)
Cohort 2a: Conditioning Regimen A
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Kidney Transplant (Procedure)
Cohort 1b: Conditioning Regimen B
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Fludarabine (Drug)
Cohort 1b: Conditioning Regimen B
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Cyclophosphamide 100 mg/Kg (Drug)
Cohort 1b: Conditioning Regimen B
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Total Body Irradiation (Radiation)
Cohort 1b: Conditioning Regimen B
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: ATG (Drug)
Cohort 1b: Conditioning Regimen B
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Rituximab (Drug)
Cohort 1b: Conditioning Regimen B
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Melphalan (Drug)
Cohort 1b: Conditioning Regimen B
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System (Device)
Cohort 1b: Conditioning Regimen B
An initial cohort of 4 patients will be enrolled as part of the initial Phase 1b safety run-in evaluation. Patients will undergo an αβdepleted hematopoietic stem cell transplant (HSCT) after receiving conditioning regimen B (conditioning regimen type is dependent on underlying disease and not part of the experimental goals). In the presence of donor myeloid engraftment, at least 3 months post-HSCT, patients will undergo a living donor kidney transplant (KT) using same donor as HSCT. In the absence of any clinical signs of kidney rejection, pharmacological immunosuppression (used for KT) will be tapered off by Day +90 post-KT.
干预措施: Kidney Transplant (Procedure)
Cohort 2a: Conditioning Regimen B
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Fludarabine (Drug)
Cohort 2a: Conditioning Regimen B
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Cyclophosphamide 100 mg/Kg (Drug)
Cohort 2a: Conditioning Regimen B
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Total Body Irradiation (Radiation)
Cohort 2a: Conditioning Regimen B
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: ATG (Drug)
Cohort 2a: Conditioning Regimen B
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Rituximab (Drug)
Cohort 2a: Conditioning Regimen B
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Melphalan (Drug)
Cohort 2a: Conditioning Regimen B
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: CliniMACS® TCR α/β Reagent Kit and CliniMACS® CD19 System (Device)
Cohort 2a: Conditioning Regimen B
If the intervention is determined to be safe and non-futile, the study will continue to enroll eight more patients under Phase 2a following the same treatment as Phase 1b.
干预措施: Kidney Transplant (Procedure)
结局指标
主要结局
Number of patients who are able to discontinue immunosuppression post-KT
时间窗: Day +90 post-KT
Donor chimerism equal or greater to 95% after successful HSCT/KT therapy allows for withdrawal of immunosuppressive therapy in patient
次要结局
- Number of patients with de novo chronic GVHD(+1 year post-KT)
- Number of patients with persistent full donor chimerism(Day +180 and 1 year post-KT)
- Number of patients with successful kidney function(+1 year post-KT)
- Number of patients with myloid engraftment(Day +42 post-HSCT)
- Number of cases of secondary malignancies(+5 year post-KT)
- Number of patients with acute GvHD(Day +90 and Day +180 post-HSCT)
- Number of patients with chronic GvHD(+1 year post-HSCT)
- Number of patients with de novo acute GVHD(+1 year post-KT)
- Number of patients with functional tolerance to donor cells(6- and 12-months post-KT)
研究者
Alice Bertaina
Associate Professor of Pediatrics
Stanford University