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

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.

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.