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

Information source: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Liver Transplantation

Intervention: Anti-Thymocyte Globulin - Rabbit (Biological); darTreg Infusion (Biological); Everolimus (Drug); Tacrolimus (Drug); Mycophenolate mofetil (Drug); Prednisone (Drug); Acetaminophen (Drug); Diphenhydramine (Drug); Anti-Infective Prophylaxis (Drug); Leukapheresis (Procedure); Blood draws (Procedure); Liver biopsies (Procedure); Liver transplantation (Procedure)

Phase: Phase 1

Status: Recruiting

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Sandy Feng, MD, PhD, Principal Investigator, Affiliation: University of California, San Francisco
Jeffrey Bluestone, PhD, Principal Investigator, Affiliation: University of California, San Francisco
Sang-Mo Kang, MD, FACS, Principal Investigator, Affiliation: University of California, San Francisco
Qizhi Tang, PhD, Principal Investigator, Affiliation: University of California, San Francisco

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

Clinical Details

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

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Incidence and severity of biopsy proven acute and/or chronic rejection

Incidence of Grade 3 or higher infections

Incidence of Grade 3 or higher wound complications

Incidence of anemia, neutropenia, and/or thrombocytopenia

Incidence of adverse events attributable to the darTreg infusion including infusion reaction / cytokine release syndrome, and malignant cellular transformation

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.

Eligibility

Minimum age: 21 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

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. Exclusion Criteria:

- Below are exclusion criteria to be assessed prior to Stage 1 study procedures.

Subjects who meet any of these criteria are not eligible for Stage 1 study procedures. Note that subjects in Cohort 1a or 1b will NOT undergo leukapheresis regardless of eligibility.

- End stage liver disease secondary to Hepatitis C Virus (HCV) or autoimmune

etiology (autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis)

- International Normalized Ratio (INR) > 2. 0

- History of previous organ, tissue or cell transplant

- Serologic evidence of human immunodeficiency (HIV) 1 or -2 infection

- Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) sero-negativity (EBV or CMV

naïve candidates)

- Chronic use of systemic glucocorticoids or other Immunosuppression (IS), or

biologic immunomodulators

- Chronic condition requiring anti-coagulation after liver transplantation

- Any chronic illness or prior treatment which, in the opinion of the

investigator, precludes study participation

- Participation in any other studies that involved investigational drugs or

regimens in the preceding year

- Hemoglobin <9. 0 g/dL within 10 days prior to screening

- Neutrophils <1,500/μL within 10 days prior to screening

- Platelets <60,000/μL within 10 days prior to screening

- Peripheral blood Tregs <30/μL at time of screening

- Urine protein/creatinine ratio >1. 0 at any time prior to screening.

- Treg-Supportive IS Exclusion Criteria B (Stage 2):

- Below are exclusion criteria to be assessed prior to administration of

Thymoglobulin®. Subjects who meet any of these criteria should not receive Thymoglobulin®:

- Calculated Model for End Stage Liver Disease (MELD) score >/= 25 at the

time of deceased donor liver transplant

- Last alpha-fetoprotein (AFP) obtained prior to liver transplantation >400

μg/L for candidates with Hepatocellular Carcinoma (HCC)

- Unacceptable leukapheresis product for participants enrolled in Cohorts 2,

3, or 4 (includes patients with detectible Hepatitis B Virus (HBV) DNA at time of leukapheresis)

- Absence of donor spleen or lymphoctyes for participants enrolled in Cohorts

2, 3, or 4

- Human leukocyte antigen (HLA)-DR matched to donor at both loci

- Subject is < 21 or >70 years of age at the time of transplantation

- Located in the intensive care unit 72 hours after transplantation

- Hemoglobin <9. 0 g/dL at time of first Thymoglobulin® dose administration

- Absolute neutrophil count <1,200/μL at time of first Thymoglobulin® dose

administration

- Platelets <50,000/μL at time of first Thymoglobulin® dose administration

- Positive pregnancy test for females of child bearing potential

- Unexpected histopathology on back table liver biopsy that contraindicates

the initiation of Treg supportive IS regimen.

- Development of a condition requiring chronic anti-coagulation.

- Below are exclusion criteria to be assessed prior to conversion to Everolimus

(EVR)-based IS regimen. Subjects who meet any of these criteria should not be converted to EVR-based IS regimen. EVR cannot be initiated prior to 30 days after liver transplantation:

- Explanted liver with evidence of increased risk of recurrent cancer risk

(hepatocellular (HCC) tumor burden exceeding the Milan criteria; presence of vascular invasion; cholangiocarcinoma morphology)

- Insufficient depletion of recipient T cells, defined as a nadir cluster of

differentiation 3 (CD3) count > 50/mm^3

- Alanine Aminotransferase (ALT) and alkaline phosphatase >2. 0 x upper limit

of normal within 7 days prior to conversion

- Evidence of hepatic artery stenosis or thrombosis by Doppler examination or

angiography within 7 days prior to conversion

- Inability to taper off corticosteroids completely prior to initiation of

Everolimus (EVR)

- Urine protein/creatinine ratio >1. 0 within 7 days prior to conversion

- Calculated Modification of Diet in Renal Disease (MDRD) glomerular

filtration rate <50 ml/min within 7 days prior to conversion

- Physical examination documentation of abnormal wound healing or

uncontrolled wound infection

- Clinical suspicion of biliary obstruction

- Hemoglobin <9 g/dL within 7 days prior to conversion

- Absolute neutrophil count <1,200/μL within 7 days prior to conversion

- Platelets <50,000/μL within 1 week of conversion

- Development of a condition requiring chronic anti-coagulation.

- Below are exclusion criteria to be assessed prior to darTreg infusion for

subjects in Cohorts 2, 3, and 4 only. Subjects in Cohort 2, 3, or 4 who meet any of these criteria should not receive a darTreg-infusion:

- Inability or unwillingness of participant to give additional written

informed consent

- Unacceptable darTreg product

- Detectible circulating Epstein-Barr Virus (EBV) or cytomegalovirus (CMV)

DNA within 10 days prior to darTreg infusion

- Detectible HBV DNA within 10 days prior to darTreg infusion

- Alanine Aminotransferase (ALT) and alkaline phosphatase >1. 5x upper limit

of normal within 10 days of darTreg infusion

- 12 hour tacrolimus trough levels of > 6 μg/L within 10 days prior to

darTreg infusion

- 24 hour Everolimus (EVR) trough levels of < 5 μg/L within 10 days prior to

darTreg infusion

- Received Mycophenolate Mofetil (MMF) within 10 days prior to darTreg

infusion

- Evidence of acute rejection or chronic rejection according to Banff

criteria on protocol allograft biopsy based on local assessment

- Positive pregnancy test for females of child bearing potential

- Inability or unwillingness of participant to comply with study protocol or

procedures.

Locations and Contacts

University of California, San Francisco, San Francisco, California 94143, United States; Recruiting
Sharon Blaschka, MSN, NP-C, Phone: 415-476-3229, Email: sharon.blaschka@ucsf.edu
Sandy Feng, MD, PhD, Principal Investigator

Mayo Clinic, Rochester, Minnesota 55905, United States; Not yet recruiting
Kristin Cornwell, Phone: 507-284-6814, Email: cornwell.kristin@mayo.edu
Timucin Taner, MD, PhD, Principal Investigator

Additional Information

National Institute of Allergy and Infectious Diseases (NIAID)

University of California San Francisco Donor-Alloantigen-Reactive Regulatory T Cell Therapy in Liver Transplantation Trial Site

Starting date: December 2014
Last updated: April 24, 2015

Page last updated: August 23, 2015

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