Donor-Alloantigen-Reactive Regulatory T Cell (darTregs) in Liver Transplantation

Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Liver Transplantation (RTB-002)

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02188719

Acronym

deLTa

Enrollment

Registered

2014-07-14

Start date

2014-12-17

Completion date

2019-06-18

Last updated

2020-09-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Liver Transplantation

Keywords

Donor-Alloantigen-Reactive Regulatory T Cell Therapy, Tregs, Cell- and Tissue-Based Therapy, Immunotherapy, Adoptive, Liver Transplantation

Brief summary

The purpose of this study is look at the safety of: * Taking a specific combination of immunosuppressant drugs after liver transplantation * Receiving one of three different doses of donor-alloantigen-reactive regulatory T cells (darTregs) while taking this specific combination of drugs

Detailed description

After liver transplantation, immunosuppressants must be taken every day to prevent the body from injuring the transplanted liver by a process called rejection. People who take these drugs may experience side effects. Studies show that some of body's cells, called T regulatory cells (Tregs), may play a part in accepting the transplanted liver. The investigators are learning about whether scientists can take Tregs from the blood of a liver transplant recipient and teach them to protect the transplanted liver from rejection. In the laboratory, the recipient Tregs are exposed to cells from the liver donor. Research data suggests that giving these donor reactive Tregs back to the transplant recipient might allow a liver transplant recipient to take lower doses of immunosuppressants, or perhaps to stop them altogether, without rejecting the liver.

Interventions

BIOLOGICALAnti-Thymocyte Globulin - Rabbit

Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects will be given a dose range of 3.0-4.5 mg/kg total, in divided doses of 1.5 mg/kg/day. Subjects who meet eligibility criteria for Thymoglobulin® administration will be given 1.5 mg/kg intravenously (IV) on post-operative day 3, within 72 hours of transplantation. Additional doses of 1.5 mg/kg IV will be administered until CD3 count is \<50/mm\^3 or when the maximal dose of 4.5/mg/kg has been given.

BIOLOGICALdarTreg Infusion

A single dose darTreg infusion (Cohorts 2 - 4) will be received as per protocol.

DRUGEverolimus

Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects meeting eligibility criteria for Treg-supportive IS regimen will begin EVR no sooner than 30 days after liver transplantation and no later than 44 days after transplantation; with target trough levels of 6-8 μg/L.EVR target trough levels will be further reduced to 4-6 μg/L 24 - 26 weeks after transplantation.

DRUGTacrolimus

Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Between 30 and 44 days following transplant: Subjects who are not eliminated by Exclusion Criteria C1 (Protocol Section 14.3.1) will proceed in the study and receive either TAC-based or EVR- based IS, based on eligibility Criteria C2 (Section 4.3.4 ) * TAC-based IS: reduce TAC trough level to 3-8 μg/dL; continue MMF * EVR-based IS: reduce TAC trough level to 3-8 μg/dL; EVR target trough level of 6-8 μg/dL; decrease then discontinue MMF

DRUGMycophenolate mofetil

Liver transplantation/Treg-supportive immunosuppression (IS) treatment. 1000 mg total daily dose. MMF will be initiated within 24 hours of transplantation. MMF must be discontinued as soon as target EVR trough levels have been achieved.

DRUGPrednisone

Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Solumedrol 500 mg will be given IV on the day of transplantation. Additional Solumedrol will be prescribed according to site-specific standard of care. Oral prednisone should be initiated once oral medication is tolerated.

DRUGAcetaminophen

Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 650mg of acetaminophen will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.

DRUGDiphenhydramine

Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 25-50mg of diphenhydramine will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.

DRUGAnti-Infective Prophylaxis

Intravenous ganciclovir and/or oral Valcyte will be administered for the prophylaxis of cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) for at least six months after liver transplantation.

PROCEDURELeukapheresis

Leukapheresis is necessary to ensure collection of adequate numbers of autologous Tregs to support ex vivo expansion of darTregs for infusion after liver transplantation. Participants enrolled in Cohorts 3 and 4 will undergo leukapheresis. Participants enrolled in Cohort 2 will have either whole blood collection or leukapheresis for the purpose of isolating autologous Tregs for later manufacture. If a cohort 2 subject has a hemoglobin level \>/=10.5 gm/dL, he or she will undergo phlebotomy. If the patient has a hemoglobin level \</=10.5 gm/dL and remains eligible for the study, the patient will undergo leukapheresis.

PROCEDUREBlood draws

Blood draws are necessary to carefully and frequently evaluate allograft function after liver transplantation and treatment with Treg-supportive IS as well as after darTreg infusion. Peripheral blood samples will be collected and analyzed per protocol throughout subject participation in this study.

PROCEDURELiver biopsies

Subjects will have a liver biopsy for this study 12-14 weeks after transplantation. For subjects receiving darTregs, a second biopsy will be performed 7-10 days after darTregs infusion.

PROCEDURELiver transplantation

Inclusion in this trial is in the setting of subjects defined as having end-stage liver disease and listed for primary solitary liver transplant.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

21 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Subjects who meet all of the following criteria are eligible for enrollment as study participants: * Able to understand and provide informed consent * End-stage liver disease and listed for primary solitary liver transplant * Have a calculated Model for End Stage Liver Disease (MELD) score ≤ 25 at the time of study entry/consent * Female and male subjects with reproductive potential must agree to use effective methods of birth control for the duration of the study. * If history of Hepatitis C Virus (HCV), have completed or are in current treatment for HCV AND have no detectable HCV RNA. * Subjects with HCC meeting Milan criteria.

Exclusion criteria

* Below are

Design outcomes

Primary

Measure	Time frame	Description
Percent of Participants With Biopsy-Proven Acute and/or Chronic Rejection	Transplantation to 40 Weeks Post Transplantation	Biopsy-proven acute rejection graded as Mild, Moderate or Severe, per 1997 Banff classification. Chronic Rejection graded using Banff 2000 classification. References: 1.) Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document developed by an international panel of experts in liver transplantation pathology, hepatology, and surgery (Hepatology 1997; 25(3): 658-663). 2.) Update of the International Banff Schema for Liver Allograft Rejection: Working Recommendations for the Histopathologic Staging and Reporting of Chronic Rejection (Hepatology 2000; 31(3): 792-799).
Percent of Participants With Grade 3 or Higher Infectious Adverse Event(s)	Transplantation to 40 Weeks Post Transplantation	The severity of infectious adverse events (AEs) was classified into grades as follows: * 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
Percent of Participants With Grade 3 or Higher Wound Complication(s) Adverse Event(s)	Transplantation to 40 Weeks Post Transplantation	The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009): * Grade 3 wound complications are defined as Hernia without evidence of strangulation; fascial disruption/dehiscence; primary wound closure or revision by operative intervention indicated * Grade 4 complications are defined as Hernia with evidence of strangulation; major reconstruction flap, grafting, resection, or amputation indicated
Percent of Participants With Grade 2 or Higher Hematologic Adverse Events (AEs) of Anemia, Neutropenia, and/or Thrombocytopenia	Transplantation to 40 Weeks Post Transplantation	The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009): * Grade 1 = mild AE * Grade 2 = moderate AE * Grade 3 = severe and undesirable AE * Grade 4 = life-threatening or disabling AE * Grade 5 = death
Percent of Participants With Adverse Events (AEs) Attributable to the Donor Alloantigen Reactive Tregs (darTregs) Infusion	Transplantation to 40 Weeks Post Transplantation	AEs classified by the site investigator/clinician as possibly or definitely related to the study treatment, the Donor Alloantigen Reactive Tregs (darTregs) infusion. These AEs include: * infusion reaction * Grade 3 or higher cytokine release syndrome (Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009) grading criteria * malignant cellular transformation.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Cohort 1 Participants received Thymoglobulin®+EVR IS but will not receive darTregs	6
Cohort 2 Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.	9
Cohort 3 Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 200 million(range 100 to 240 million) cells. No participants were enrolled in this cohort.	0
Cohort 4 Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 800 million(range 400 to 960 million) cells. No participants were enrolled in this cohort.	0
Total	15

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Screen B Ineligible (Page 55, Protocol)	0	1	0	0

Baseline characteristics

Characteristic	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	3 Participants	0 Participants	0 Participants	4 Participants
Age, Categorical Between 18 and 65 years	5 Participants	6 Participants	0 Participants	0 Participants	11 Participants
Age, Continuous	59 years STANDARD_DEVIATION 5.5	62 years STANDARD_DEVIATION 4.2	—	—	61 years STANDARD_DEVIATION 4.8
Alanine Aminotransferase (ALT)	47.0 U/L STANDARD_DEVIATION 66.6	216.4 U/L STANDARD_DEVIATION 543.4	—	—	148.7 U/L STANDARD_DEVIATION 421.5
Alkaline Phosphatase	64.0 U/L STANDARD_DEVIATION 17.3	102.8 U/L STANDARD_DEVIATION 44.4	—	—	87.3 U/L STANDARD_DEVIATION 40.2
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	1 Participants	—	—	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants	8 Participants	—	—	13 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	—	—	0 Participants
Gamma-Glutamyl Transferase (GGT)	40.0 U/L STANDARD_DEVIATION 11.3	115.8 U/L STANDARD_DEVIATION 97	—	—	100.6 U/L STANDARD_DEVIATION 91.4
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	—	—	0 Participants
Race (NIH/OMB) Asian	1 Participants	5 Participants	—	—	6 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	—	—	0 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	0 Participants	0 Participants	—	—	0 Participants
Race (NIH/OMB) White	5 Participants	4 Participants	—	—	9 Participants
Region of Enrollment United States	6 Count of Participants	9 Count of Participants	—	—	15 Count of Participants
Sex: Female, Male Female	2 Participants	0 Participants	—	—	2 Participants
Sex: Female, Male Male	4 Participants	9 Participants	—	—	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 9
other Total, other adverse events	6 / 6	6 / 9
serious Total, serious adverse events	4 / 6	4 / 9

Outcome results

Primary

Percent of Participants With Adverse Events (AEs) Attributable to the Donor Alloantigen Reactive Tregs (darTregs) Infusion

AEs classified by the site investigator/clinician as possibly or definitely related to the study treatment, the Donor Alloantigen Reactive Tregs (darTregs) infusion. These AEs include: * infusion reaction * Grade 3 or higher cytokine release syndrome (Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009) grading criteria * malignant cellular transformation.