Clinical trial NCT03654040: Liver Transplantation With Tregs at UCSF
Official title: A Phase I/II Drug Withdrawal Study of Alloantigen-Specific Tregs in Liver Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Liver Transplant
Keywords: alloantigen-reactive Tregs (arTreg)
immunosuppression
operational tolerance
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
name: PPD Development, LP
name: Rho Federal Systems Division, Inc.
First posted: 2018-08-31
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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:
* There are no exclusion criteria for living donors.

Deceased Donor:

-There are no exclusion criteria for deceased donors.

Primary outcomes:
measure: Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg
timeFrame: From arTreg infusion through completion of study participation
measure: Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna
timeFrame: From ≤3 days prior to arTreg infusion through completion of study participation (Up to 3 months)
measure: Number of Operationally Tolerant Participants
timeFrame: 52 (± 4 weeks) after the last dose of immunosuppression
Secondary outcomes:
measure: Number of Participants Who Develop a Malignancy
timeFrame: Time of enrollment through completion of study participation (Up to 1.8 years)
measure: Incidence of ≥Grade 3 Infections Following arTreg Infusion
timeFrame: From arTreg infusion through completion of study participation
measure: Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
timeFrame: From arTreg infusion through completion of study participation
measure: Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
timeFrame: From arTreg infusion through completion of study participation
measure: Number of Chronic Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
timeFrame: From arTreg infusion through completion of study participation
measure: Proportion of Participants Who Successfully Discontinue Tacrolimus
timeFrame: Post-transplant through Completion of Study Participation
measure: Duration of Operational Tolerance
timeFrame: Post-transplant through Completion of Study Participation
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Sandy Feng, MD, PhD
role: STUDY_CHAIR
References: