Liver Transplant
Conditions
Keywords
alloantigen-reactive Tregs (arTreg), immunosuppression, operational tolerance
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.
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 at least 90 to 500 x 10\^6 total cells. Participants who successfully withdraw from all immunosuppression (IS) will undergo a research biopsy at 52 weeks following IS 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 IS discontinuation. 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 IS 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.
Interventions
BIOLOGICALarTreg
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.
PROCEDUREleukapheresis
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.
DRUGcyclophosphamide
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.
DRUGmesna
Mesna is administered: * Intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide, and * In conjunction with the cyclophosphamide, per institutional practice with CTX.
DRUGeverolimus
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.
Sponsors
Immune Tolerance Network (ITN)
PPD Development, LP
Rho Federal Systems Division, Inc.
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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. 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 5. Positive Epstein-Barr virus (EBV) antibody test, and 6. 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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg | From arTreg infusion through completion of study participation | * 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 \[NCI-CTCAE version 5.0, published November 27, 2017\]. |
| Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna | From ≤3 days prior to arTreg infusion through completion of study participation (Up to 3 months) | * 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 \[NCI-CTCAE version 5.0, published November 27, 2017\]. |
| Number of Operationally Tolerant Participants | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | Intensity of AR and/or clinical rejection events will be graded. 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. |
| Number of Chronic Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion | From arTreg infusion through completion of study participation | Diagnosed in accordance with Banff global assessment criteria. |
| Number of Participants Who Develop a Malignancy | Time of enrollment through completion of study participation (Up to 1.8 years) | The number of participants that are diagnosed with malignancy, any type. |
| Duration of Operational Tolerance | Post-transplant through Completion of Study Participation | Durability of operational tolerance defined as the time from achieving the primary endpoint to immunosuppression (IS) reinitiation or to the end of trial participation. |
| Proportion of Participants Who Successfully Discontinue Tacrolimus | Post-transplant through Completion of Study Participation | 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. |
| Incidence of ≥Grade 3 Infections Following arTreg Infusion | From arTreg infusion through completion of study participation | Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual \[NCI-CTCAE version 5.0, published November 27, 2017\]. |
| 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 | 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. |
Countries
United States
Participant flow
Recruitment details
30 prospective transplant recipients and 12 living donors were enrolled from a single study center in the US between April 2021 and February 2023. The study was terminated by the sponsor in February 2023 prior to any participant receiving the investigational product, arTregs.
Pre-assignment details
Participants were enrolled prior to transplant & had to wait for an available liver which was received per the institution's standard of care. If recipient rec'd a liver from a living donor, the donor also enrolled into the study to collect biological samples to aid in the manufacturing of the investigation product, arTregs. Immunosuppression medication was required to be stabilized and converted from tacrolimus to everolimus prior to transplant recipient receiving the investigational product
Participants by arm
| Arm | Count |
|---|---|
| Enrolled, Transplant Recipient Did Not Receive arTregs These participants were consented and enrolled into the study but did not receive arTregs. | 30 |
| Enrolled Living Donor These participants were living donors of the prospective transplant recipient who consented and enrolled into the study. | 12 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Failure to initiate study therapy | 2 | 0 |
| Overall Study | Failure to meet eligibility criteria | 14 | 2 |
| Overall Study | Manufacturing unable to accept specimens | 1 | 0 |
| Overall Study | No longer transplant candidate | 1 | 0 |
| Overall Study | Received deceased liver | 0 | 1 |
| Overall Study | Recipient ineligible | 0 | 2 |
| Overall Study | Study terminated by sponsor | 8 | 2 |
| Overall Study | Transplanted at another center | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Enrolled Living Donor | Enrolled, Transplant Recipient Did Not Receive arTregs |
|---|---|---|---|
| Age, Continuous | 49.9 years STANDARD_DEVIATION 13.69 | 37.3 years STANDARD_DEVIATION 14.09 | 54.6 years STANDARD_DEVIATION 10.35 |
| Age, Customized Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Age, Categorical >=65 years | 4 Participants | 0 Participants | 4 Participants |
| Age, Customized Age, Categorical Between 18 and 65 years | 37 Participants | 11 Participants | 26 Participants |
| Age, Customized Age, Categorical Missing | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 8 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) White | 27 Participants | 9 Participants | 18 Participants |
| Region of Enrollment United States | 42 participants | 12 participants | 30 participants |
| Sex/Gender, Customized Female | 20 Participants | 6 Participants | 14 Participants |
| Sex/Gender, Customized Male | 23 Participants | 5 Participants | 18 Participants |
| Sex/Gender, Customized Unknown | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 30 | 0 / 12 |
| other Total, other adverse events | 3 / 30 | 0 / 12 |
| serious Total, serious adverse events | 3 / 30 | 0 / 12 |
Outcome results
Primary
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 \[NCI-CTCAE version 5.0, published November 27, 2017\].
Time frame: From ≤3 days prior to arTreg infusion through completion of study participation (Up to 3 months)
Population: These participants were consented and enrolled into the study and received at least part of the supportive regimen of leukapheresis, cyclophosphamide, or mesna.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Enrolled, Received arTregs | Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna | 0 Participants |
Primary
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 \[NCI-CTCAE version 5.0, published November 27, 2017\].
Time frame: From arTreg infusion through completion of study participation
Population: Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.
Primary
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.
Time frame: 52 (± 4 weeks) after the last dose of immunosuppression
Population: Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe
Secondary
Duration of Operational Tolerance
Durability of operational tolerance defined as the time from achieving the primary endpoint to immunosuppression (IS) reinitiation or to the end of trial participation.
Time frame: Post-transplant through Completion of Study Participation
Population: Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.
Secondary
Incidence of ≥Grade 3 Infections Following arTreg Infusion
Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual \[NCI-CTCAE version 5.0, published November 27, 2017\].
Time frame: From arTreg infusion through completion of study participation
Population: Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.
Secondary
Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
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.
Time frame: From arTreg infusion through completion of study participation
Population: Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.
Secondary
Number of Chronic Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
Diagnosed in accordance with Banff global assessment criteria.
Time frame: From arTreg infusion through completion of study participation
Population: Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.
Secondary
Number of Participants Who Develop a Malignancy
The number of participants that are diagnosed with malignancy, any type.
Time frame: Time of enrollment through completion of study participation (Up to 1.8 years)
Population: Participants who enrolled, but did not receive arTregs
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enrolled, Received arTregs | Number of Participants Who Develop a Malignancy | 1 participants |
Secondary
Proportion of Participants Who Successfully Discontinue Tacrolimus
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.
Time frame: Post-transplant through Completion of Study Participation
Population: Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.
Secondary
Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
Intensity of AR and/or clinical rejection events will be graded. 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.
Time frame: From arTreg infusion through completion of study participation
Population: Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.