EVR and EPO for Liver Transplant Tolerance

Official title

Everolimus and Epoetin for Sustained Liver Transplant Tolerance (EVEREST)(ITN101ST)

Overview

This is an open label, single-arm, multicenter phase 1b study of stable adult liver transplant recipients on a tacrolimus (TAC)-based immunosuppression (IS) regimen who will transition from TAC to Everolimus (EVR), receive five doses of EPO and concurrently initiate phased withdrawal from EVR. The primary objective is to test the safety of administering Everolimus (EVR) and epoetin alfa (EPO) to induce operational tolerance in stable adult liver transplant recipients

Interventions

• Drug Everolimus
  The starting dose of EVR will be based on the maintenance TAC dose of the subject at study entry: 1. EVR 1 mg PO BID if TAC dose is \<=2 mg BID 2. EVR 2 mg PO BID if TAC dose is 2.5-7 mg BID 3. EVR 3 mg PO BID if TAC dose is \>7 mg BID The dosage will be adjusted as needed to achieve and maintain EVR trough concentration of 5-8 ng/mL.
• Drug Epoetin alfa
  The dose used in this study is 10,000 units SC every 8 weeks (at study weeks 16, 24, 32, 40 and 48) for five doses

Primary outcome measures

• The proportion of subjects free of opportunistic infection attributed to the investigational study regimen [Time frame: At 52 weeks post-immunosuppression withdrawal (ISW)]
• The proportion of subjects free of malignancy attributed to the investigational study regimen [Time frame: At 52 weeks post-immunosuppression withdrawal (ISW)]
• The proportion of subjects free of serious adverse events (SAEs) attributed to the investigational study regimen [Time frame: At 52 weeks post-immunosuppression withdrawal (ISW)]

Secondary outcome measures (12)

• Incidence of acute rejection [Time frame: From baseline to 156 weeks post-ISW completion]
• Severity of acute rejection [Time frame: From baseline to 156 weeks post-ISW completion]
• Timing of acute rejection [Time frame: From baseline to 156 weeks post-ISW completion]
• Incidence of chronic rejection [Time frame: From baseline to 156 weeks post-ISW completion]
• Severity of chronic rejection [Time frame: From baseline to 156 weeks post-ISW completion]
• Timing of chronic rejection [Time frame: From baseline to 156 weeks post-ISW completion]
• Incidence of de novo class II donor specific antibody (DSA) [Time frame: From baseline to 156 weeks post-ISW completion]
• Incidence of graft loss [Time frame: From baseline to 156 weeks post-ISW completion]
• Incidence of all-cause mortality [Time frame: From baseline to 156 weeks post-ISW completion]
• Incidence of study-related Serious Adverse Event (SAE)s [Time frame: From baseline to 156 weeks post-ISW completion]
• Incidence of opportunistic infections [Time frame: From baseline to 156 weeks post-ISW completion]
• Incidence of malignancy [Time frame: From baseline to 156 weeks post-ISW completion]

Eligibility criteria

Inclusion criteria

• Subject must be able to understand and provide informed consent
• 1-10 years post-liver transplant
• Tacrolimus-containing maintenance immunosuppression (IS) regimen without corticosteroid. Mycophenolate mofetil (MMF) dose must be <=2000 mg daily or mycophenolic acid (MPA) dose<=1440 mg daily (if on MMF or MPA). Tacrolimus level must be <8 ng/ml on the 2 most recent laboratory results within 3 months.
• Gamma glutamyl transferase (GGT) and alanine transaminase (ALT) <= upper limit of normal (ULN)
• Estimated glomerular filtration rate (GFR) >=40 mL/min/1.73 m\^2 using the CKD-EPI 2021 equation
• Female subjects of reproductive potential must have a negative pregnancy test upon study entry
• Female subjects with reproductive potential, must agree to use Food and Drug Administration (FDA)-approved methods of birth control for the duration of the study
• Subjects must have current vaccinations or documented immunity as per the Division of Allergy, Immunology, and Transplantation (DAIT) vaccine guidance for subjects in transplant trials
• Negative result of most recent tuberculosis (TB) testing or appropriately completed latent tuberculosis infection (LTBI) therapy. Testing should be conducted using either a purified protein derivative (PPD) or interferon-gamma release assay (i.e., QuantiFERON-TB, T-SPOT.TB). Results from tests performed within 12 months prior to study entry are acceptable in the absence of any intervening exposure to TB. Subjects with a positive test for LTBI must complete appropriate therapy for LTBI. LTBI treatment regimens should be among those endorsed by the Centers for Disease Control and Prevention (CDC)
• Negative FDA-approved test for human immunodeficiency virus (HIV) diagnosis at screening or as documented in medical record, up to 12 months prior to screening)
• Negative hepatitis C antibody test at screening or as documented in medical record, up to 12 months prior to screening, in subjects without a history of hepatitis C. If there is a history of treated hepatitis C, then documentation of two consecutive negative hepatitis C virus (HCV) quantitative RNA polymerase chain reaction (PCR) tests separated by at least 3 months is required. Untreated subjects with positive HCV antibody and a single negative quantitative HCV RNA are eligible. Historical negative HCV RNA results are acceptable in the above two cases with positive HCV antibody
• Negative hepatitis B surface antigen and negative hepatitis B core antibody in subjects without a history of hepatitis B virus (HBV) infection, up to 12 months prior to screening. Those with known hepatitis B infection or positive hepatitis B surface antigen or positive hepatitis B core antibody must be on antiviral therapy and have negative HBV DNA quantitative PCR at screening

Exclusion criteria

• Inability of a subject to comply with study protocol
• Any medical condition requiring chronic systemic corticosteroid, e.g., severe reactive airways disease. Use of inhaled steroids is not an exclusion
• Autoimmune cause of liver disease (including autoimmune hepatitis (AIH), primary sclerosing cholangitis, primary biliary cirrhosis)
• Diagnosis of rejection within 52 weeks prior to screening
• Donor human leukocyte antigen (HLA) typing unavailable or inadequate for assigning donor-specific antibody (DSA)
• Need for uninterrupted anticoagulation
• Known active current or history of invasive fungal infection, or mycobacterial infection within 1 year prior to screening
• Human immunodeficiency virus (HIV)-positive
• Serious uncontrolled concomitant major organ disease
• Recipient of non-liver solid organ or bone marrow transplant
• Any infection requiring hospitalization and IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks
• Malignancy within the last 5 years except treated basal and squamous cell cancer of the skin or treated in situ cervical cancer. History of hepatocellular carcinoma in the explanted liver is acceptable provided that

• the last alpha fetoprotein obtained within 3 months prior to liver transplantation was < 400 microg/L, and
• the recipients' explanted liver did not have evidence of increased risk of recurrent cancer, i.e., explant was within the Milan criteria, with no vascular invasion, and with no cholangiocarcinoma morphology
• Neutropenia (absolute neutrophil count or ANC <1000 microliter) within 4 weeks prior to study enrollment
• History of hypersensitivity to Epoetin (EPO) or mammalian Target of Rapamycin inhibitor (mTOR-I)
• History of angioedema
• History of hereditary disorders of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. History of lactose intolerance is not an exclusion
• History of genetic disorders predisposing to thrombosis including but not limited to Factor V Leiden mutation, prothrombin 20210, protein C deficiency, protein S deficiency, antithrombin III deficiency
• History of venous or arterial thrombosis or thromboembolism, acute MI, or thrombotic stroke except for a history of isolated portal vein thrombosis in the setting of hepatic cirrhosis
• History of Budd Chiari syndrome
• Hemoglobin > 13.5 g/dl
• Plasma fibrinogen or D-dimer level > ULN
• Planned major surgery within the next 12 months
• Uncontrolled severe hypertension
• Uncontrolled clinically significant cardiac arrhythmia
• Proteinuria with urine protein/creatinine >0.5 g/g
• Severe hyperlipidemia with total cholesterol >350 mg/dl or triglycerides >1000 mg/dl
• Current alcohol, drug, or chemical dependency
• Currently pregnant or nursing
• Current treatment with an estrogen-containing oral contraceptive, or systemic estrogen replacement therapy
• Treatment with an immunomodulatory biological drug within 12 weeks of study entry
• Immunization with live vaccine within 2 weeks of study baseline visit
• Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational drug, whichever is longer) of screening
• Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the subject's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• University of California San Francisco School of Medicine — San Francisco
• Northwestern University Feinberg School of Medicine — Chicago
• University of Pennsylvania Medical Center — Philadelphia

Identifiers

NCT: NCT06832189 · DAIT ITN101ST

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗