Clinical trial NCT03577431: Liver Transplantation With Tregs at MGH
Official title: A Phase I/II Drug Withdrawal Study of Alloantigen-Specific Tregs in Liver Transplantation (ITN073ST)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
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)
First posted: 2018-07-05
Enrollment: 9
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 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.

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

  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 prior to 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 be eligible for this study:

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 requiring or potentially requiring immunosuppression
  2. For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor
  3. Known contraindication to cyclophosphamide or Mesna administration
  4. Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection
  5. The need for chronic anti-coagulation 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 form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the investigator, may interfere with study compliance
  9. 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.
  10. 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.
  11. 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:

  <!-- -->

  1. 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.

Primary outcomes:
measure: Number of Adverse Events (AEs) Attributed to the Investigational Product, arTreg-CSB
timeFrame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg-CSB
timeFrame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Number of Adverse Events (AEs) Attributed to the Investigational Product's Supportive Regimen (Leukapheresis, Cyclophosphamide and Mesna)
timeFrame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Severity of Adverse Events (AEs) Attributed to the Investigational Product's Supportive Regimen (Leukapheresis, Cyclophosphamide and Mesna)
timeFrame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Number of Operationally Tolerant Participants
timeFrame: 52 weeks (±4 weeks) after the last dose of immunosuppression
Secondary outcomes:
measure: Number of Adverse Events (AEs) Attributed to Leukapheresis
timeFrame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Severity of Adverse Events (AEs) Attributed to Leukapheresis
timeFrame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Number of Adverse Events (AEs) Attributed to Cyclophosphamide
timeFrame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Severity of Adverse Events (AEs) Attributed to Cyclophosphamide
timeFrame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Number of Adverse Events (AEs) Attributed to Mesna
timeFrame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Severity of Adverse Events (AEs) Attributed to Mesna
timeFrame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Number of Participants Who Experience ≥Grade 3 Infections Following arTreg-CSB Infusion
timeFrame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Number of Biopsy-Proven Acute or Chronic Rejections
timeFrame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Severity of Biopsy-Proven Acute Rejections
timeFrame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
measure: Proportion of Participants with a Composite Outcome Measure of CR, Steroid Refractory AR, Retransplantation or Death Following Everolimus Conversion
timeFrame: From ≥30 days post-transplant through completion of study participation (Up to 4.5 years)
measure: Number of AEs Attributed to Immunosuppression Withdrawal
timeFrame: From ≥30 days post-transplant through completion of study participation (Up to 4.5 years)
measure: Severity of AEs Attributed to Immunosuppression Withdrawal
timeFrame: From ≥30 days post-transplant through completion of study participation (Up to 4.5 years)
measure: Number of Participants who Develop a Malignancy
timeFrame: Day of transplant through completion of study participation (Up to 4.5 years)
measure: Number of Participants who Develop de novo Donor Specific Antibodies (DSA)
timeFrame: Baseline (pre liver transplant) through completion of study participation (Up to 4.5 years)
measure: Number of Participants who Develop de novo non-DSA HLA Antibodies
timeFrame: Baseline (pre liver transplant) through Completion of Study Participation (Up to 4.5 years)
measure: Proportion of Participants who, Though Clinically Stable for 52 Weeks after Discontinued Immunosuppression per Protocol Schedule, do not Fulfill the Study Definition of Tolerance
timeFrame: Post-Transplant through Completion of Study Participation (Up to 4.5 years)
measure: Duration of Operational Tolerance
timeFrame: Post-transplant through Completion of Study Participation (Up to 4.5 years)
measure: Proportion of Participants who Successfully Discontinue Tacrolimus
timeFrame: Post-transplant through Completion of Study Participation (Up to 4.5 years)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital: Transplantation
state: Massachusetts
Study officials:
affiliation: University of Pennsylvania Medical Center: Transplantation
name: James F. Markmann, MD, PhD
role: STUDY_CHAIR
References: