TACE With or Without Sorafenib in Intermediate Stage Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This multicenter prospective nonrandomized study is to evaluate the efficacy of TACE combined with sorafenib compared with TACE monotherapy in term of overall survival in intermediate-stage HCC.

Detailed Description
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Sorafenib, a multikinase inhibitor, has been successfully applied for solid tumors such as renal cancer and HCC. According to the Barcelona Clinic Liver Cancer (BCLC) staging classification, transarterial chemoembolization (TACE) has been recommended as a first line-therapy for patients at intermediate stage - BCLC B class (multinodular asymptomatic tumors without an invasive pattern). Because sorafenib may improve the efficacy of locoregional therapy by decreasing post-TACE angiogenesis, sorafenib in combination with TACE has attracted considerable attention as a promising therapy

Official Title
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Transarterial Chemoembolization (TACE) With or Without Sorafenib in Intermediate Stage Hepatocellular Carcinoma: a Multicenter Prospective Nonrandomized Study

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Sorafenib
* Procedure: TACE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Prior informed consent Intermediate stage HCC/ BCLC B stage Confirmed Diagnosis of HCC: Cirrhotic subjects: Clinical diagnosis by AASLD criteria. HCC can be defined in cirrhotic subjects by one imaging technique (CT scan, MRI, or second generation contrast ultrasound) showing a nodule larger than 2 cm with contrast uptake in the arterial phase and washout in venous or late phases or two imaging techniques showing this radiological behavior for nodules of 1-2 cm in diameter. Cytohistological confirmation is required for subjects who do not fulfill these eligibility criteria. Non-cirrhotic subjects: For subjects without cirrhosis, histological or cytological confirmation is mandatory. Documentation of original biopsy for diagnosis is acceptable Child Pugh class A/B(7) class without ascites or hepatic encephalopathy ECOG Performance Status of 0-1 At least one uni-dimensional lesion measurable by CT-scan or MRI according to the RECIST 1.1, mRECIST and EASL criteria, respectively. Single lesion>5cm 2-3 lesions, at least one lesion>3cm; if more than 4 lesions, no limitation of the tumor size, but the sum of size of all tumor lesions should be less than 50% of liver parenchyma. Male or female subject ≥ 18 years of age Ability to swallow oral medications Life expectancy of at least 12 weeks Pregnancy test negative within 14 days before treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 4 weeks after the completion of trial Adequate bone marrow, liver and renal functions as assessed by central lab by means of the following laboratory requirements from samples within 7 days prior to randomization: Hemoglobin > 9.0 g/dl Absolute neutrophil count (ANC) >1,500/mm3 Platelet count ≥50x109/L ALB ≥28g/L Total bilirubin < 2 mg/dL ALT and AST < 5 x upper limit of normal BUN and creatinine < 1.5 x upper limit of normal INR < 1.7, or PT < 4 seconds above control Exclusion Criteria: Diffuse HCC or tumor size ≥50% of liver parenchyma Vascular invasion Presence of extrahepatic metastasis Poor blood supply for the liver tumor lesions; poor blood supply refers that the tumor lesions fail to show obvious contrast uptake in the arterial phase and washout in venous or late phases by CT scan or MRI Any contraindications for hepatic embolization procedures: Known hepatofugal blood flow Known porto-systemic shunt Renal failure / insufficiency requiring hemo-or peritoneal dialysis Target lesions having previously been treated with local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) Investigational drugs or other molecular target drugs ongoing or completed < 4 weeks prior to the baseline scan Prior transarterial embolization or anti-tumor systemic chemotherapy Any ≥ CTC AE grade 2 acute toxic effects of any prior local treatment Patients with untreated varices or active bleeding History of cardiac disease: Congestive heart failure >New York Heart Association (NYHA) class 2 Uncontrolled hypertension Known history of HIV infection Active clinically serious infections (> grade 2 NCI-CTCAE Version 4.0), except for HBV and HCV infection Clinically significant gastrointestinal bleeding within 4 weeks prior to start of study drug Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months prior to the first dose of study drug Previous or concurrent cancer that is distinct in primary site or histology from HCC. Any cancer curatively treated >3 years prior to entry is permitted Any contraindication for sorafenib or doxorubicin administration Pregnant or breast-feeding subjects Any disease which could affect the evaluation of the study drug: unstable angina, active CAD, uncontrolled arrhythmias, and myocardial infarction Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study Major surgery within 4 weeks prior to start of study drug (e.g. thoracolaparotomy is not allowed, but noninvasive surgery, e.g. biopsy, is allowed) Autologous bone marrow transplant or stem cell rescue within 1 year prior to start of study drug History of organ allograft

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib combined with TACE<br>220 subjects in this study group will receive the treatment of sorafenib combined with conventional TACE. | Drug: Sorafenib<br>* Sorafenib will be supplied as 200 mg tablets. All subjects will take two tablets of sorafenib (200 mg tablets) twice daily (each morning and evening).<br>* Other names: •Bay 43-9006, Sorafenib (Nexavar®);Procedure: TACE<br>* The first treatment of TACE should be completed within 3-7 days after the administration of sorafenib started. In all cases, TACE consists of an injection containing a mixture of chemotherapeutic agents and lipiodol followed by embolization with polyvinyl alcohol (PVA) particles until complete stasis was achieved in the tumor-feeding vessels.Tumor-feeding vessels should be selected/superselected whenever possible. TACE will be repeated on demand depending on the radiological response.<br>* Other names: conventional transarterial chemeombolization;|
| Active Comparator: TACE monotherapy<br>110 subjects in this study group will receive the treatment of conventional TACE monotherapy. | Procedure: TACE<br>* The first treatment of TACE should be completed within 3-7 days after the administration of sorafenib started. In all cases, TACE consists of an injection containing a mixture of chemotherapeutic agents and lipiodol followed by embolization with polyvinyl alcohol (PVA) particles until complete stasis was achieved in the tumor-feeding vessels.Tumor-feeding vessels should be selected/superselected whenever possible. TACE will be repeated on demand depending on the radiological response.<br>* Other names: conventional transarterial chemeombolization;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival analysis is measured from the treatment start until death occurred from any cause | The last patient has been on study for 1.5 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression | The time to progression is measured from the treatment start to the radiologically confirmed progression | The time to progression will be assessed at the end of the study, up to 3 years | 
| Tumor response | Tumor response will be evaluated according to RECIST, mRECIST and EASL criteria, respectively. Tumor response will be presented in the terms of complete response, partial response, stable disease and progression disease | Tumor response will be assessed at week 4 and week 8 after initiation of treatment and thereafter every 8 weeks (±7 days), up to 3 years | 
| Adverse events | The terms and grade of adverse events will be presented according to the Common Terminology Criteria for Adverse Events(CTCAE:version 4.0) | The adverse events will be assessed every 4 weeks, up to 3 years | 
| Prognostic factor | The Cox proportional model will be used to assess the prognostic factors | The analysis will be perfomed when the last patient has been on study for 1.5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCC, sorafenib, TACE, overall survival