A Phase III Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The purpose of the study is: Find out if patients receiving sorafenib will live longer. Find out if sorafenib has any effect on patient reported outcomes. Find out if sorafenib prevents the growth of or shrinks liver tumors and/or their metastases. Determine the pharmacokinetics (PK) in patients with liver cancer.

Detailed Description
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The following abbreviations were used in the Adverse Event section: international normalized ratio (inr) Common Terminology Criteria for Adverse Events (ctcae) Not Otherwise Specified (nos) Gastrointestinal (gi) Central nervous system (cns) Absolute Neutrophil Count (anc) Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Creatine phosphokinase (cpk) Gammaglutamyltransferase (ggt) Genitourinary (gu) Atrioventricular (av)

Official Title
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A Phase III Randomized, Placebo-controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

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: Ages eligible for study: 18 years and above, Genders eligible for study: both Patients who have a life expectancy of at least 12 weeks Patients with histologically or cytologically documented Hepatocellular Carcinoma (HCC) Patients must have at least one tumor lesion that meets both of the following criteria: (1) Accurately measured in at least one dimension according to RECIST (Response Evaluation Criteria in Solid Tumors) (2) Not previously treated with local therapy Patients who have an ECOG (Eastern Cooperative Oncology Group) PS (Performance Status) of 0, 1, or 2 Exclusion Criteria: Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta [Noninvasive papillary carcinoma], Tis [Carcinoma in situ: flat tumor] & T1 [Tumor invades subepithelial connective tissue]). Any cancer curatively treated > 3 years prior to entry is permitted Renal failure requiring hemo- or peritoneal dialysis History of cardiac disease Active clinically serious infections Known history of human immunodeficiency virus (HIV) infection Known central nervous system tumors including metastatic brain disease Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib (Nexavar, BAY43-9006)<br>Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study. | Drug: Sorafenib (Nexavar, BAY43-9006)<br>* Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment.<br>|
| Placebo Comparator: Placebo<br>Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study. | Drug: Placebo<br>* Sorafenib-matching placebo tablets were orally administered twice daily (bid).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival was defined as the time from date of starting treatment to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact. | from randomization to death due to any cause until an average 7.2 months later up to the data cut-off date approximately 19 months after start of enrollment | 
| Time to Symptomatic Progression (TTSP) | TTSP was defined as the time from randomization to the first documented symptomatic progression. | from randomization to the first documented symptomatic progression until an average 4.8 months later up to the data cut-off date approximately 19 months after start of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | TTP was defined as the time from randomization to disease progression (radiological only). Subjects without tumor progression at the time of analysis were censored at their last date of tumor evaluation. | from randomization to disease progression based on radiological assessment until an average 2.8 months later up to the data cut-off date approximately 19 months after start of enrollment | 
| Disease Control (DC) | The DC is defined as the number of subjects with a best response rating of complete response (CR), partial response (PR), or stable disease (SD) that is maintained at least 28 days from the first manifestation of that rating. Definitions: CR = disappearance of all clinical and radiological tumor lesions; PR = at least 30% decrease in sum of the longest diameters of tumor lesions; SD = neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease. | time from randomization to end of treatment up to the data cutoff date approximately 19 months after start of enrollment | 
| Patients Reported Outcome (PRO) by Use of the FACT-Hep Questionnaire | PRO is a disease-specific measure, developed as symptom-focused approach in HCC and measured by the response rates for the PWB and FWB subscales of the 45-item Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. The FACT-Hep response rate was based on the number of subjects who achieved the 8-point minimally important difference (MID) for this subscale. FACT-Hep total score ranges from 0 to 180, where the highest score represents a maximum achievable quality of life (QoL) value. | from randomization to end of treatment up to the data cutoff date approximately 19 months after start of enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Cancer, Cancer