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

NCT02474199 | Completed Phase 1 Results DMC

• 1 other identifier: DAIT CTOTC-12
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 3

Brief Summary

This research study is for liver transplant recipients and their respective living donors. The purpose of this study is:

1. 1.To see if it is safe for liver recipients to receive one dose of donor reactive T regulatory cells (Tregs)
2. 2.To see if the Tregs allows a liver recipient to take less, or completely stop medications normally taken after receiving an organ transplant.

Conditions

Liver Transplant Recipient; Living Donor (of the Respective Liver Transplant Recipient)

Keywords

Regulatory T Cells ( Treg); Donor Alloantigen Reactive Tregs (darTregs); Liver Transplant; Alloantigen Reactive Tregs; Calcineurin Inhibitors (CNI); immunosuppressants (IS)

Outcome Measures

Primary Outcomes (4)

• Number of Participants Who Experienced Grade 3 or Higher Adverse Events (AEs) Deemed Attributable to darTreg Infusion

  The National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was used to grade the severity of all AEs. A participant was considered to have met this endpoint if they experienced at least one CTCAE Grade 3 or higher AE deemed attributable (i.e., considered at least possibly related) to darTreg infusion (infusion reaction, cytokine release syndrome).

  From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

• Number of Participants With Study Defined Grade 3 or Higher Infections

  The following grading system was applied to AEs of infection: * Grade 1: asymptomatic; clinical or diagnostic observation only; intervention with oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required * Grade 2: symptomatic; intervention with intravenous antibiotic, antifungal, or antiviral agent; invasive intervention may be required * Grade 3: any infection associated with hemodynamic compromise requiring pressors; any infection necessitating intensive care unit level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection * Grade 4: life-threatening infection * Grade 5: death resulting from infection A participant was considered to have met this endpoint if they experienced at least one Grade 3 or higher infection.

  From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

• Number of Participants With Any Malignancy

  Number of participants with any malignancy, including Post -Transplant Lymphoproliferative Disorder (PTLD). PTLD is a specific type of malignancy that can occur following transplantation of a solid organ and is characterized by a proliferation of B cells, which may result in lymphoma.

  From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

• Proportion of Liver Transplant Recipients Who Are Able to Reduce Calcineurin Inhibitor Dosing by 75 Percent and Discontinue a Second Immunosuppression Drug (if Applicable) With Stable Liver Function Tests (LFTs) for ≥ 12 Weeks

  The ability to reduce baseline, standard of care calcineurin inhibitor dosing following transplantation was measured by determining the number of subjects who were able to tolerate a 75 percent reduction in their calcineurin inhibitors along with discontinuation of either prednisone or mycophenolate mofetil following initiation of immunosuppression withdrawal.

  From initiation of immunosuppression withdrawal to 24 weeks after darTregs infusion

Secondary Outcomes (4)

• Number of Liver Transplant Recipients Who Experience the Composite Outcome

  From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion

• Number of Participants Who Experience at Least One Episode of Biopsy Proven Acute Rejection, Clinical Acute Rejection, or Chronic Rejection

  From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion

• Count of Participants by Severity of Biopsy Proven Acute Rejection and/or Chronic Rejection

  From initiation of immunosuppression withdrawal to 52 weeks after darTregs infusion

• Number of Participants Achieving Efficacy Status Post Receipt of a Single Intravenous (IV) Dose of Donor Alloantigen Reactive Regulatory T Cells (darTregs)

  From initiation of immunosuppression withdrawal to 52 weeks after darTreg infusion

Study Arms (1)

darTregs

EXPERIMENTAL

Donor Alloantigen Reactive Tregs (darTregs). Participants will receive a target dose of 400X10\^6 darTregs (range 300-500 x10\^6) infused intravenously (IV) over an approximate 20-30 minute interval

Biological: darTregs; Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Immunosuppression (IS) Withdrawal; Procedure: Study Mandated Procedures

Interventions

darTregs BIOLOGICAL

A single intravenous infusion as described administered over a 20-30 minute interval with close monitoring prior to, during, and after the infusion.

Also known as: Donor Alloantigen Reactive Tregs

darTregs

Acetaminophen DRUG

Pre-medication for darTregs infusion. A dose of 15 mg/kg will be administered 30 to 60 minutes prior to the darTregs infusion.

darTregs

Diphenhydramine DRUG

Pre-medication for darTregs infusion. A dose of 1-2 mg/kg diphenhydramine will be administered 30 to 60 minutes prior to the darTregs infusion.

Also known as: Diphenhydramine Hydrochloride

darTregs

Immunosuppression (IS) Withdrawal DRUG

Subjects:1.) who fulfill study eligibility criteria will withdraw IS 2.) enter the study on calcineurin inhibitor (CNI) monotherapy or a CNI-based regimen with either Prednisone or MMF as a second IS medication 3.) will proceed with changes in CNI dosing according to the protocol's CNI withdrawal algorithm.During the last 2 weeks of IS withdrawal (e.g., Step 2 in algorithm -CNI reduced 25%-"pre darTregs"), a single dose of darTregs will be infused IV. The subject will then, if eligible, proceed with IS withdrawal within 2 weeks after the infusion. Eligible subjects meeting the primary endpoint of 75% reduction in CNI from baseline after darTregs will be offered the opportunity to continue IS withdrawal until complete discontinuation of IS.

Also known as: IS Withdrawal, CNI based IS regimen

darTregs

Study Mandated Procedures PROCEDURE

Blood draws (venipuncture); collection of peripheral blood mononuclear cells (PBMCs) by a procedure known as leukapheresis or venipuncture; buccal (cheek) swab for HLA typing; liver biopsies (per protocol and for cause).

darTregs

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Clinical Trials in Organ Transplantation in Children: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (3)

University of California at San Francisco

San Francisco, California, 94143, United States

Location

Northwestern University Comprehensive Transplant Ctr

Chicago, Illinois, 60611, United States

Location

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

Related Publications (2)

• Tang Q, Leung J, Peng Y, Sanchez-Fueyo A, Lozano JJ, Lam A, Lee K, Greenland JR, Hellerstein M, Fitch M, Li KW, Esensten JH, Putnam AL, Lares A, Nguyen V, Liu W, Bridges ND, Odim J, Demetris AJ, Levitsky J, Taner T, Feng S. Selective decrease of donor-reactive Tregs after liver transplantation limits Treg therapy for promoting allograft tolerance in humans. Sci Transl Med. 2022 Nov 2;14(669):eabo2628. doi: 10.1126/scitranslmed.abo2628. Epub 2022 Nov 2.

  PMID: 36322627 DERIVED

• Wood-Trageser MA, Lesniak D, Gambella A, Golnoski K, Feng S, Bucuvalas J, Sanchez-Fueyo A, Demetris AJ. Next-generation pathology detection of T cell-antigen-presenting cell immune synapses in human liver allografts. Hepatology. 2023 Feb 1;77(2):355-366. doi: 10.1002/hep.32666. Epub 2022 Aug 1.

  PMID: 35819312 DERIVED

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Clinical Trials in Organ Transplantation in Children (CTOT-C)

MeSH Terms

Interventions

Acetaminophen; Diphenhydramine; Immunosuppression Therapy

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Ethylamines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Sandy Feng

  University of California at San Francisco

  PRINCIPAL INVESTIGATOR

• Jeffrey Bluestone, PhD

  University of California at San Francisco

  STUDY CHAIR

• Qizhi Tang, PhD

  University of California at San Francisco

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2015
• First Posted: June 17, 2015
• Study Start: June 6, 2016
• Primary Completion: December 16, 2019
• Study Completion: December 16, 2019
• Last Updated: February 9, 2021
• Results First Posted: February 9, 2021

Record last verified: 2021-01

Locations

US (3)