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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01374750
Recruitment Status : Completed
First Posted : June 16, 2011
Last Update Posted : June 1, 2016
Information provided by (Responsible Party):
Kwang-Woong Lee, Seoul National University Hospital

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.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Drug: Sirolimus Drug: m-TOR inhibitor free Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : May 2010
Actual Primary Completion Date : May 2016
Actual Study Completion Date : May 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Sirolimus

Arm Intervention/treatment
Active Comparator: m-TOR inhibitor free
Immunosuppressive drug
Drug: m-TOR inhibitor free
calcineurin inhibitors
Other Names:
  • Tacrolimus
  • Cyclosporine

Experimental: Sirolimus
Immunosuppressive drug
Drug: Sirolimus
Other Name: Rapamune

Primary Outcome Measures :
  1. To evaluate recurrence-free survival [ Time Frame: 3 years ]
    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

Secondary Outcome Measures :
  1. To evaluate the survival rate [ Time Frame: 3 years ]
    The recurrence is defined by tumor recurrence in imaging study. The recurrence free survival will be calculated by Kaplan-Meier method.

  2. To evaluate the renal function [ Time Frame: 3 years ]
    Renal function will be evaluated by calculated GFR (Cockcroft-Gault method) at postoperative 6month, 12month, 18month, 24month, 30month, and 36month.

  3. To evaluate the safety with sirolimus [ Time Frame: 3 years ]
    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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 study.

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01374750

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Korea, Republic of
Seoul National University Hospital
Seoul, Korea, Republic of
Sponsors and Collaborators
Seoul National University Hospital
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Principal Investigator: Kwang-woong Lee Seoul National University Hospital
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Responsible Party: Kwang-Woong Lee, general surgery professor, Seoul National University Hospital Identifier: NCT01374750    
Other Study ID Numbers: KWLee1004-052-316
H-1004-052-316 ( Registry Identifier: H-1004-052-316 )
First Posted: June 16, 2011    Key Record Dates
Last Update Posted: June 1, 2016
Last Verified: May 2016
Additional relevant MeSH terms:
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Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Anti-Bacterial Agents
Antibiotics, Antineoplastic
Antineoplastic Agents