Liver Transplantation With Tregs at UCSF

NCT03654040 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: DAIT ITN074STUM1AI109565NIAID CRMS ID#: 38481
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

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.

Conditions

Liver Transplant

Keywords

alloantigen-reactive Tregs (arTreg); immunosuppression; operational tolerance

Outcome Measures

Primary Outcomes (3)

• Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg

  * AEs will be attributed to alloantigen-reactive Tregs (arTreg) when the AE is reported with possible or related attribution to arTreg. * Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual \[NCI-CTCAE version 5.0, published November 27, 2017\].

  From arTreg infusion through completion of study participation

• Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna

  * AEs will be attributed to the supportive regimen for this study when the AE is reported with possible or related attribution to leukapheresis, cyclophosphamide, or mesna. * Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual \[NCI-CTCAE version 5.0, published November 27, 2017\].

  From ≤3 days prior to arTreg infusion through completion of study participation (Up to 3 months)

• Number of Operationally Tolerant Participants

  Operational tolerance is defined as: * Discontinuation of all immunosuppression (IS) for 52 weeks, * Alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) ≤ 50 U/L for ≥ 2 measurements separated by ≥1 week in the 6 weeks prior to the liver biopsy at 52 weeks after the last IS dose, and * Liver biopsy at 52 weeks (±4 weeks) after the last IS dose that meets the biopsy criteria for operational tolerance, as assessed by central pathology.

  52 (± 4 weeks) after the last dose of immunosuppression

Secondary Outcomes (7)

• Number of Participants Who Develop a Malignancy

  Time of enrollment through completion of study participation (Up to 1.8 years)

• Incidence of ≥Grade 3 Infections Following arTreg Infusion

  From arTreg infusion through completion of study participation

• Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion

  From arTreg infusion through completion of study participation

• Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion

  From arTreg infusion through completion of study participation

• Number of Chronic Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion

  From arTreg infusion through completion of study participation

Study Arms (1)

arTreg

EXPERIMENTAL

arTreg: alloantigen-reactive T regulatory cells The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, leukapheresis, cyclophosphamide, and mesna. Note: Participants who receive at least the minimum Treg product (arTreg) dose of 30 to \<90 x10\^6 total cells will be included in intent-to-treat analysis.

Biological: arTreg; Procedure: leukapheresis; Drug: cyclophosphamide; Drug: mesna; Drug: everolimus

Interventions

arTreg BIOLOGICAL

Eligible participants will receive a single dose of Treg product (arTreg). The target dose is at least 90 x 10\^6 total cells. Method of receipt: peripheral intravenous (IV) infusion, administered over 20 to 30 minutes.

Also known as: donor alloantigen-reactive regulatory T cells, CD4+CD25+CD127[lo] Treg cells

arTreg

leukapheresis PROCEDURE

Leukapheresis will be the method employed to recover peripheral blood mononuclear cells (PBMCs) from the allograft recipient. The recipient will undergo the procedure prior to initiating the cyclophosphamide conditioning regimen. Procedure on Day -3 (-1 day) prior to Treg product (arTreg) IV infusion.

Also known as: apheresis

arTreg

cyclophosphamide DRUG

40 mg/kg administered intravenously (IV) following leukapheresis and between 1 to 3 days prior to Treg product (arTreg) infusion, per institutional standard of care.

Also known as: Cytoxan®, CTX

arTreg

mesna DRUG

Mesna is administered: * Intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide, and * In conjunction with the cyclophosphamide, per institutional practice with CTX.

Also known as: Mesnex®

arTreg

everolimus DRUG

EVR is approved for prophylaxis of allograft rejection in adults receiving a liver transplant. Per protocol: Post transplantation, subject will initially receive standard IS with tacrolimus (TAC),plus a mycophenolate product and/or steroids.Subsequently, evaluation for eligibility to be converted to EVR-based IS regimen will occur and, when applicable, proceed. Once the optimal EVR trough level is achieved,TAC dose will be reduced. When target EVR and TAC levels are maintained over two consecutive measurements, ALT liver function test (LFT) is ≤50 U/L, GGT LFT is ≤ the upper limit of normal or ≤ 1.5 times the baseline GGT, subject will be considered successfully converted to EVR-based IS regimen. EVR doses will be administered/monitored/adjusted over time.

Also known as: EVR, Afinitor®, Zortress®

arTreg

Eligibility Criteria

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

You may qualify if:

• Eligibility:
• Recipient:
• Individuals must meet all of the following criteria to be eligible for this study:
• Able to understand and provide informed consent
• End-stage liver disease and listed for a living or deceased-donor primary solitary liver transplant
• Agreement to use contraception
• 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
• Positive Epstein-Barr virus (EBV) antibody test, and
• 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:
• Able to understand and provide informed consent
• Meets site-specific clinical donor eligibility requirements
• Meets donor eligibility manufacturing requirements within 7 days before or after the blood collection for manufacturing, and
• Willingness to donate appropriate biologic samples.

You may not qualify if:

• Recipient:
• Individuals who meet any of the following criteria will not be eligible for this study:
• History of previous organ, tissue or cell transplant
• For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor
• Known contraindication to cyclophosphamide or mesna
• Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection
• 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
• End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis) or other contraindications to drug withdrawal
• Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule
• Any condition that, in the opinion of the investigator, may interfere with study compliance
• 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
• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator
• PPD Development, LP: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Immune Tolerance Network web site

MeSH Terms

Interventions

Leukapheresis; Blood Component Removal; Cyclophosphamide; Mesna; Everolimus

Intervention Hierarchy (Ancestors)

Cytapheresis; Biological Therapy; Therapeutics; Leukocyte Reduction Procedures; Cell Separation; Cytological Techniques; Clinical Laboratory Techniques; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Sirolimus; Macrolides; Lactones

Limitations and Caveats

The study was terminated by the sponsor in February 2023 prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.

Results Point of Contact

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

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Sandy Feng, MD, PhD

  University of California, 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: August 28, 2018
• First Posted: August 31, 2018
• Study Start: April 22, 2021
• Primary Completion: March 6, 2023
• Study Completion: March 6, 2023
• Last Updated: April 23, 2024
• Results First Posted: April 23, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: The aim is to share data available to the public within 24 months upon completion of the study.
• Access Criteria: ImmPort public data access.

Locations

US (1)