Transcatheter Arterial Chemoembolization Therapy In Combination With Sorafenib

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of the combination therapy with Transcatheter Arterial Chemoembolization (TACE) and sorafenib compared to TACE alone in patients with unresectable hepatocellular carcinoma (HCC) who are not candidates for surgical resection or percutaneous ablation therapy.

Detailed Description
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TACE with sorafenib Group Sorafenib will be administrated at a dose of 400mg o.d. before the first TACE. After 2days drug rest, TACE will be conducted. Sorafenib will be resumed at a dose of 400mg o.d. from 3 days after TACE(the resumption day can be postponed until 21 days after TACE). When tolerability is confirmed at 1 week after resumption, the dose of sorafenib will be increased to 400mg b.i.d. When tumor increases, TACE will be repeated. Control group TACE will be conducted at scheduled day. When tumor increases, TACE will be repeated. The treatment regimen will be continued until untreatable progression which is defined as follows: Child-Pugh grade C Tumor growth (125 percent from baseline status) Vascular invasion(Vp3,Vp4) Extra hepatic spread which size is more than 10mm

Official Title
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Phase II Study: Transcatheter Arterial Chemoembolization Therapy In Combination With Sorafenib (TACTICS)

Conditions
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Hepatocellular Carcinoma, Unresectable Hepatocellular Carcinoma, Carcinoma, Hepatocellular, Liver Neoplasm

Intervention / Treatment
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* Drug: TACE with sorafenib
* Procedure: TACE alone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 20 Years or over Patients who were fully informed of the study beforehand and signed the informed consent to participate in the study. Patients who are expected to live more than 12 weeks. Patients diagnosed with typical HCC by biopsy,cytology, or diagnostic imaging such as dynamic CT(MRI).Typical HCC is defined by AASLD criteria. Patients in whom complete resection of the tumor by hepatectomy or complete tumor necrosis by local tumor necrosis therapy(RFA) cannot be expected to succeed. Patients with tumors which are confirmed to the liver and can be treated by TACE(the maximum diameter equal to or less than 10cm,and the maximum number of nodule equal to or less than 10). Patients with viable and measurable target lesion. patients with no or one history of TACE therapy. patients with an ECOG PS(Performance Status) Score of 0 or 1. patients with Child-Pugh class A. Patients with laboratory values that meet the following criteria: Hemoglobin ≥ 8.5 g/dl Granulocytes ≥ 1500/mm3 Platelet count ≥ 50,000 /mm3 Total serum bilirubin ≤ 3 mg/dl AST and ALT ≤ 6 times upper limits of normal Serum creatinine ≤ 1.5 times upper limits of normal Exclusion Criteria: History of malignant tumor, excluding the following cases: Curatively treated early stage cancer with a low risk of recurrence ,such as carcinoma in situ of the cervix, basal cell carcinoma, superficial bladder tumor, and early gastric cancer. Malignant tumor that was curatively treated more than 3 years prior to study entry and has not recurred since then Cardiac disease that meet any of the following criteria: NYHA Class III or higher congestive heart failure History of symptomatic coronary artery disease or myocardial infarction within 6 months before enrollment Arrhythmia requiring control by antiarrhythmic drugs such as beta-blockers or digoxin Serious and active infection, except for HBV and HCV History of HIV infection Renal dialysis Diffuse tumor lesion Extrahepatic metastasis Vascular invasion Intracranial tumor Preexisting or history of hepatic encephalopathy Clinically uncontrolled ascites or pleural effusion Clinically severe gastrointestinal bleeding within 4 weeks of the start of treatment Esophageal and/or gastric varices which has high risk of bleeding History of thrombosis and/or embolism within 6 months of the start of treatment History of receiving any of the following therapies: Systemic chemotherapy for advanced HCC(including sorafenib therapy) Local therapy, such as radiofrequency ablation, TACE, or hepatic arterial infusion within 3 months of the start of treatment Current treatment with CYP3A4 inducing agents Invasive surgery within 4 weeks of the start of treatment History of allogenic transplantation History of bone marrow transplant or haemopoietic stem cell transplant within 4 weeks of the start of this study Unable to take oral medications Gastrointestinal problems that may affect absorption or pharmacokinetics of the study drugs Use of drugs that may affect absorption or pharmacokinetics of the study drugs Concurrent disease or disability that may affect evaluation of the effects of the study drugs Enrollment in another study within 4 weeks of study entry Female patients who are pregnant, lactating, possibly pregnant, or planning to become pregnant Risk of allergic reactions to the study drugs Drug abuse or other physical, psychological , or social problems that may interfere with the participation in the study or evaluation of study results Any condition that could jeopardize the safety of the patient or their compliance in the study

Ages Eligible for Study
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Minimum Age: 20 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 |
| --- | --- |
| Experimental: TACE with sorafenib<br>TACE(on demand) with sorafenib till untreatable progression | Drug: TACE with sorafenib<br>* Sorafenib will be administrated at a dose of 400mg o.d. before the first TACE. After 2days drug rest, TACE will be conducted. Sorafenib will be resumed at a dose of 400mg o.d. from 3 days after TACE(the resumption day can be postponed until 21 days after TACE). When tolerability is confirmed at 1 week after resumption, the dose of sorafenib will be increased to 400mg b.i.d. When tumor increases, TACE will be repeated.<br>* Other names: TACE with Nexavar;|
| Active Comparator: TACE alone<br>TACE(on demand) till unreatable progression | Procedure: TACE alone<br>* TACE will be conducted at scheduled day. When tumor increases, TACE will be repeated.<br>* Other names: TACE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Patients will be evaluated for these endpoints every 8 weeks | every 8 week | 
| Overall Survival | The overall survival is defined as time from randomization to death due to any cause, and will be evaluated every 8 weeks in the protocol treatment, and every one year in the follow-up period,respectively. | every 8 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To Progression | Time to progression is defined as time from randomization to radiological progression and will be evaluated every 8 week. | every 8 weeks | 
| Objective Response Rate | Objective Response Rate is defined as best response | 4week after TACE | 
| Tumor markers | Change of tumor markers | every 4 weeks | 
| Safety | Number of participants with adverse events as a measure of safety and tolerability(According to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) | every 4 weeks | 
| Time To Untreatable Progression(TTUP) | Time to untreatable progression is defined as time from randomization to untreatable progression and will be evaluated every 8 week. | every 8 week till untreatable progression, assessed up to 100 months | 
| Time to Child-Pugh C | Time to Child-Pugh C is defined as time from randomization to Child-Pugh C and will be evaluated every 8 week. | every 8 week till liver deterioration to Child-Pugh C, assessed up to 100 months | 
| Time to intrahepatic tumor progression | Time to intrahepatic tumor progression is defined as time from randomization to intrahepatic tumor progression and will be evaluated every 8 week. | every 8 week till intrahepatic tumor progression, assessed up to 100 months | 
| Time to vascular invasion | Time to vascular invasion is defined as time from randomization to vascular invasion and will be evaluated every 8 week. | every 8 week till vascular invasion, assessed up to 100 months | 
| Time to Extrahepatic spread | Time to extrahepatic spread is defined as time from randomization to extrahepatic spread and will be evaluated every 8 week. | every 8 week till extrahepatic spread, assessed up to 100 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcatheter arterial chemoembolization, TACE, sorafenib, Time to untreatable progression, TTUP