Liver Transplantation With Tregs at UCSF

Study Overview
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Brief Summary
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This is a single-center, prospective, open-label, non-randomized clinical trial exploring cellular therapy to facilitate immunosuppression withdrawal in liver transplant recipients.

Detailed Description
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The researchers in this study plan to enroll 9 participants. Eligible participants will receive a single dose of Treg product (arTreg). The target dose is at least 90 x 10^6 total cells. Participants who successfully withdraw from all immunosuppression (IS) will undergo a research biopsy at 52 weeks following IS 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 IS discontinuation. 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. Participants who do not successfully withdraw from all IS 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.

Official Title
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A Phase I/II Drug Withdrawal Study of Alloantigen-Specific Tregs in Liver Transplantation

Conditions
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Liver Transplant

Intervention / Treatment
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* Biological: arTreg
* Procedure: leukapheresis
* Drug: cyclophosphamide
* Drug: mesna
* Drug: everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligibility: Recipient: 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 For candidates with a history of hepatitis C virus (HCV), completed treatment for HCV, maintaining a sustained viral response of ≥24 weeks duration by the day of transplant Positive Epstein-Barr virus (EBV) antibody test, and Immunizations are up-to-date based on the Advisory Committee on Immunization Practices (ACIP) recommendations for individuals with Liver Disease and Adult Vaccination, unless the investigator determines that administering a recommended immunization is not in the patient's best interest. 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 before or after the blood collection for manufacturing, and Willingness to donate appropriate biologic samples. Deceased Donor: Deceased donors must meet the following criteria for their recipients to remain eligible: Meets site-specific clinical donor eligibility requirements and Meets donor eligibility manufacturing requirements. Note: 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. Exclusion Criteria: Recipient: Individuals who meet any of the following criteria will not be eligible for this study: History of previous organ, tissue or cell transplant For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor Known contraindication to cyclophosphamide or mesna Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection The need for chronic anti-coagulation or anti-platelet agents other than aspirin 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 condition that, in the opinion of the investigator, may interfere with study compliance History of cardiac disease (ischemic heart disease requiring revascularization, history of or current treatment for dysrhythmia, or evidence of congestive heart failure), unless cleared by a cardiologist Any 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 This includes past, present or future enrollment in studies that affect eligibility at the time of everolimus (EVR) conversion History of malignancy or any concomitant malignancy, except: 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: There are no exclusion criteria for living donors. Deceased Donor: -There are no exclusion criteria for deceased donors.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: arTreg<br>arTreg: alloantigen-reactive T regulatory cells The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, leukapheresis, cyclophosphamide, and mesna. Note: Participants who receive at least the minimum Treg product (arTreg) dose of 30 to <90 x10^6 total cells will be included in intent-to-treat analysis. | Biological: arTreg<br>* Eligible participants will receive a single dose of Treg product (arTreg). The target dose is at least 90 x 10^6 total cells. Method of receipt: peripheral intravenous (IV) infusion, administered over 20 to 30 minutes.<br>* Other names: CD4+CD25+CD127[lo] Treg cells;Procedure: leukapheresis<br>* Leukapheresis will be the method employed to recover peripheral blood mononuclear cells (PBMCs) from the allograft recipient. The recipient will undergo the procedure prior to initiating the cyclophosphamide conditioning regimen. Procedure on Day -3 (-1 day) prior to Treg product (arTreg) IV infusion.<br>* Other names: apheresis;Drug: cyclophosphamide<br>* 40 mg/kg administered intravenously (IV) following leukapheresis and between 1 to 3 days prior to Treg product (arTreg) infusion, per institutional standard of care.<br>* Other names: CTX;Drug: mesna<br>* Mesna is administered: Intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide, and In conjunction with the cyclophosphamide, per institutional practice with CTX.<br>* Other names: Mesnex®;Drug: everolimus<br>* EVR is approved for prophylaxis of allograft rejection in adults receiving a liver transplant. Per protocol: Post transplantation, subject will initially receive standard IS with tacrolimus (TAC),plus a mycophenolate product and/or steroids.Subsequently, evaluation for eligibility to be converted to EVR-based IS regimen will occur and, when applicable, proceed. Once the optimal EVR trough level is achieved,TAC dose will be reduced. When target EVR and TAC levels are maintained over two consecutive measurements, ALT liver function test (LFT) is ≤50 U/L, GGT LFT is ≤ the upper limit of normal or ≤ 1.5 times the baseline GGT, subject will be considered successfully converted to EVR-based IS regimen. EVR doses will be administered/monitored/adjusted over time.<br>* Other names: Zortress®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg | AEs will be attributed to alloantigen-reactive Tregs (arTreg) when the AE is reported with possible or related attribution to arTreg. Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual [NCI-CTCAE version 5.0, published November 27, 2017]. | From arTreg infusion through completion of study participation (Up to 4.5 years) | 
| Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna | AEs will be attributed to the supportive regimen for this study when the AE is reported with possible or related attribution to leukapheresis, cyclophosphamide, or mesna. Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual [NCI-CTCAE version 5.0, published November 27, 2017]. | From ≤3 days prior to arTreg infusion through completion of study participation (Up to 4.5 years) | 
| Number of Operationally Tolerant Participants | Operational tolerance is defined as: Discontinuation of all immunosuppression (IS) for 52 weeks, Alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) ≤ 50 U/L for ≥ 2 measurements separated by ≥1 week in the 6 weeks prior to the liver biopsy at 52 weeks after the last IS dose, and Liver biopsy at 52 weeks (±4 weeks) after the last IS dose that meets the biopsy criteria for operational tolerance, as assessed by central pathology. | 52 (± 4 weeks) after the last dose of immunosuppression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of ≥Grade 3 Infections Following arTreg Infusion | Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual [NCI-CTCAE version 5.0, published November 27, 2017]. | From arTreg infusion through completion of study participation (Up to 4.5 years) | 
| Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at any Time after Alloantigen-Reactive Tregs (arTreg) Infusion | Definitions: AR: Diagnosed in accordance with Banff global assessment criteria Clinical Rejection: Participants who are treated empirically based on investigator clinical suspicion in cases where a biopsy is indeterminate or in rare cases, where a biopsy cannot be performed. | From arTreg infusion through completion of study participation (Up to 4.5 years) | 
| Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at any Time after Alloantigen-Reactive Tregs (arTreg) Infusion | Definitions: AR: Diagnosed in accordance with Banff global assessment criteria Clinical Rejection: Participants who are treated empirically based on investigator clinical suspicion in cases where a biopsy is indeterminate or in rare cases, where a biopsy cannot be performed. Intensity of AR and/or clinical rejection events will be graded. | From arTreg infusion through completion of study participation (Up to 4.5 years) | 
| Number of Chronic Rejection Events at Any Time after Alloantigen-Reactive Tregs (arTreg) Infusion | Diagnosed in accordance with Banff global assessment criteria. | From arTreg infusion through completion of study participation (Up to 4.5 years) | 
| Number of Participants who Develop a Malignancy | The number of participants that are diagnosed with malignancy, any type. | Day of transplant through completion of study participation (Up to 4.5 years) | 
| Proportion of Participants who Successfully Discontinue Tacrolimus | Proportion of participants who, per protocol: fulfill eligibility for tacrolimus withdrawal, subsequently achieve their last dose of tacrolimus, remain tacrolimus-free for ≥12 weeks, their liver function tests, ALT and GGT, are ≤50 U/L, and their liver biopsy performed between 12 to 26 weeks status post the last dose of tacrolimus fulfills biopsy findings* for minimization of immunosuppression. Biopsy findings: Liver histology will be assessed by central pathology. Biopsy findings for minimization of immunosuppression, per protocol. Reference: Demetris AJ, Bellamy C, Hubscher SG, et al. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transplant 2016. | Post-transplant through Completion of Study Participation (Up to 4.5 years) | 
| Duration of Operational Tolerance | Durability of operational tolerance defined as the time from achieving the primary endpoint to immunosuppression (IS) reinitiation or to the end of trial participation. | Post-transplant through Completion of Study Participation (Up to 4.5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alloantigen-reactive Tregs (arTreg), immunosuppression, operational tolerance