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Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction

Official Title:

Safety of Donor Alloantigen Reactive Tregs to Facilitate Minimization and/or Discontinuation of Immunosuppression in Adult Liver Transplant Recipients (CTOTC-12)

Basic Trial Information

Phase Type Age Sponsor Protocol IDs Status
Phase 1/Phase 2 Interventional 18 - 70 Years National Institute of Allergy and Infectious Diseases (NIAID) DAIT CTOTC-12
NCT02474199
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

This research study is for liver transplant recipients and their respective living donors.

The purpose of this study is:

1. To see if it is safe for liver recipients to receive one dose of donor reactive T regulatory cells (Tregs)

2. To see if the Tregs allows a liver recipient to take less, or completely stop medications normally taken after receiving an organ transplant.

Eligibility

Study Enrollment Inclusion Criteria:
  • Subjects who meet all of the following criteria are eligible for enrollment:
           Able to understand and provide informed consent
           Have received a primary, solitary, living donor liver transplant more 24 months
           and less than 84 months ago
           Have a living donor who is willing to consent to a one time blood draw of 100
           mLs to enable the manufacture of Donor Alloantigen Reactive Regulatory T cells
           (darTregs)
           Eighteen to 70 years of age at the time of study entry/consent
           Liver function test (LFT) results: have Alanine Aminotransferase
           (ALT)consistently <60 U/L and either alkaline phosphatase consistently <150 U/L
           or Gamma-glutamyl transferase (GGT) consistently <60 U/L
           Currently receiving a Calcineurin Inhibitor (CNI) with 12 hour trough levels
           consistently <6.0 ng/mL for tacrolimus; <150 ng/mL for cyclosporine
           Currently receiving CNI monotherapy or CNI and one of the following:
                 Prednisone: maximum dose of 5mg daily
                 Mycophenolate mofetil (MMF): maximum dose of 500 mg administered twice
                 daily for Cellcept or 360mg twice daily for Myfortic.
           Female and male participants with reproductive potential must agree to use
           effective methods of birth control for the duration of the study.
           If history of Hepatocellular carcinoma (HCC), liver transplantation (LT)
           recipients who have:
                 α-fetoprotein (AFP) less than 100 μg/L at the time of transplant AND
                 Explanted liver:
                  - with tumor burden within the Milan criteria and
                  - without macro- or micro-vascular invasion and
                  - without any lesions with poorly differentiated HCC and
                  - without cholangiocarcinoma morphology
                 Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score less
                 than or equal to 3
           If history of HCC, at the time of enrollment, subjects must also:
                 Be 36 months or more post-transplant AND
                 Without evidence of recurrent HCC defined as:
                  - AFP within normal limits for performing laboratory;
                  - Confirmatory chest CT and
                  - Confirmatory CT or MRI of the abdomen and pelvis.
           If history of hepatitis C virus (HCV) , recipients must be:
                 Cured of HCV as defined by achieving Sustained virologic response (SVR) and
                 be greater than or equal to six months after the end of treatment
                 HCV RNA negative at time of study enrollment
Study Enrollment Exclusion Criteria:
  • Participants who meet any of these criteria are not eligible for study enrollment:
           Transplant for liver disease secondary to autoimmune disease (e.g. autoimmune
           hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis)
           Matched at both human leukocyte antigen (HLA)-DR loci to the donor
           Organ, tissue or cell transplant prior to or after the primary solitary living
           donor liver transplant
           For subjects with hepatitis B, detectible hepatitis B virus (HBV) DNA
           History of malignancy within 5 years of enrollment. History of adequately
           treated in-situ cervical carcinoma and/or skin cancer (basal or squamous cell)
           will be permitted.
           Serologic evidence of human immunodeficiency 1 or 2 infection
           Epstein Barr Virus (EBV) seronegativity (EBV naïve) if living donor is EBV
           seropositive
           Cytomegalovirus (CMV) seronegativity (CMV naïve) if living donor is CMV
           seropositive
           Calculated Glomerular filtration rate (GFR) less than 50 mL/min/1.73m^2 at the
           time of enrollment
           An episode of Acute Rejection (AR) within one year of enrollment
           Systemic illness requiring or likely to require recurrent or chronic
           immunosuppression (IS) drug use
           Any chronic condition for which anti-coagulation cannot be safely interrupted
           for liver biopsy
           Positive pregnancy test
           Participation in any other studies that involved investigational drugs or
           regimens in the preceding year
           Any other condition, in the investigator's judgment, that increases the risk of
           darTregs infusion or prevents safe trial participation
           Unwilling or unable to adhere to study requirements and procedures
           Screening liver biopsy with any of the following histological criteria, as
           determined by the reading of a central pathologist.
darTregs Infusion Inclusion Criteria:
  • Subjects must meet all criteria below to receive darTregs infusion:
           Stable liver tests, defined as ALT and either alkaline phosphatase or GGT either
           within normal limits OR <\=1.5 X baseline
           No detectible circulating EBV or CMV DNA prior to Treg infusion, assessed at the
           time of PBMC collection for manufacture
           For subjects with hepatitis B virus (HBV), no detectible circulating HBV DNA,
           assessed at the time of PBMC collection for manufacture
           Able to understand and provide informed consent.
darTregs Infusion Exclusion Criteria:
Subjects who meet any of these criteria are not eligible for darTregs infusion:

     1. Diagnosis of AR after initiation of IS withdrawal
     2. Any vaccination given within 28 days prior to Treg collection for Treg production
     3. Receipt of a vaccination within 14 days prior to Treg infusion
     4. Unacceptable darTregs product
     5. Positive pregnancy test
     6. Clinical evidence of viral syndrome less than 7 days prior to darTregs infusion.
Inclusion Criteria for Resuming IS Withdrawal after darTregs Infusion:
Subjects are eligible to resume IS withdrawal after darTregs infusion if all criteria
below are met:

     1. Subject received at least 100 x 10^6 darTregs
     2. ALT and either alkaline phosphatase or GGT remain within normal limits or <\= 1.5 x
         baseline after darTregs infusion
     3. For subjects with elevated liver tests as defined above, local pathology reading of
         liver biopsy 6-10 days after darTregs infusion is without AR according to Banff
         criteria
     4. IS withdrawal resumes no later than 14 days after darTregs infusion
     5. Site principal investigator determines it is acceptable for the study subject to
         resume IS withdrawal.

Detailed Description

Doctors give drugs called immunosuppressants (IS) to people who receive a liver transplant.
IS must be taken every day to prevent the body from injuring the transplanted liver by a
process called rejection. Liver transplant recipients usually have to take these drugs for
the rest of their lives. These drugs have harmful side effects. Researchers are looking for
ways to keep a transplanted liver working normally with as little IS medications as
possible. Finding a way to lower and then stop these medications will allow the liver
recipient to avoid unwanted side effects.
Another area of research looks at how blood cells work to reject or accept an organ
transplant. Studies show that some of the recipient's own cells, called T regulatory cells
(Tregs), may play a part in accepting the transplanted liver and preventing rejection.
A recipient's Tregs can be grown in the laboratory to increase their number. Exposing the
recipient's Tregs to the liver donor's cells will stimulate the Tregs that recognize the
liver donor to grow vigorously. Giving these "donor reactive" Tregs back to the transplant
recipient through a vein (intravenously) might allow a liver transplant recipient to take
lower doses of IS, or perhaps to stop them altogether, without rejecting the liver.
The study team will collect information about the Treg infusion, liver tests and drug doses
during IS withdrawal, and any problems that may arise in the study. Blood, liver tissue, and
buccal (cheek) cells will be collected for research tests.

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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