A Phase II Randomized, Double-blind, Placebo-controlled Study of Sorafenib or Placebo in Combination With Transarterial Chemoembolization (TACE) Performed With DC Bead and Doxorubicin for Intermediate Stage Hepatocellular Carcinoma (HCC).

Study Overview
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Brief Summary
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This study will look at whether our drug (sorafenib) in combination with chemotherapy delivered directly into your tumor using beads (DC Bead) will slow the progression of the disease. The beads used with the chemotherapy will slowly release the chemotherapy reducing the adverse effects that normally occur with chemotherapy.

Detailed Description
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Safety issues will be reported in Adverse Event section. In addition to the secondary outcome measures, Biomarkers and Patient Report Outcome will also be analyzed as other variables.

Official Title
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A Phase II Randomized, Double-blind, Placebo-controlled Study of Sorafenib or Placebo in Combination With Transarterial Chemoembolization (TACE) Performed With DC Bead and Doxorubicin for Intermediate Stage Hepatocellular Carcinoma (HCC).

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Sorafenib (Nexavar, BAY43-9006)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Unresectable, multinodular asymptomatic tumor without vascular invasion or extrahepatic spread Confirmed Diagnosis of HCC: Cirrhotic subjects: Clinical diagnosis by American Association for the Study of Liver Diseases (AASLD) criteria HCC can be defined in cirrhotic subjects by one imaging technique (Computed tomography [CT] scan, Magnetic resonance imaging [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 without ascites Adequate bone marrow, liver and renal function as assessed by central lab by means of the following laboratory requirements from samples within 7 days prior to randomization: Exclusion Criteria: Patients on a liver transplantation list or with advanced liver disease as defined below: Child Pugh B and C Active gastrointestinal bleeding Encephalopathy Ascites Lesions having previously been treated with local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) or cryoablation can not be selected as the target lesions.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib (Nexavar, BAY43-9006) + TACE<br>Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Patients were then also treated with Transarterial Chemoembolization (TACE) performed with DC Bead (300 to 500 microns) and doxorubicin (150 mg) between 3 to 7 days after the first dose of sorafenib, TACE was also performed on Days 1 (+ 4 days) of cycle 1, 3, 7, 13 and then every 6 cycles thereafter (an optional TACE procedure could be performed between Day 1 of Cycle 7 and Cycle 13 and between Day 1 of Cycles 13 and 19, if deemed necessary by the Investigator.) | Drug: Sorafenib (Nexavar, BAY43-9006)<br>* 800 mg sorafenib (4 tablets) will be taken daily (400mg b.i.d. [twice daily], 2 tablets). Transarterial Chemoembolization (TACE) using DC Bead<br>|
| Placebo Comparator: Placebo + TACE<br>Placebo was to be orally administered as 2 tablets bid (twice daily). Patients were then also treated with TACE performed with DC Bead (300 to 500 microns) and doxorubicin (150 mg) between 3 to 7 days after the first dose of placebo, TACE was also performed on Days 1 (+ 4 days) of cycle 1, 3, 7, 13 and then every 6 cycles thereafter (an optional TACE procedure could be performed between Day 1 of Cycle 7 and Cycle 13 and between Day 1 of Cycles 13 and 19, if deemed necessary by the Investigator.) | Drug: Placebo<br>* 4 tablets of placebo will be taken daily (2 tablets b.i.d). TACE using DC Bead<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) - Independent Radiological Review (Primary Analysis) | TTP is defined as the time (days) from randomization to radiological confirmed disease progression. Participants without progression at the time of analysis were censored at their last date of tumor evaluation. | From randomization of the first participant until 28 months later (cut-off date) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival (OS) was defined as the time (days) from randomization to death due to any cause. Participants still alive at the time of analysis were censored at their last date of last contact. | From randomization of the first participant until 28 months later (cut-off date) | 
| Time to Untreatable Progression (TTUP) | Time to untreatable progression (TTUP) was defined as the time (days) from randomization to untreatable progression. Participants without untreatable progression at the time of analysis were censored at their last date of tumor evaluation. | From randomization of the first participant until 28 months later (cut-off date) | 
| Time to Vascular Invasion/Extrahepatic Spread (TTVI/ES) | Time to vascular invasion/extrahepatic spread (TTVI/ES) was defined as the time (days) from randomization to vascular invasion/extrahepatic spread. Participants without vascular invasion/extrahepatic spread at the time of analysis were censored at their last date of tumor evaluation. | From randomization of the first participant until 28 months later (cut-off date) | 
| Tumor Response - Independent Radiological Review | Tumor Response was defined as the number of participants with a confirmed Complete Response (CR)=disappearance of all clinical and radiological tumor lesions, Partial Response (PR)= at least 30% decrease in sum of the longest diameters (LD) of tumor lesions, Stable Disease (SD)= neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease, or Progressive Disease (PD)=at least 20% increase in the sum of LD of measured lesions, observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. | From randomization of the first participant until 28 months later (cut-off date) | 
| Tumor Response - Investigator Assessment | Tumor Response was defined as the number of participants with a confirmed Complete Response (CR)=disappearance of all clinical and radiological tumor lesions, Partial Response (PR)= at least 30% decrease in sum of the longest diameters (LD) of tumor lesions, Stable Disease (SD)= neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease, or Progressive Disease (PD)=at least 20% increase in the sum of LD of measured lesions, observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. | From randomization of the first participant until 28 months later (cut-off date) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sorafenib, TACE, DC bead, Combination