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A Randomized Phase Ⅱ, Trial With Sirolimus-containing Versus mTOR-inhibitor Free Immunosuppression in Patients Undergoing Living Donor Liver Transplantation for Hepatocellular Carcinoma Exceeding Milan Criteria

Phase 2
18 Years
80 Years
Open (Enrolling)
Hepatocellular Carcinoma

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Trial Information

A Randomized Phase Ⅱ, Trial With Sirolimus-containing Versus mTOR-inhibitor Free Immunosuppression in Patients Undergoing Living Donor Liver Transplantation for Hepatocellular Carcinoma Exceeding Milan Criteria

The Milan criteria were adopted in most of western countries for deceased donor allocation
because they identify a subgroup of candidates with hepatocellular carcinoma (HCC) for whom
transplant results are similar to those in patients transplanted for end- stage liver
disease without HCC. There is a debate involving expanding the indications beyond the Milan
criteria in living donor liver transplantation (LDLT). Some transplant surgeons argue that
despite the poorer results, LDLT for advanced HCC may be justified, since donors voluntarily
accept the risks of donor hepatectomy to dedicate a graft for HCC patients, who may
otherwise have no effective treatment. Especially, in Korea where living donor liver
transplantation (LDLT) is commonly performed, the expansion of Milan criteria is inevitable.
Sirolimus is a macrolide antibiotic produced by Streptomyces hygroscopic that has
demonstrated potent immunosuppressive activity in a number of studies. The efficacy of
sirolimus as immunosuppressives has been demonstrated in randomized clinical trials in
kidney transplantation. The use of sirolimus in liver transplantation is rapidly increasing
from the standpoint of reducing the conventional calcineurin inhibitor toxicity. Sirolimus
emerged as an effective alternative for patients with renal insufficiency related to
calcineurin inhibitor toxicity. In recent studies, no differences have been observed with
respect to rejection or major complications.The use of sirolimus in transplant patients is
associated with a dose-dependent increase in serum cholesterol and triglycerides that may
require treatment. In recent studies in liver transplant recipients using sirolimus as part
of a primary immunosuppressive regimen, the occurrence of acute cellular rejection is
relatively low. There is data suggesting that sirolimus is associated with hepatic artery
thrombosis. Numerous current studies have shown that sirolimus may have inhibitory effects
on the development of cancer. Immunosuppressive agent with antineoplastic activity is
inherently attractive in the setting of liver transplantation for HCC. If sirolimus shows
some degree of anti-tumor effect in transplant recipients with advanced HCC, the indication
of LDLT for advanced HCC can be expanded.Our hypothesis is that sirolimus based-regimen will
improve the HCC recurrence free survival. If sirolimus-based protocol shows better
recurrence free survival, the indication of LDLT for HCC can be expanded. LDLT can be one of
the best treatment modalities for advanced HCC. The patients with advanced HCC can have
benefit by liver transplantation.

Inclusion Criteria

Inclusion Criteria :

1. Age ≥ 18 yrs and weight ≥ 40 kg.

2. Histologically proven HCC exceeding Milan criteria before randomization, regardless
of the prior therapy

3. Signed and dated written informed consent

4. Lack of relevant exclusion criteria

5. Women who were of childbearing potential must have had a negative qualitative serum
pregnancy test before Investigational agent administration and must have agreed to
use a medically acceptable method of contraception during treatment period of the

Exclusion Criteria :

1. Multiple organ recipients

2. Deceased donor liver transplant

3. Known hypersensitivity to Simulect®, sirolimus, tacrolimus, cyclosporine, or MMF or
its derivatives

4. Hyperlipidemia refractory to optimal medical management (cholesterol >300 mg/dl;
Triglycerides > 350 mg/dl)

5. Evidence of significant local or systemic infection at the time of randomization.

6. Known HIV-positive patients

7. Women of child-bearing potential not willing to take contraception

8. Patients with non-HCC malignancies within the past 5 years, excluding successfully
treated squamous cell carcinoma and basal cell carcinoma of the skin

9. Patients with HCC involvement of a major branch(portal vein, hepatic vein, etc.) of
any hepatic blood vessel on pathological evaluation c.f. Major branch is defined as
the first or the second order branch (e.g. In case of the portal vein, right and left
portal vein, right anterior and posterior portal vein, and left medial and lateral
portal vein)

10. Patients with any evidence of extrahepatic HCC metastasis

11. Patients with a psychological, familial, sociologic or geographic condition
potentially hampering compliance with the study protocol and follow-up schedule

12. Use of any investigational drug or treatment up to 4 weeks before enrolling in the
study and during the 24-month treatment period.

13. Hepatic artery stenosis or occlusion diagnosed by Doppler

14. Patients with severe renal insufficiency at randomization time point (GFR < 40mL/min,
Proteinuria > 800mg/24hrs)

15. Patients with severe leucopenia and/or thrombocytopenia refractory to medical
treatment (ANC < 500/ul,platelet < 30K/ul)

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate recurrence-free survival

Outcome Description:

To evaluate the anti-tumor effect of sirolimus-based immunosuppressive regimen in patients following living donor liver transplantation for hepatocellular carcinoma exceeding Milan criteria with respect to recurrence-free survival

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Kwang-woong Lee

Investigator Role:

Principal Investigator

Investigator Affiliation:

Seoul National University Hospital


South Korea: Institutional Review Board

Study ID:




Start Date:

May 2010

Completion Date:

May 2015

Related Keywords:

  • Hepatocellular Carcinoma
  • Carcinoma
  • Carcinoma, Hepatocellular