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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A 36 Month Multi-center, Open Label, Randomized, Comparator Study to Evaluate the Efficacy and Safety of Everolimus Immunosuppression Treatment in Liver Transplantation for Hepatocellular Carcinoma Exceeding Milan Criteria

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Everolimus
* Drug: Tacrolimus
* Drug: Myfortic
* Drug: CellCept
* Drug: Imuran


Participation Criteria
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Eligibility Criteria
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Screening 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 Screening 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 Randomization Screening Inclusion Criteria : - 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). Randomization Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus and Tacrolimus<br>Everolimus Dosing: 1.5 mg BID (3.0 mg/day) Tacrolimus Dosing: 0.05 mg/kg BID | Drug: Everolimus<br>* Everolimus Dosing: 1.5 mg BID (3.0 mg/day) for 12 months<br>* Other names: Afinitor;Drug: Tacrolimus<br>* Tacrolimus Dosing: 0.05 mg/kg BID for 12 months<br>* Other names: Prograf;|
| Active Comparator: Tacrolimus and Myfortic or CellCept or Imuran<br>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 | Drug: Tacrolimus<br>* Tacrolimus Dosing: 0.05 mg/kg BID for 12 months<br>* Other names: Prograf;Drug: Myfortic<br>* Myfortic®: 360 mg to 1080 mg BID for 12 months<br>* Other names: Mycophenolic Acid;Drug: CellCept<br>* CellCept: 500 mg to 1500 mg BID for 12 months<br>* Other names: Mycophenolate Mofetil;Drug: Imuran<br>* 0.5 mg/kg to 2 mg/kg QD for 12 months<br>* Other names: Azathioprine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival (DFS) defined as the time from randomization to the time of tumor recurrence or death, whichever occurs first. |  | Through Month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor recurrence sites |  | Through Month 36 | 
| Hepatitis C recurrence rate |  | Through Month 36 | 
| Renal function |  | Through Month 36 | 
| Acute cellular rejection |  | Through Month 36 | 
| Post-transplant diabetes |  | Through Month 36 | 
| Hypertension |  | Through Month 36 | 
| Hyperlipidemia |  | Through Month 36 | 
| Wound healing and associated risk factors |  | Through Month 36 | 
| Hernia repair |  | Through Month 36 | 
| Hepatic arterial thrombosis |  | Through Month 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunosuppressive Agents, Liver Transplantation