Efficacy of Sirolimus In Liver Transplantation for Hepatocellular Carcinoma (HCC)

NCT ID: NCT01374750

Last Updated: 2016-06-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-31
• Study Completion Date: 2016-05-31

Brief Summary

The purpose of this study is 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.

Detailed Description

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.

Conditions

Hepatocellular Carcinoma

Study Design

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

Study Groups

m-TOR inhibitor free

Immunosuppressive drug

Group Type: ACTIVE_COMPARATOR

m-TOR inhibitor free

Intervention Type: DRUG

calcineurin inhibitors

Sirolimus

Immunosuppressive drug

Group Type: EXPERIMENTAL

Sirolimus

Intervention Type: DRUG

Sirolimus

Interventions

Sirolimus

Sirolimus

Intervention Type: DRUG

m-TOR inhibitor free

calcineurin inhibitors

Intervention Type: DRUG

Other Intervention Names

Rapamune; Tacrolimus; Cyclosporine

Eligibility 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

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 study.

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Seoul National University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Kwang-Woong Lee

general surgery professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kwang-woong Lee

Role: PRINCIPAL_INVESTIGATOR

Seoul National University Hospital

Locations

Seoul National University Hospital

Seoul, , South Korea

Countries

South Korea

Other Identifiers

H-1004-052-316

Identifier Type: REGISTRY

Identifier Source: secondary_id

KWLee1004-052-316

Identifier Type: -

Identifier Source: org_study_id