Donor-Alloantigen-Reactive Regulatory T Cell (darTregs) in Liver Transplantation

Official Title:

Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Liver Transplantation (RTB-002)

Basic Trial Information

Phase Type Age Sponsor Protocol IDs Status
Phase 1 Interventional 21 - 70 Years National Institute of Allergy and Infectious Diseases (NIAID) DAIT RTB-002
NCT02188719
Enrolling patients

Study Design:


Principal Investigator

Professor of Surgery
Division of Transplant Surgery
Director, Abdominal Transplant Fellowship Program

Clinical Research Coordinator

UCSF Medical Center at Parnassus
(415) 476-2574 Phone

Trial Summary

The purpose of this study is look at the safety of:

- Taking a specific combination of immunosuppressant drugs after liver transplantation

- Receiving one of three different doses of donor-alloantigen-reactive regulatory T cells (darTregs) while taking this specific combination of drugs

Eligibility

Inclusion Criteria:
  • Subjects who meet all of the following criteria are eligible for enrollment as study
    participants:
        - Able to understand and provide informed consent
        - End-stage liver disease and listed for primary solitary liver transplant
        - Have a calculated Model for End Stage Liver Disease (MELD) score ≤ 25 at the
           time of study entry/consent
        - Female and male subjects with reproductive potential must agree to use effective
           methods of birth control for the duration of the study.
        - If history of HCV, have completed or are in current treatment for HCV AND have
           no detectable HCV RNA.
        - Subjects with HCC meeting Milan criteria.
Exclusion Criteria:
  • Below are exclusion criteria to be assessed at study enrollment, prior to Stage 1
    study procedures. Subjects who meet any of these criteria are not eligible for Stage
    1 study procedures. Note that subjects in Cohort 1a or 1b will NOT undergo
    leukapheresis regardless of eligibility.
        - End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis,
           primary biliary cirrhosis, or primary sclerosing cholangitis)
        - International Normalized Ratio (INR) > 2.0
        - History of less than 5 years remission of malignancy, except for 1) HCC or 2)
           history of adequately treated in-situ cervical carcinoma, or adequately treated
           basal or squamous cell carcinoma of the skin.
        - History of previous organ, tissue or cell transplant
        - Serologic evidence of human immunodeficiency (HIV) 1 or -2 infection
        - Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) sero-negativity (EBV or CMV
           naïve candidates)
        - Chronic use of systemic glucocorticoids or other Immunosuppression (IS), or
           biologic immunomodulators
        - Chronic condition requiring anti-coagulation after liver transplantation
        - Any chronic illness or prior treatment which, in the opinion of the
           investigator, precludes study participation
        - Participation in any other studies that involved investigational drugs or
           regimens in the preceding year
        - Hemoglobin <9.0 g/dL within 10 days prior to screening
        - Neutrophils <1,500/μL within 10 days prior to screening
        - Platelets <40,000/μL within 10 days prior to screening
  • Thymoglobulin Exclusion Criteria B (Stage 2):
        - Below are exclusion criteria to be assessed prior to administration of
           Thymoglobulin®. Subjects who meet any of these criteria should not receive
           Thymoglobulin®:
              - Calculated Model for End Stage Liver Disease (MELD) score >/= 25 at the
                 time of deceased donor liver transplant
              - Last alpha-fetoprotein (AFP) obtained prior to liver transplantation >400
                 μg/L for candidates with Hepatocellular Carcinoma (HCC)
              - Unacceptable leukapheresis product for participants enrolled in Cohorts 2,
                 3, or 4 per UCSF HICTF manufacturing specifications
              - Absence of donor spleen or lymphocytes for any participants
              - Human leukocyte antigen (HLA)-DR (DR is one of class II antigens) matched
                 to donor at both loci
              - Subject is < 21 or >70 years of age at the time of transplantation
              - Located in the intensive care unit 72 hours after transplantation
              - Hemoglobin <8.0 g/dL
              - Absolute neutrophil count <1,200/μL
              - Platelets <40,000/μL
              - Positive pregnancy test for females of child bearing potential
              - Unexpected histopathology on back table liver biopsy that contraindicates
                 the initiation of Treg supportive IS regimen.
              - Development of a condition requiring chronic anti-coagulation.
              - Hypersensitivity to rabbit proteins or any excipient in Thymoglobulin®.
              - Detectable HCV RNA or less than six months after end of treatment for HCV
                 at the time of transplantation (i.e., does not meet criteria for SVR).
        - Below are exclusion criteria to be assessed prior to conversion to Everolimus
           (EVR)-based IS regimen. (Assessed at day 30-44 after transplantation for
           continuation in the trial) All subjects regardless of eligibility for EVR
           conversion, with any of the following will not receive darTregs and will move
           into safety follow up:
              - Explanted liver with evidence of increased risk of recurrent cancer risk
                 (hepatocellular (HCC) tumor burden exceeding the Milan criteria; presence
                 of vascular invasion; cholangiocarcinoma morphology)
              - Insufficient depletion of recipient T cells, defined as a nadir CD3 count
                 ≥50 cells μ/L (50 cells /mcL) or total lymphocyte count ≥ 0.1x 109/L if CD3
                 count is unavailable
              - Development of a condition requiring chronic anti-coagulation.
              - Clinical evidence of biliary obstruction
              - Alanine Aminotransferase (ALT) >2.0 x upper limit of normal (ULN)
              - Inability to taper off corticosteroids by 44 days (+/- 2 days) after
                 transplant
              - Detectable circulating HCV RNA.
Everolimus Conversion Criteria C2 (assessed prior to conversion to EVR based IS regimen;
EVR cannot be initiated prior to 30 days after liver transplantation). Subjects with any
of the following will remain on TAC-based IS regimen.
  • Evidence of hepatic artery stenosis or thrombosis by Doppler examination or
    angiography within 7 days prior to conversion
  • Urine protein/creatinine ratio >1.0 within 7 days prior to conversion
  • Calculated GFR less than 30 ml/min per MDRD4 equation within 7 days prior to
    conversion
  • Physical examination documentation of abnormal wound healing or uncontrolled wound
    infection
  • Hemoglobin <8.0 g/dL within 7 days prior to conversion
  • Absolute neutrophil count <1,200/μL within 7 days prior to conversion
  • Platelets <50,000/μL within 7 days prior to conversion
    *Below are exclusion criteria to be assessed prior to darTreg infusion for subjects
    in Cohorts 2, 3, and 4 only. Subjects in Cohort 2, 3, or 4 who meet any of these
    criteria should not receive a darTreg-infusion:
  • Inability or unwillingness of participant to give additional written informed consent
  • Unacceptable darTreg product
  • Detectible circulating Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) DNA within
    10 days prior to darTreg infusion
  • Detectible HBV DNA within 10 days prior to darTreg infusion
  • Detectable circulating HCV RNA within 10 days prior to darTreg infusion.
  • Alanine Aminotransferase (ALT) >1.5x upper limit of normal within 10 days of darTreg
    infusion
  • Most recent, but not greater than 10 days prior to darTreg infusion,12 hour TAC
    trough levels of > 8 μg/L for all subjects
  • Most recent, but not greater than 10 days prior to darTreg infusion,12 hour EVR
    trough levels of < 5 μg/L for subjects on EVR
  • For subjects on EVR-based IS, received Mycophenolate Mofetil (MMF) within 10 days
    prior to darTreg infusion
  • Evidence of acute rejection or chronic rejection according to Banff criteria on
    protocol allograft biopsy based on local assessment
  • Received any vaccination within 14 days prior to darTreg infusion
  • Positive pregnancy test for females of child bearing potential
  • Inability or unwillingness of participant to comply with study protocol or
    procedures.
  • Calculated glomerular filtration rate (eGFR) less than 40 ml/min per MDRD4 equation
    within 7 days prior to infusion.

Detailed Description

After liver transplantation, immunosuppressants must be taken every day to prevent the body
from injuring the transplanted liver by a process called rejection. People who take these
drugs may experience side effects.
Studies show that some of body's cells, called T regulatory cells (Tregs), may play a part
in accepting the transplanted liver. The investigators are learning about whether scientists
can take Tregs from the blood of a liver transplant recipient and teach them to protect the
transplanted liver from rejection. In the laboratory, the recipient Tregs are exposed to
cells from the liver donor. Research data suggests that giving these "donor reactive" Tregs
back to the transplant recipient might allow a liver transplant recipient to take lower
doses of immunosuppressants, or perhaps to stop them altogether, without rejecting the
liver.

Important

Final eligibility is determined by the health professionals conducting the trial and the protocol approved by the Committee on Human Resources (CHR) at the University of California, San Francisco (UCSF). The Patient Consent Form for this trial is available upon request. For more information about this trial, please see the full posting at ClinicalTrials.gov.

Information about this trial was obtained from the NIH Clinical Trials website, http://clinicaltrials.gov on 2/7/2017. UCSF specific information including the PI (Principal Investigator), trial enrollment status, and UCSF Study ID, supplement the ClinicalTrials.gov study posting.
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