Safety and Efficacy of Everolimus Treatment in Liver Transplantation for Liver Cancer

NCT ID: NCT02081755

Last Updated: 2026-01-27

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: PHASE4
• Total Enrollment: 336 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-31
• Study Completion Date: 2027-03-31

Brief Summary

This study is a prospective Phase IV study to determine if the use of Everolimus results in lower liver tumor recurrence and improved patient and graft survival after liver transplant for hepatocellular carcinoma (HCC). The immunosuppressive comparators will be Everolimus and Tacrolimus therapy compared to Tacrolimus and Mycophenolic acid/Mycophenolate Mofetil/Azathioprine. Primary outcomes data is disease free survival (the time from randomization to HCC recurrence or death). Secondary outcomes are rate of recurrence of Hepatitis C, problems related to wound healing, hernia repair within the first 12 months, hepatic arterial thrombosis, renal function, acute cellular rejection, post-transplant diabetes, hypertension, and hyperlipidemia.

Detailed Description

The study population will consist of approximately 336 patients (224 Everolimus and Tacrolimus and 112 Tacrolimus and Mycophenolic acid/Mycophenolate Mofetil/Azathioprine). Initial screening criteria will include the presence of hepatocellular carcinoma in patients 18 years or older who are candidates to receive a primary orthotopic liver transplant (from deceased or living donor). Within 7 - 12 days post-transplant, patients will be re-evaluated for eligibility for randomization. The criteria include: pre-transplant imaging that shows HCC disease exceeding Milan criteria; pathology review for tumor burden and/or presence of microvascular invasion; AFP >200IU/mL; pre-transplant ablation or resection with HCC recurrence; progression or new tumors; evaluation to rule out any hepatic vessel complication.

Subjects will remain in study treatment until Month 12 at which time the subject and investigator will determine the preferred immunosuppressive regimen. Subjects will be followed for an additional 24 months for outcome data as described above.

Conditions

Carcinoma, Hepatocellular

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Everolimus and Tacrolimus

Everolimus Dosing: 1.5 mg BID (3.0 mg/day) Tacrolimus Dosing: 0.05 mg/kg BID

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

Everolimus Dosing: 1.5 mg BID (3.0 mg/day) for 12 months

Tacrolimus

Intervention Type: DRUG

Tacrolimus Dosing: 0.05 mg/kg BID for 12 months

Tacrolimus and Myfortic or CellCept or Imuran

Myfortic: 360 mg to 1080 mg BID OR CellCept: 500 mg to 1500 mg BID OR Imuran: 0.5mk/kg to 2mg/kg QD AND Tacrolimus Dosing: 0.05 mg/kg BID

Group Type: ACTIVE_COMPARATOR

Tacrolimus

Intervention Type: DRUG

Tacrolimus Dosing: 0.05 mg/kg BID for 12 months

Myfortic

Intervention Type: DRUG

Myfortic®: 360 mg to 1080 mg BID for 12 months

CellCept

Intervention Type: DRUG

CellCept: 500 mg to 1500 mg BID for 12 months

Imuran

Intervention Type: DRUG

0.5 mg/kg to 2 mg/kg QD for 12 months

Interventions

Everolimus

Everolimus Dosing: 1.5 mg BID (3.0 mg/day) for 12 months

Intervention Type: DRUG

Tacrolimus

Tacrolimus Dosing: 0.05 mg/kg BID for 12 months

Intervention Type: DRUG

Myfortic

Myfortic®: 360 mg to 1080 mg BID for 12 months

Intervention Type: DRUG

CellCept

CellCept: 500 mg to 1500 mg BID for 12 months

Intervention Type: DRUG

Imuran

0.5 mg/kg to 2 mg/kg QD for 12 months

Intervention Type: DRUG

Other Intervention Names

Zortress; Afinitor; Prograf; Mycophenolic Acid; Mycophenolate Mofetil; Azathioprine

Eligibility Criteria

Inclusion Criteria

• Have a diagnosis of hepatocellular carcinoma (HCC) and high risk for HCC recurrence
• Able to provide written informed consent
• Male and female patients of any race, 18 years or older
• De novo recipients of a primary orthotopic liver transplant from a deceased or living donor
• Patients willing to comply with study requirements
• Women of child-bearing potential (WOCBP) must agree to use an effective method(s) of contraception during treatment and during the post treatment follow-up period

• For patients with a history of any hepatic vessel thrombosis, occlusion, stent placement, or major revision of liver vessels, must have a Doppler ultrasound prior to randomization to rule out any hepatic vessel complication, including hepatic arterial thrombosis (HAT).

Exclusion Criteria

• Past or present malignancy within the last 5 years.
• Severe infection considered by the local site investigator to be unsafe for study participation.
• Use of other investigational drugs at the time of screening or within the last 30 days.
• Patients scheduled for a combined transplant (such as liver-kidney), or having a previous solid organ, bone marrow, or autologous islet cell transplant.
• Recipients of donor/recipient ABO incompatible grafts.
• Recipients of organs from human immunodeficiency virus (HIV) or HBsAg positive donors.
• Macrovascular tumor invasion.
• Proteinuria greater than 2 grams/24 hours.
• Conditions which can result in impaired absorption, distribution, metabolism or excretion of the study treatment.
• Patients with non-infectious pneumonitis.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
• Women of child-bearing potential (WOCBP) not practicing an effective method(s) of contraception.
• Patients who receive sirolimus (Rapamune®) as part of their transplant immunosuppression regimen

• Patients who receive sirolimus (Rapamune) any time prior to randomization will be withdrawn from the study.
• Patients who develop clinically significant systemic infections requiring active use of IV antibiotics any time prior to randomization.
• Wound healing problem, per Investigator's assessment, that would make the patient ineligible for study randomization
• Confirmed presence of a thrombosis in a major hepatic artery(s), major hepatic vein(s), portal vein or inferior vena cava via Doppler ultrasound or other imaging obtained prior to randomization.
• Proteinuria greater than 2 grams/24 hours.
• Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive everolimus or be randomized into the study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Baylor Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Goran Klintmalm, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Baylor Health Care System

Locations

University of California at San Francisco

San Francisco, California, United States

Northwestern University School of Medicine

Chicago, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Mount Sinai Medical Center

New York, New York, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Tennessee- Methodist University Hospital

Memphis, Tennessee, United States

Baylor University Medical Center

Dallas, Texas, United States

Countries

United States

Other Identifiers

013-307

Identifier Type: -

Identifier Source: org_study_id