Liver Transplantation With Tregs at UCSF

NCT ID: NCT03654040

Last Updated: 2024-04-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-22
• Study Completion Date: 2023-03-06

Brief Summary

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

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 to 500 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.

Conditions

Liver Transplant

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

arTreg

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.

Group Type: EXPERIMENTAL

arTreg

Intervention Type: BIOLOGICAL

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.

leukapheresis

Intervention Type: PROCEDURE

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.

cyclophosphamide

Intervention Type: DRUG

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.

mesna

Intervention Type: DRUG

Mesna is administered:

• Intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide, and
• In conjunction with the cyclophosphamide, per institutional practice with CTX.

everolimus

Intervention Type: DRUG

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.

Interventions

arTreg

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.

Intervention Type: BIOLOGICAL

leukapheresis

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.

Intervention Type: PROCEDURE

cyclophosphamide

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.

Intervention Type: DRUG

mesna

Mesna is administered:

• Intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide, and
• In conjunction with the cyclophosphamide, per institutional practice with CTX.

Intervention Type: DRUG

everolimus

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.

Intervention Type: DRUG

Other Intervention Names

donor alloantigen-reactive regulatory T cells; CD4+CD25+CD127[lo] Treg cells; apheresis; Cytoxan®; CTX; Mesnex®; EVR; Afinitor®; Zortress®

Eligibility Criteria

Inclusion Criteria

Eligibility:

Recipient:

• Individuals must meet all of the following criteria to be eligible for this study:

1. Able to understand and provide informed consent

2. End-stage liver disease and listed for a living or deceased-donor primary solitary liver transplant

3. Agreement to use contraception

4. 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

5. Positive Epstein-Barr virus (EBV) antibody test, and

6. 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:

1. Able to understand and provide informed consent

2. Meets site-specific clinical donor eligibility requirements

3. Meets donor eligibility manufacturing requirements within 7 days before or after the blood collection for manufacturing, and

4. Willingness to donate appropriate biologic samples.

Deceased Donor:

Deceased donors must meet the following criteria for their recipients to remain eligible:

1. Meets site-specific clinical donor eligibility requirements and

2. 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:

1. History of previous organ, tissue or cell transplant

2. For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor

3. Known contraindication to cyclophosphamide or mesna

4. Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection

5. 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

6. End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis) or other contraindications to drug withdrawal

7. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule

8. Any condition that, in the opinion of the investigator, may interfere with study compliance

9. 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

10. 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

11. History of malignancy or any concomitant malignancy, except:

• hepatocellular carcinoma,
• completely treated in-situ cervical carcinoma, or
• completely treated basal cell carcinoma.

12. Chronic use of systemic glucocorticoids or other immunosuppressives, or biologic immunomodulators.

Living Donor:

Deceased Donor:

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Immune Tolerance Network (ITN)

NETWORK

Sponsor Role: collaborator

PPD Development, LP

INDUSTRY

Sponsor Role: collaborator

Rho Federal Systems Division, Inc.

INDUSTRY

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sandy Feng, MD, PhD

Role: STUDY_CHAIR

University of California, San Francisco

Locations

University of California, San Francisco

San Francisco, California, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID)

https://www.niaid.nih.gov/about/dait

Division of Allergy, Immunology, and Transplantation (DAIT)

http://www.immunetolerance.org

Immune Tolerance Network web site

Other Identifiers

UM1AI109565

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NIAID CRMS ID#: 38481

Identifier Type: OTHER

Identifier Source: secondary_id

DAIT ITN074ST

Identifier Type: -

Identifier Source: org_study_id