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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Sirolimus
* Drug: m-TOR inhibitor free


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : Age ≥ 18 yrs and weight ≥ 40 kg. Histologically proven HCC exceeding Milan criteria before randomization, regardless of the prior therapy Signed and dated written informed consent Lack of relevant exclusion criteria 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. Exclusion Criteria : Multiple organ recipients Deceased donor liver transplant Known hypersensitivity to Simulect®, sirolimus, tacrolimus, cyclosporine, or MMF or its derivatives Hyperlipidemia refractory to optimal medical management (cholesterol >300 mg/dl; Triglycerides > 350 mg/dl) Evidence of significant local or systemic infection at the time of randomization. Known HIV-positive patients Women of child-bearing potential not willing to take contraception Patients with non-HCC malignancies within the past 5 years, excluding successfully treated squamous cell carcinoma and basal cell carcinoma of the skin 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) Patients with any evidence of extrahepatic HCC metastasis Patients with a psychological, familial, sociologic or geographic condition potentially hampering compliance with the study protocol and follow-up schedule Use of any investigational drug or treatment up to 4 weeks before enrolling in the study and during the 24-month treatment period. Hepatic artery stenosis or occlusion diagnosed by Doppler Patients with severe renal insufficiency at randomization time point (GFR < 40mL/min, Proteinuria > 800mg/24hrs) Patients with severe leucopenia and/or thrombocytopenia refractory to medical treatment (ANC < 500/ul,platelet < 30K/ul)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| Active Comparator: m-TOR inhibitor free<br>Immunosuppressive drug | Drug: m-TOR inhibitor free<br>* calcineurin inhibitors<br>* Other names: Cyclosporine;|
| Experimental: Sirolimus<br>Immunosuppressive drug | Drug: Sirolimus<br>* Sirolimus<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate recurrence-free survival | 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 | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the survival rate | The recurrence is defined by tumor recurrence in imaging study. The recurrence free survival will be calculated by Kaplan-Meier method. | 3 years | 
| To evaluate the renal function | Renal function will be evaluated by calculated GFR (Cockcroft-Gault method) at postoperative 6month, 12month, 18month, 24month, 30month, and 36month. | 3 years | 
| To evaluate the safety with sirolimus | Safety of sirolimus will be evaluated by the comparison of proportion of patients with serious adverse events during the follow-up period between two groups (m-TOR goup vs. m-TOR free group). Other minor side effects will be monitored and compared between two groups as well. | 3 years |