A Phase I/II Drug Withdrawal Study of Alloantigen-Specific Tregs in Liver Transplantation (ITN073ST)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 9
- 试验地点
- 2
- 主要终点
- Number of Adverse Events (AEs) Attributed to the Investigational Product's Supportive Regimen (Leukapheresis, Cyclophosphamide and Mesna)
研究概览
简要总结
This is a single-center, prospective, open-label, non-randomized clinical trial exploring cellular therapy to facilitate immunosuppression withdrawal in liver transplant recipients.
详细描述
The researchers in this study plan to enroll 9 participants who will receive at least the target Treg product (arTreg-CSB) dose of 2.5 x 10^6 cells. Participants who receive at least 1 x 10^6 cells but < 2.5 x 10^6 cells as a result of low cell yield will be included in intent-to-treat (ITT) analysis.
Participants who successfully withdraw from all immunosuppression will undergo a research biopsy at 52 weeks following drug discontinuation to determine whether they meet the primary efficacy outcome of operational tolerance. Participants determined to be operationally tolerant will be followed until 104 weeks following drug discontinuation and have a research biopsy at that time to confirm that they remain operationally tolerant. Participants who fail drug withdrawal after 52 weeks but before 104 weeks will be followed until week 104 or 12 weeks after resuming immunosuppression, whichever is longer. The research biopsy at week 104 will be optional for these participants.
Participants who do not successfully withdraw from all immunosuppression will complete 104 weeks of High Intensity Safety Follow-up after failing immunosuppression withdrawal.
*** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.
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
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eligibility:
- •Individuals must meet all of the following criteria to be eligible for this study:
- •Able to understand and provide informed consent
- •End-stage liver disease and listed for a living or deceased-donor primary solitary liver transplant
- •Agreement to use contraception
- •Positive Epstein-Barr virus (EBV) antibody test and
- •In the absence of contraindication, vaccinations must be up to date per the DAIT Guidance for Patients in Transplant Trials (Refer to the Manual of Procedures)
- •Living Donor:
- •Living donors must meet all of the following criteria to be eligible for this study:
- •Able to understand and provide informed consent
- •Meets site-specific clinical donor eligibility requirements
- •Meets donor eligibility manufacturing requirements within 7 days prior to blood collection for manufacturing and
- •Willingness to donate appropriate biologic samples.
- •Deceased Donor:
- •Deceased donors must meet the following criteria for their recipients to be eligible for this study:
- •1. Meets site-specific clinical donor eligibility requirements and
- •Meets donor eligibility manufacturing requirements.
- •There are several stages to this study.
- •Eligibility is evaluated at many time points during the study to assess whether a participant is safe to proceed to the next study stage.
排除标准
- •Individuals who meet any of the following criteria will not be eligible for this study:
- •History of previous organ, tissue or cell transplant requiring or potentially requiring immunosuppression
- •For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor
- •Known contraindication to cyclophosphamide or Mesna administration
- •Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection
- •The need for chronic anti-coagulation that cannot be safely discontinued for a minimum of 1 week to safely perform a liver biopsy
- •End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis) or other contraindications to drug withdrawal
- •Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule
- •Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the investigator, may interfere with study compliance
- •Past or current medical problems, treatments or findings that are not listed above, which, in the opinion of the investigator, may:
- •-- pose additional risks from participation in the study,
- •interfere with the candidate's ability to comply with study requirements, or
- •impact the quality or interpretation of the data obtained from the study.
- •History of malignancy with a risk of recurrence judged by the investigator to be >1%, except for:
- •-- hepatocellular carcinoma,
- •-- completely treated in-situ cervical carcinoma, or
- •-- completely treated basal cell carcinoma.
- •Chronic use of systemic glucocorticoids or other immunosuppressives, or biologic immunomodulators.
- •Living Donor:
- •Living donors who meet the following criteria will not be eligible for this study:
- •Any condition that, in the opinion of the investigator, may pose additional risks from participation in the study, may: -- interfere with the participant's ability to comply with study requirements or --impact the quality or interpretation of the data obtained from the study.
- •Deceased Donor:
- •Recipients of livers from deceased donors who meet the following criteria are ineligible for this study:
- •1. Any condition that, in the opinion of the investigator, may pose additional risks or may impact the quality or interpretation of the data obtained from the study.
研究组 & 干预措施
arTreg-CSB
arTreg CSB: alloantigen-reactive T regulatory cells costimulatory blockade per protocol.
The investigational product is donor alloantigen-specific T regulatory cells (arTreg-CSB). Supportive regimen for receipt of arTregs-CSB includes everolimus, leukapheresis, cyclophosphamide, and mesna.
Participants will receive a single dose of Treg product (arTreg-CSB). The target dose is 2.5 to 125 x 10^6 total cells. arTreg-CSB will be administered as a single peripheral intravenous (IV) infusion over approximately 15 to 30 minutes.
Note: Participants who receive at least the minimum Treg product (arTreg-CSB) dose of 1 to < 2.5 x 10^6 cells will be included in intent-to-treat analysis.
干预措施: mesna (Drug)
arTreg-CSB
arTreg CSB: alloantigen-reactive T regulatory cells costimulatory blockade per protocol.
The investigational product is donor alloantigen-specific T regulatory cells (arTreg-CSB). Supportive regimen for receipt of arTregs-CSB includes everolimus, leukapheresis, cyclophosphamide, and mesna.
Participants will receive a single dose of Treg product (arTreg-CSB). The target dose is 2.5 to 125 x 10^6 total cells. arTreg-CSB will be administered as a single peripheral intravenous (IV) infusion over approximately 15 to 30 minutes.
Note: Participants who receive at least the minimum Treg product (arTreg-CSB) dose of 1 to < 2.5 x 10^6 cells will be included in intent-to-treat analysis.
干预措施: everolimus (Drug)
arTreg-CSB
arTreg CSB: alloantigen-reactive T regulatory cells costimulatory blockade per protocol.
The investigational product is donor alloantigen-specific T regulatory cells (arTreg-CSB). Supportive regimen for receipt of arTregs-CSB includes everolimus, leukapheresis, cyclophosphamide, and mesna.
Participants will receive a single dose of Treg product (arTreg-CSB). The target dose is 2.5 to 125 x 10^6 total cells. arTreg-CSB will be administered as a single peripheral intravenous (IV) infusion over approximately 15 to 30 minutes.
Note: Participants who receive at least the minimum Treg product (arTreg-CSB) dose of 1 to < 2.5 x 10^6 cells will be included in intent-to-treat analysis.
干预措施: arTreg-CSB (Biological)
arTreg-CSB
arTreg CSB: alloantigen-reactive T regulatory cells costimulatory blockade per protocol.
The investigational product is donor alloantigen-specific T regulatory cells (arTreg-CSB). Supportive regimen for receipt of arTregs-CSB includes everolimus, leukapheresis, cyclophosphamide, and mesna.
Participants will receive a single dose of Treg product (arTreg-CSB). The target dose is 2.5 to 125 x 10^6 total cells. arTreg-CSB will be administered as a single peripheral intravenous (IV) infusion over approximately 15 to 30 minutes.
Note: Participants who receive at least the minimum Treg product (arTreg-CSB) dose of 1 to < 2.5 x 10^6 cells will be included in intent-to-treat analysis.
干预措施: leukapheresis (Procedure)
arTreg-CSB
arTreg CSB: alloantigen-reactive T regulatory cells costimulatory blockade per protocol.
The investigational product is donor alloantigen-specific T regulatory cells (arTreg-CSB). Supportive regimen for receipt of arTregs-CSB includes everolimus, leukapheresis, cyclophosphamide, and mesna.
Participants will receive a single dose of Treg product (arTreg-CSB). The target dose is 2.5 to 125 x 10^6 total cells. arTreg-CSB will be administered as a single peripheral intravenous (IV) infusion over approximately 15 to 30 minutes.
Note: Participants who receive at least the minimum Treg product (arTreg-CSB) dose of 1 to < 2.5 x 10^6 cells will be included in intent-to-treat analysis.
干预措施: cyclophosphamide (Drug)
结局指标
主要结局
Number of Adverse Events (AEs) Attributed to the Investigational Product's Supportive Regimen (Leukapheresis, Cyclophosphamide and Mesna)
时间窗: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
The number of AEs attributed to the investigational product's supportive regimen (leukapheresis, cyclophosphamide, and mesna). AEs will be attributed to the supportive regimen when the AE is reported with possible or related attribution to leukapheresis, cyclophosphamide, or mesna.
Severity of Adverse Events (AEs) Attributed to the Investigational Product's Supportive Regimen (Leukapheresis, Cyclophosphamide and Mesna)
时间窗: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Assessment of the intensity of AEs attributed to the investigational product's supportive regimen (e.g., leukapheresis, cyclophosphamide, and mesna). AEs will be attributed to the supportive regimen when the AE is reported with possible or related attribution to leukapheresis, cyclophosphamide, or mesna. Assessment of the intensity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
Number of Operationally Tolerant Participants
时间窗: 52 weeks (±4 weeks) after the last dose of immunosuppression
Operational tolerance is defined as: * Discontinuation of immunosuppression for 52 weeks, * Alanine aminotransferase (ALT) ≤ 50 U/L, and * A liver biopsy at 52 weeks (±4 weeks) after the last dose of immunosuppression that meets the criteria noted per protocol. * Liver histology will be assessed by central pathology.
Number of Adverse Events (AEs) Attributed to the Investigational Product, arTreg-CSB
时间窗: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
The number of AEs attributed to the investigational product, arTreg-CSB. AEs will be attributed to arTreg-CSB when the AE is reported with possible or related attribution to arTreg-CSB.
Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg-CSB
时间窗: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Assessment of the intensity of AEs attributed to the investigational product, arTreg-CSB. AEs will be attributed to arTreg-CSB when the AE is reported with possible or related attribution to arTreg-CSB. Grading according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
次要结局
- Proportion of Participants who Successfully Discontinue Tacrolimus(Post-transplant through Completion of Study Participation (Up to 4.5 years))
- Number of Adverse Events (AEs) Attributed to Leukapheresis(From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Severity of Adverse Events (AEs) Attributed to Leukapheresis(From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Number of Adverse Events (AEs) Attributed to Cyclophosphamide(From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Severity of Adverse Events (AEs) Attributed to Cyclophosphamide(From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Number of Adverse Events (AEs) Attributed to Mesna(From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Number of Participants Who Experience ≥Grade 3 Infections Following arTreg-CSB Infusion(From arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Number of Biopsy-Proven Acute or Chronic Rejections(From arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Severity of Adverse Events (AEs) Attributed to Mesna(From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Severity of Biopsy-Proven Acute Rejections(From arTreg-CSB infusion through completion of study participation (Up to 4.5 years))
- Proportion of Participants with a Composite Outcome Measure of CR, Steroid Refractory AR, Retransplantation or Death Following Everolimus Conversion(From ≥30 days post-transplant through completion of study participation (Up to 4.5 years))
- Number of AEs Attributed to Immunosuppression Withdrawal(From ≥30 days post-transplant through completion of study participation (Up to 4.5 years))
- Severity of AEs Attributed to Immunosuppression Withdrawal(From ≥30 days post-transplant through completion of study participation (Up to 4.5 years))
- Number of Participants who Develop a Malignancy(Day of transplant through completion of study participation (Up to 4.5 years))
- Number of Participants who Develop de novo Donor Specific Antibodies (DSA)(Baseline (pre liver transplant) through completion of study participation (Up to 4.5 years))
- Number of Participants who Develop de novo non-DSA HLA Antibodies(Baseline (pre liver transplant) through Completion of Study Participation (Up to 4.5 years))
- Proportion of Participants who, Though Clinically Stable for 52 Weeks after Discontinued Immunosuppression per Protocol Schedule, do not Fulfill the Study Definition of Tolerance(Post-Transplant through Completion of Study Participation (Up to 4.5 years))
- Duration of Operational Tolerance(Post-transplant through Completion of Study Participation (Up to 4.5 years))