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Liver Transplantation With Tregs at UCSF (LITTMUS-UCSF)

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ClinicalTrials.gov Identifier: NCT03654040
Recruitment Status : Recruiting
First Posted : August 31, 2018
Last Update Posted : April 27, 2021
Sponsor:
Collaborators:
Immune Tolerance Network (ITN)
PPD
Rho Federal Systems Division, Inc.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease Intervention/treatment Phase
Liver Transplant Biological: arTreg Procedure: leukapheresis Drug: cyclophosphamide Drug: mesna Drug: everolimus Phase 1 Phase 2

Detailed Description:

The researchers in this study plan to enroll 9 participants. Eligible participants will receive a single dose of Treg product (arTreg). The target dose is 90 to 500 x 10^6 total cells. However, if a minimum arTreg dose of 30 to < 90 x 10^6 cells is manufactured, the product will be infused in a maximum of 4 participants. Participants who receive at least the minimum arTreg dose referenced, 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.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 9 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Drug Withdrawal Study of Alloantigen-Specific Tregs in Liver Transplantation
Actual Study Start Date : April 22, 2021
Estimated Primary Completion Date : April 2025
Estimated Study Completion Date : March 2028

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: arTreg

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

Eligible participants will receive a single dose of Treg product (arTreg). The target dose is 90 to 500 x 10^6 total cells. However, if a minimum arTreg dose of 30 to < 90 x 10^6 total cells is manufactured, the product will be infused in 4 participants. If the dose obtained after product manufacture is < 30 x 10^6 cells, the product will not be infused. When the dose obtained after product manufacture is > 500 x 10^6 cells, a dose aliquot will be prepared so that the administered dose will be ≤ 500 x 10^6 cells, and ≥ 90 to 500 x 10^6 total cells.

Method of receipt: peripheral intravenous (IV) infusion, administered over 20 to 30 minutes.

Other Names:
  • donor alloantigen-reactive regulatory T cells
  • CD4+CD25+CD127[lo] Treg cells

Procedure: leukapheresis

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.

Other Name: apheresis

Drug: cyclophosphamide
40 mg/kg administered intravenously (IV) following leukapheresis and between 1 to 3 days prior to Treg product (arTreg) infusion.
Other Names:
  • Cytoxan®
  • CTX

Drug: mesna

Mesna is administered:

  • Intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide, and
  • In conjunction with the cyclophosphamide and based on the local standard of care.
Other Name: Mesnex®

Drug: everolimus
EVR, an immunosuppressant (IS), is approved for the prophylaxis of allograft rejection in adults receiving a liver transplant. Post transplantation,subject initially receives standard IS with tacrolimus (TAC),plus a mycophenolate product and/or steroids.Between day 30 and week 48 post-transplant, evaluation for eligibility to be converted to EVR-based IS regimen occurs. At start of conversion from TAC to EVR,EVR will be started at 1.5 mg taken orally BID,with dose adjustments to achieve optimal trough blood level.7-14 days after EVR is started, mycophenolic acid compound will be discontinued. Once optimal EVR trough level is achieved, TAC dose will be reduced to achieve trough level of 3-5 ng/mL.When target EVR and TAC levels are maintained over two consecutive measurements, and liver function tests, ALT and GGT, are ≤50 U/L, subject will be considered successfully converted to EVR-based IS regimen. EVR doses will be administered/monitored/adjusted over time, per protocol.
Other Names:
  • EVR
  • Afinitor®
  • Zortress®




Primary Outcome Measures :
  1. Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg [ Time Frame: From arTreg infusion through completion of study participation (Up to 4.5 years) ]
    • 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].

  2. Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna [ Time Frame: From ≤3 days prior to arTreg infusion through completion of study participation (Up to 4.5 years) ]
    • 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].

  3. Number of Operationally Tolerant Participants [ Time Frame: 52 (± 4 weeks) after the last dose of immunosuppression ]

    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.


Secondary Outcome Measures :
  1. Incidence of ≥Grade 3 Infections Following arTreg Infusion [ Time Frame: From arTreg infusion through completion of study participation (Up to 4.5 years) ]
    Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual [NCI-CTCAE version 5.0, published November 27, 2017].

  2. Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at any Time after Alloantigen-Reactive Tregs (arTreg) Infusion [ Time Frame: From arTreg infusion through completion of study participation (Up to 4.5 years) ]

    Definitions:

    • AR: Diagnosed in accordance with Banff global assessment criteria
    • Clinical Rejection: Participants who are treated empirically based on investigator clinical suspicion in cases where a biopsy is indeterminate or in rare cases, where a biopsy cannot be performed.

  3. Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at any Time after Alloantigen-Reactive Tregs (arTreg) Infusion [ Time Frame: From arTreg infusion through completion of study participation (Up to 4.5 years) ]

    Definitions:

    • AR: Diagnosed in accordance with Banff global assessment criteria
    • Clinical Rejection: Participants who are treated empirically based on investigator clinical suspicion in cases where a biopsy is indeterminate or in rare cases, where a biopsy cannot be performed.

    Intensity of AR and/or clinical rejection events will be graded.


  4. Number of Chronic Rejection Events at Any Time after Alloantigen-Reactive Tregs (arTreg) Infusion [ Time Frame: From arTreg infusion through completion of study participation (Up to 4.5 years) ]
    Diagnosed in accordance with Banff global assessment criteria.

  5. Number of Participants who Develop a Malignancy [ Time Frame: Day of transplant through completion of study participation (Up to 4.5 years) ]
    The number of participants that are diagnosed with malignancy, any type.

  6. Proportion of Participants who Successfully Discontinue Tacrolimus [ Time Frame: Post-transplant through Completion of Study Participation (Up to 4.5 years) ]

    Proportion of participants who, per protocol:

    • fulfill eligibility for tacrolimus withdrawal,
    • subsequently achieve their last dose of tacrolimus,
    • remain tacrolimus-free for ≥12 weeks,
    • their liver function tests, ALT and GGT, are ≤50 U/L,
    • and their liver biopsy performed between 12 to 26 weeks status post the last dose of tacrolimus fulfills biopsy findings* for minimization of immunosuppression.

      • Biopsy findings: Liver histology will be assessed by central pathology. Biopsy findings for minimization of immunosuppression, per protocol. Reference: Demetris AJ, Bellamy C, Hubscher SG, et al. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transplant 2016.

  7. Duration of Operational Tolerance [ Time Frame: Post-transplant through Completion of Study Participation (Up to 4.5 years) ]
    Durability of operational tolerance defined as the time from achieving the primary endpoint to immunosuppression (IS) reinitiation or to the end of trial participation.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Negative test for hepatitis C infection by hepatitis C virus (HCV) PCR RNA
    5. For candidates with a history of HCV, completed treatment for HCV, maintaining a sustained viral response of ≥24 weeks duration by the day of transplant
    6. Positive Epstein-Barr virus (EBV) antibody test and
    7. 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 participant's best interest.

      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 before or after the 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 remain eligible:

  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
    2. For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor
    3. Known contraindication to cyclophosphamide or mesna
    4. Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection
    5. 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
    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 condition that, in the opinion of the investigator, may interfere with study compliance
    9. 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
    10. 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

        • This includes past, present or future enrollment in studies that affect eligibility at the time of everolimus (EVR) conversion
    11. History of malignancy or any concomitant malignancy, except:

      • hepatocellular carcinoma,
      • completely treated in-situ cervical carcinoma, or
      • completely treated basal cell carcinoma.
    12. Chronic use of systemic glucocorticoids or other immunosuppressives, or biologic immunomodulators.

      Living Donor:

  • There are no exclusion criteria for living donors.

Deceased Donor:

-There are no exclusion criteria for deceased donors.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03654040


Locations
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United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Tyler Lunow-Luke    415-353-8465    Tyler.Lunow-Luke@ucsf.edu   
Principal Investigator: Sandy Feng, MD, PhD         
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
PPD
Rho Federal Systems Division, Inc.
Investigators
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Study Chair: Sandy Feng, MD, PhD University of California, San Francisco
Additional Information:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03654040    
Other Study ID Numbers: DAIT ITN074ST
UM1AI109565 ( U.S. NIH Grant/Contract )
NIAID CRMS ID#: 38481 ( Other Identifier: DAIT NIAID )
First Posted: August 31, 2018    Key Record Dates
Last Update Posted: April 27, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The plan is to share data upon completion of the study in ImmPort, a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
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.
URL: http://www.immport.org/immport-open/public/home/home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
alloantigen-reactive Tregs (arTreg)
immunosuppression
operational tolerance
Additional relevant MeSH terms:
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Cyclophosphamide
Everolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists