A Randomized, Double-Blinded, Placebo-Controlled Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

• ClinicalTrials.gov Identifier: NCT00492752
• Recruitment Status: Completed
• First Posted: June 27, 2007
• Results First Posted: January 13, 2011
• Last Update Posted: April 16, 2014
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Carcinoma, Hepatocellular
• Interventions: Drug: Sorafenib (Nexavar, BAY43-9006); Drug: Placebo
• Enrollment: 226

Participant Flow

Recruitment Details	Subjects with advanced hepatocellular carcinoma were enrolled from 12 Oct 2005 to 26 Jan 2007 at 23 centers in China (15 centers), Taiwan (5 centers), and Korea (3 centers).
Pre-assignment Details	271 subjects were enrolled in a 28-day screening period; 226 subjects were randomized either to Sorafenib or placebo (2:1 ratio) (intent-to-treat [ITT] population: for efficacy analysis); 224 subjects received at least one dose of study drug (safety population: for safety analysis). Majority of screen failures did not meet the inclusion criteria.

Arm/Group Title	A1) Sorafenib (Nexavar, BAY43-9006) - no Open Label Phase	A2) Sorafenib (Nexavar, BAY43-9006) - With Open Label Phase	B1) Placebo - no Open Label Phase	B2) Placebo First - Then Open Label Sorafenib Treatment Phase
Arm/Group Description	Participants randomized to Sorafenib treatment until unblinding (August 19, 2007), Sorafenib 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 (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. Note: Safety Data of participants in the arm presented here are part of the data reported in Reporting Group (RG) 1.	Participants randomized to Sorafenib treatment from until unblinding (August 19, 2007) until end of trial (July 27, 2009), Sorafenib 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 (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. Note: Safety Data of participants in the arm presented here are part of the data reported in Reporting Group (RG) 1.	Participants randomized to Sorafenib-matching Placebo until unblinding (August 19, 2007), Placebo tablets matching in appearance were orally administered twice daily (bid). Note: Safety Data of participants in the arm presented here are part of the data reported in Reporting Group (RG) 2.	Participants switched to Open-label Sorafenib treatment from Placebo after unblinding (August 19, 2007), Sorafenib 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 (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment. Note: Safety Data of participants in the arm presented here are the data reported in Reporting Group (RG) 3.
Period Title: Double Blind Treatment
Started	134	16	70	6
Received Treatment	133 [1]	16 [2]	69 [3]	6 [2]
Completed	120	16	67	6
Not Completed	14	0	3	0
Reason Not Completed
Death	13	0	2	0
Adverse Event	1	0	0	0
Protocol Violation	0	0	1	0
[1] Safety Population. 1 participant never received treatment due to an Adverse Event.; [2] Safety Population; [3] Safety Population. 1 participant never received treatment due to protocol violation.
Period Title: Follow-up and/or Open Label Sorafenib
Started	120	16	67	6
Follow-up Only (no Open Label Treatment)	120	0	67	0
Follow-up First, Then Open Label	0	16	0	6
Completed	34 [1]	0	20 [2]	0
Not Completed	86	16	47	6
Reason Not Completed
Adverse Event	0	2	0	2
Death	75	5	45	1
Lost to Follow-up	8	1	2	0
Withdrawal by Subject	2	1	0	0
Progression by clinical judgement	0	1	0	2
Radiological and clinical progression	0	0	0	1
Switch to commercial drug	0	6	0	0
Progression measurement proven	1	0	0	0
[1] 1 participant completed all assessments, 33 were followed up until the end of this trial; [2] 20 participants were followed up until the end of this trial

Baseline Characteristics

Arm/Group Title		Sorafenib (Nexavar, BAY43-9006)	Placebo	Total
Arm/Group Description		Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).	Total of all reporting groups
Overall Number of Baseline Participants		150	76	226
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	150 participants	76 participants	226 participants
		51; (23 to 86)	52; (25 to 79)	51; (23 to 86)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	150 participants	76 participants	226 participants
<65 years		131	63	194
>=65 years		19	13	32
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	150 participants	76 participants	226 participants
	Female	127 84.7%	66 86.8%	193 85.4%
	Male	23 15.3%	10 13.2%	33 14.6%
Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	150 participants	76 participants	226 participants
0		33	22	55
1		108	50	158
2		9	4	13
		[1] Measure Description: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is a scale (range 0 [fully active] to 5 [dead]) that measures how cancer affects a patient. Subjects entering this study were to have an ECOG score of 0, 1 (restricted in physically strenuous activity but ambulatory), or 2 (capable of all self care but cannot carry out work activities.
Tumor burden [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	150 participants	76 participants	226 participants
Absent		32	15	47
Present		118	61	179
		[1] Measure Description: Tumor burden refers to the number of cancer cells, the size of a tumor, or the amount of cancer in the body, and is called the tumor load. Randomization was stratified by "tumor burden" assessment ie, the presence of either macroscopic vascular invasion as determined by radiological assessment and/or extra hepatic spread versus none.

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time Frame	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Outcome Measure Data

Analysis Population Description

In this study the overall survival was measured for the ITT population from the date of randomization until the date of death due to any cause. For patients alive or lost to follow-up at the time of analysis, time to death was to be censored at their last date of follow-up, or at the data cut-off of 09 Aug 2007 (23 months after randomization).

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	150	76
Median (95% Confidence Interval); Unit of Measure: days
	198; (169 to 230)	127; (114 to 166)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.014144
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.6783
	Confidence Interval	95%; 0.4962 to 0.9272
	Estimation Comments	Hazard ratio is for Sorafenib vs placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.003464
	Comments	[Not Specified]
	Method	Log Rank
	Comments	log rank test stratified by country, tumor burden, and ECOG.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.6208
	Confidence Interval	95%; 0.4498 to 0.8568
	Estimation Comments	Hazard ratio is for Sorafenib vs placebo

2. Secondary Outcome

Title	Time to Symptomatic Progression (TTSP)
Description	Time to Symptomatic Progression (TTSP) was defined as the time from date of randomization to symptomatic progression. Subjects without symptomatic progression at the time of analysis were censored at their last date of tumor evaluation.
Time Frame	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Outcome Measure Data

Analysis Population Description

Time to Symptomatic Progression was measured for the ITT population (all randomized subjects) up to the data cut-off date of of 09 Aug 2007 (23 months after randomization)

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	150	76
Median (95% Confidence Interval); Unit of Measure: days
	105; (85 to 129)	103; (73 to 124)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.497537
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.9032
	Confidence Interval	95%; 0.6705 to 1.2165
	Estimation Comments	Hazard ratio is for Sorafenib vs placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.437926
	Comments	[Not Specified]
	Method	Log Rank
	Comments	log rank test stratified by country, tumor burden, and ECOG.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8831
	Confidence Interval	95%; 0.6449 to 1.2093
	Estimation Comments	Hazard ratio is for Sorafenib vs placebo

3. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to progression (TTP) was defined as the time from date of randomization to radiologically documented disease progression. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation。
Time Frame	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Outcome Measure Data

Analysis Population Description

Time to progression was measured for the ITT population (all randomized subjects) up to the data cut-off date of 09 Aug 2007 (23 months after randomization).

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	150	76
Median (95% Confidence Interval); Unit of Measure: days
	84; (80 to 109)	41.5; (41 to 47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.000537
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.5744
	Confidence Interval	95%; 0.4154 to 0.7942
	Estimation Comments	Hazard ratio is for Sorafenib vs placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.000540
	Comments	[Not Specified]
	Method	Log Rank
	Comments	log rank test stratified by country, tumor burden, and ECOG.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.5375
	Confidence Interval	95%; 0.3763 to 0.7677
	Estimation Comments	Hazard ratio is for Sorafenib vs placebo

4. Secondary Outcome

Title	Disease Control
Description	Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD: an increase in the sum of tumor lesions sizes) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR: disappearance of tumor lesions) + total number of Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes) + total number of Stable Disease (SD: steady state of disease); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating).
Time Frame	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Outcome Measure Data

Analysis Population Description

Disease control rate was measured for the ITT population (all randomized subjects)

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	150	76
Measure Type: Number; Unit of Measure: participants
Yes	53	12
No	97	64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Disease control rate
	Estimated Value	0.3533
	Confidence Interval	95%; 0.2771 to 0.4355
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Disease control rate
	Estimated Value	0.1579
	Confidence Interval	95%; 0.0843 to 0.2596
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Change in Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) Score From Baseline to Cycle 1 and Cycle 3
Description	The FHSI-8 questionnaire was completed at baseline and every 3 weeks during treatment and at the end of treatment visit only for subjects who withdrew for reasons other than symptomatic progression. Patient reported outcome was measured using the FHSI-8 score changes from baseline throughout the study period. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms)..
Time Frame	Baseline up to Cycle 1 and Cycle 3. From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Outcome Measure Data

Analysis Population Description

FHSI-8 score changes from baseline by visit were assessed for the ITT population.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	150	76
Mean (Standard Deviation); Unit of Measure: scores on a scale
cycle 1	26 (4.8)	26 (4.8)
cycle 3	24 (6.3)	25 (5.3)

6. Secondary Outcome

Title	Change in Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score From Baseline to Cycle 3 and End of Treatment
Description	The FACT-Hep questionnaire was also completed to assess patient reported outcome. The FACT-Hep assesses hepatobiliary cancer-related quality of life. FACT-Hep total score ranges from 0 to 180 (0=All questions answered "Not at all"; 180=All questions answered "Very much").
Time Frame	Baseline up to Cycle 3 and end of treatment. From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Outcome Measure Data

Analysis Population Description

FACT-Hep score changes from baseline by visit were assessed for the ITT population.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	150	76
Mean (Standard Deviation); Unit of Measure: scores on a scale
cycle 3	-10 (25.5)	-3 (19.9)
end of treatment	-25 (27.2)	-23 (31.3)

7. Secondary Outcome

Title	Number of Participants With Different Tumor Response
Description	Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR: disappearance of tumor lesions), confirmed* Partial Response (PR: a decrease of at least 30% in the sum of tumor lesion sizes), Stable Disease (SD: steady state of disease), or Progressive Disease (PD: an increase in the sum of tumor lesions sizes)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Time Frame	From randomization/start of treatment of the first subject until approximately 23 months after randomization when the subjects on placebo were offered the option to crossover to sorafenib treatment

Outcome Measure Data

Analysis Population Description

The tumor response was measured for the ITT population.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	150	76
Measure Type: Number; Unit of Measure: participants
Complete Response (CR)	0	0
Partial Response (PR)	5	1
Stable Disease (SD)	81	21
Progressive Disease (PD)	46	41
Not assessable	18	13

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.67
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	based on tumor response rate (CR+PR)

8. Secondary Outcome

Title	Duration of Response
Description	Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented, or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last tumor assessment.
Time Frame	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Outcome Measure Data

Analysis Population Description

The duration of response was measured for the ITT population.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	5	1
Median (Full Range); Unit of Measure: days
	210; (82 to 343)	252; (252 to 252)

9. Secondary Outcome

Title	Time to Response
Description	Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) ) was defined as the time from date of randomization to the earliest date that the response was first documented.
Time Frame	From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization

Outcome Measure Data

Analysis Population Description

The time to response was measured for the ITT population.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	5	1
Median (Full Range); Unit of Measure: days
	84; (45 to 126)	42; (42 to 42)

10. Secondary Outcome

Title	Area Under the Curve From Time 0 to 12 Hours Post-dose (AUC 0-12) After 21 Days of Sorafenib Treatment
Description	The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing.
Time Frame	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1

Outcome Measure Data

Analysis Population Description

The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	24	0
Geometric Mean (Full Range); Unit of Measure: mg*h/L
	35.7; (7.8 to 149.2)

11. Secondary Outcome

Title	Normalized Area Under the Curve (AUC Norm) After 21 Days of Sorafenib Treatment
Description	The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing.
Time Frame	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1

Outcome Measure Data

Analysis Population Description

The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	24	0
Geometric Mean (Full Range); Unit of Measure: g*h/L
	6.6; (1.3 to 21.6)

12. Secondary Outcome

Title	Maximum Concentration (Cmax) After 21 Days of Sorafenib Treatment
Description	Cmax refers to the highest plasma concentration of drug reached after dosing. It is obtained by collecting a series of blood samples after dosing, and analyzing them for drug content by a sensitive and specific analytical method. The highest measured concentration is referred to as the Cmax.
Time Frame	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1

Outcome Measure Data

Analysis Population Description

The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	24	0
Geometric Mean (Full Range); Unit of Measure: mg/L
	4.44; (1.121 to 16.7)

13. Secondary Outcome

Title	Normalized Maximum Concentration (Cmaxnorm) After 21 Days of Sorafenib Treatment
Description	Cmaxnorm refers to the maximum plasma concentration of Sorafenib corrected for dose and body weight (Cmaxnorm = Cmax/(mg/kg)).
Time Frame	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1

Outcome Measure Data

Analysis Population Description

The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	24	0
Geometric Mean (Full Range); Unit of Measure: g/mL
	0.66; (0.18 to 2.43)

14. Secondary Outcome

Title	Time of Maximum Concentration (Tmax) After 21 Days of Sorafenib Treatment
Description	Tmax refers to the time after dosing when a drug attains its maximum concentration in the blood. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. The time corresponding to the highest measurable concentration (Cmax) is referred to as Tmax.
Time Frame	PK assessments made at following times: pre-dose, 1 h, 2h, 4h, 8h,and 12h after at least 21 consecutive doses during Cycle 1

Outcome Measure Data

Analysis Population Description

The stated goal in the protocol was to obtain PK data from approximately 39 patients. As this was only descriptive information, the sample size was not critical. All patients who provided PK data were included in the analysis.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description:	Sorafenib was administered orally at a dose of 400 mg (2 x 200 mg tablets) bid (twice daily); 2 dose reductions to predefined levels of 400 mg (2 x 200 mg tablets) once daily (od) and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Placebo tablets matching in appearance were orally administered bid (twice daily).
Overall Number of Participants Analyzed	24	0
Median (Full Range); Unit of Measure: hours
	4.0; (0.5 to 12)

Adverse Events

Time Frame	Reporting Group (RG) 1 + 2: Data from start of treatment until end of this trial (July 27, 2009); RG 3: Data after unblinding (August 19, 2007) until end of this trial (July 27, 2009).
Adverse Event Reporting Description	Acronyms in Adverse Event section: Gastrointestinal (GI), Common Terminology Criteria for Adverse Events (CTCAE), not otherwise specified (NOS), absolute neutrophil count (ANC), Central nervous system (CNS), Partial thromboplastin time (PTT), Alanine transaminase (ALT), Aspartate transaminase (AST), Gamma glutamyl transpeptidase (GGT).
Arm/Group Title	Sorafenib, All (Double-Blind and Open Label Phase)	Placebo, All (Double-Blind and Open Label Phase)	Placebo, Open Label Only (Participants Switched to Sorafenib)
Arm/Group Description	Reporting Group 1 (RG 1): All participants randomized to Sorafenib treatment (data from start of treatment until end of trial [July 27, 2009]). Sorafenib 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 (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Reporting Group 2 (RG 2): All participants randomized to Sorafenib-matching Placebo (data from start of treatment until end of trial [July 27, 2009]). Treatment for Double-Blind phase (before unblinding [August 19, 2007]): Placebo tablets matching in appearance were orally administered twice daily (bid); Treatment for Open Label phase (after unblinding [August 19, 2007]): Sorafenib 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 (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.	Reporting Group 3 (RG 3): Participants switched to Open-label Sorafenib treatment from Placebo ( Data after unblinding [August 19, 2007] until end of this trial [July 27, 2009]). Sorafenib 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 (2 x 200 mg tablets) once daily and 400 mg (2 x 200 mg tablets) every 2 days were permitted for treatment-emergent adverse events related to study treatment.
All-Cause Mortality
	Sorafenib, All (Double-Blind and Open Label Phase)	Placebo, All (Double-Blind and Open Label Phase)	Placebo, Open Label Only (Participants Switched to Sorafenib)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Sorafenib, All (Double-Blind and Open Label Phase)	Placebo, All (Double-Blind and Open Label Phase)	Placebo, Open Label Only (Participants Switched to Sorafenib)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	76/149 (51.01%)	34/75 (45.33%)	3/6 (50.00%)
Blood and lymphatic system disorders
Edema: Limb * 1	2/149 (1.34%)	0/75 (0.00%)	0/6 (0.00%)
Cardiac disorders
Hypertension * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Cardiac General - Other * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
Gastrointestinal disorders
Anorexia * 1	2/149 (1.34%)	0/75 (0.00%)	0/6 (0.00%)
Ascites * 1	7/149 (4.70%)	3/75 (4.00%)	0/6 (0.00%)
Colitis * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Diarrhea * 1	4/149 (2.68%)	0/75 (0.00%)	0/6 (0.00%)
Distension * 1	2/149 (1.34%)	2/75 (2.67%)	0/6 (0.00%)
Dysphagia * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Mucositis (Functional/Symptomatic), Oral Cavity * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Nausea * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Ileus * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
GI - Other * 1	2/149 (1.34%)	1/75 (1.33%)	0/6 (0.00%)
Stricture, GI, Biliary Tree * 1	2/149 (1.34%)	0/75 (0.00%)	0/6 (0.00%)
Vomiting * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
General disorders
Death Not Associated With CTCAE Term, Disease Progression NOS * 1	22/149 (14.77%)	8/75 (10.67%)	1/6 (16.67%)
Death Not Associated With CTCAE Term, Multi - Organ Failure * 1	3/149 (2.01%)	3/75 (4.00%)	1/6 (16.67%)
Death Not Associated With CTCAE Term, Sudden Death * 1	3/149 (2.01%)	1/75 (1.33%)	0/6 (0.00%)
Fever * 1	5/149 (3.36%)	3/75 (4.00%)	0/6 (0.00%)
Fatigue * 1	2/149 (1.34%)	1/75 (1.33%)	0/6 (0.00%)
Constitutional Symptoms - Other * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Rigors / Chills * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Pain, Back * 1	1/149 (0.67%)	1/75 (1.33%)	0/6 (0.00%)
Pain, Chest Wall * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Pain, Tumor Pain * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Pain, Abdomen NOS * 1	7/149 (4.70%)	3/75 (4.00%)	0/6 (0.00%)
Pain, Bone * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
Pain, Other * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Pain, Pelvis * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Hepatobiliary disorders
Liver Dysfunction * 1	6/149 (4.03%)	8/75 (10.67%)	0/6 (0.00%)
Hepatobiliary - Other * 1	1/149 (0.67%)	1/75 (1.33%)	0/6 (0.00%)
Infections and infestations
Febrile Neutropenia * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Infection - Other * 1	2/149 (1.34%)	1/75 (1.33%)	0/6 (0.00%)
Infection With Unknown ANC, Biliary Tree * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
Infection With Unknown ANC, Lung (Pneumonia) * 1	4/149 (2.68%)	1/75 (1.33%)	0/6 (0.00%)
Infection With Unknown ANC, Wound * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Metabolism and nutrition disorders
Bilirubin (Hyperbilirubinemia) * 1	3/149 (2.01%)	1/75 (1.33%)	0/6 (0.00%)
Hypoglycemia * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Hypokalemia * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Metabolic / Lab - Other * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Musculoskeletal and connective tissue disorders
Fracture * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy (Possibly Related to Cancer Treatment) * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Nervous system disorders
CNS Ischemia * 1	2/149 (1.34%)	0/75 (0.00%)	0/6 (0.00%)
Encephalopathy * 1	1/149 (0.67%)	3/75 (4.00%)	0/6 (0.00%)
Neuropathy: Motor * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Neurology - Other * 1	1/149 (0.67%)	0/75 (0.00%)	1/6 (16.67%)
Seizure * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Syncope (Fainting) * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
Renal and urinary disorders
Renal Failure * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Renal - Other * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Respiratory, thoracic and mediastinal disorders
Aspiration * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
Pulmonary - Other * 1	3/149 (2.01%)	1/75 (1.33%)	0/6 (0.00%)
Pneumothorax * 1	0/149 (0.00%)	0/75 (0.00%)	1/6 (16.67%)
Dyspnea (Shortness of Breath) * 1	4/149 (2.68%)	1/75 (1.33%)	0/6 (0.00%)
Skin and subcutaneous tissue disorders
Hand-Foot Skin Reaction * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Vascular disorders
CNS Hemorrhage * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Hemorrhage, GI, Abdomen NOS * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Hemorrhage, GI, Anus * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
Hemorrhage, GI, Varices (Esophageal) * 1	4/149 (2.68%)	1/75 (1.33%)	0/6 (0.00%)
Hemorrhage, GI, Stomach * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Hemorrhage, GI, Liver * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
Hemorrhage, GI, Upper GI NOS * 1	9/149 (6.04%)	4/75 (5.33%)	0/6 (0.00%)
Hemorrhage - Other * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Hemorrhage Pulmonary, Nose * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
Hemorrhage Pulmonary, Respiratory Tract NOS * 1	0/149 (0.00%)	1/75 (1.33%)	0/6 (0.00%)
Thrombosis/Thrombus/Embolism * 1	1/149 (0.67%)	0/75 (0.00%)	0/6 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, NCI-CTCAE v. 3.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Sorafenib, All (Double-Blind and Open Label Phase)	Placebo, All (Double-Blind and Open Label Phase)	Placebo, Open Label Only (Participants Switched to Sorafenib)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	144/149 (96.64%)	65/75 (86.67%)	4/6 (66.67%)
Blood and lymphatic system disorders
Blood - Other * 1	8/149 (5.37%)	1/75 (1.33%)	0/6 (0.00%)
Hemoglobin * 1	29/149 (19.46%)	10/75 (13.33%)	0/6 (0.00%)
Leukocytes * 1	18/149 (12.08%)	4/75 (5.33%)	0/6 (0.00%)
Platelets * 1	35/149 (23.49%)	10/75 (13.33%)	1/6 (16.67%)
PTT * 1	12/149 (8.05%)	4/75 (5.33%)	0/6 (0.00%)
Edema: Limb * 1	10/149 (6.71%)	8/75 (10.67%)	0/6 (0.00%)
Cardiac disorders
Hypertension * 1	33/149 (22.15%)	4/75 (5.33%)	0/6 (0.00%)
Ear and labyrinth disorders
Tinnitus * 1	12/149 (8.05%)	0/75 (0.00%)	0/6 (0.00%)
Endocrine disorders
Hypothyroidism * 1	0/149 (0.00%)	0/75 (0.00%)	1/6 (16.67%)
Eye disorders
Cataract * 1	1/149 (0.67%)	0/75 (0.00%)	1/6 (16.67%)
Optic Disc Edema * 1	0/149 (0.00%)	0/75 (0.00%)	1/6 (16.67%)
Gastrointestinal disorders
Anorexia * 1	46/149 (30.87%)	13/75 (17.33%)	0/6 (0.00%)
Ascites * 1	41/149 (27.52%)	13/75 (17.33%)	0/6 (0.00%)
Constipation * 1	20/149 (13.42%)	12/75 (16.00%)	0/6 (0.00%)
Diarrhea * 1	64/149 (42.95%)	12/75 (16.00%)	3/6 (50.00%)
Distension * 1	24/149 (16.11%)	15/75 (20.00%)	0/6 (0.00%)
GI - Other * 1	10/149 (6.71%)	1/75 (1.33%)	0/6 (0.00%)
Mucositis (Clinical Exam), Oral Cavity * 1	6/149 (4.03%)	2/75 (2.67%)	1/6 (16.67%)
Nausea * 1	37/149 (24.83%)	19/75 (25.33%)	0/6 (0.00%)
Vomiting * 1	25/149 (16.78%)	13/75 (17.33%)	0/6 (0.00%)
General disorders
Fatigue * 1	51/149 (34.23%)	15/75 (20.00%)	0/6 (0.00%)
Fever * 1	38/149 (25.50%)	8/75 (10.67%)	0/6 (0.00%)
Insomnia * 1	25/149 (16.78%)	17/75 (22.67%)	0/6 (0.00%)
Weight Loss * 1	62/149 (41.61%)	13/75 (17.33%)	0/6 (0.00%)
Pain, Abdomen NOS * 1	54/149 (36.24%)	16/75 (21.33%)	0/6 (0.00%)
Pain, Back * 1	23/149 (15.44%)	9/75 (12.00%)	0/6 (0.00%)
Pain, Chest Wall * 1	12/149 (8.05%)	2/75 (2.67%)	0/6 (0.00%)
Pain, Chest/Thorax NOS * 1	1/149 (0.67%)	2/75 (2.67%)	1/6 (16.67%)
Pain, Dental/Teeth/Peridontal * 1	1/149 (0.67%)	0/75 (0.00%)	1/6 (16.67%)
Pain, Head/Headache * 1	12/149 (8.05%)	1/75 (1.33%)	1/6 (16.67%)
Pain, Joint * 1	6/149 (4.03%)	0/75 (0.00%)	1/6 (16.67%)
Pain, Liver * 1	10/149 (6.71%)	9/75 (12.00%)	0/6 (0.00%)
Pain, Muscle * 1	10/149 (6.71%)	1/75 (1.33%)	0/6 (0.00%)
Pain, Other * 1	11/149 (7.38%)	2/75 (2.67%)	0/6 (0.00%)
Pain, Stomach * 1	3/149 (2.01%)	4/75 (5.33%)	0/6 (0.00%)
Pain, Throat/Pharynx/Larynx * 1	10/149 (6.71%)	1/75 (1.33%)	1/6 (16.67%)
Flu - Like Syndrome * 1	3/149 (2.01%)	1/75 (1.33%)	1/6 (16.67%)
Pain, Bone * 1	8/149 (5.37%)	5/75 (6.67%)	0/6 (0.00%)
Hepatobiliary disorders
Hepatobiliary - Other * 1	8/149 (5.37%)	6/75 (8.00%)	0/6 (0.00%)
Immune system disorders
Allergic Reaction * 1	2/149 (1.34%)	4/75 (5.33%)	0/6 (0.00%)
Infections and infestations
Infection - Other * 1	10/149 (6.71%)	6/75 (8.00%)	0/6 (0.00%)
Metabolism and nutrition disorders
Alkaline Phosphatase * 1	39/149 (26.17%)	14/75 (18.67%)	0/6 (0.00%)
ALT * 1	49/149 (32.89%)	18/75 (24.00%)	2/6 (33.33%)
Amylase * 1	8/149 (5.37%)	0/75 (0.00%)	0/6 (0.00%)
AST * 1	63/149 (42.28%)	23/75 (30.67%)	1/6 (16.67%)
Bilirubin (Hyperbilirubinemia) * 1	56/149 (37.58%)	24/75 (32.00%)	2/6 (33.33%)
Creatinine * 1	10/149 (6.71%)	3/75 (4.00%)	0/6 (0.00%)
GGT * 1	9/149 (6.04%)	7/75 (9.33%)	0/6 (0.00%)
Hyperglycemia * 1	8/149 (5.37%)	7/75 (9.33%)	0/6 (0.00%)
Hyperkalemia * 1	7/149 (4.70%)	5/75 (6.67%)	0/6 (0.00%)
Hyperuricemia * 1	10/149 (6.71%)	6/75 (8.00%)	0/6 (0.00%)
Hypoalbuminemia * 1	34/149 (22.82%)	16/75 (21.33%)	0/6 (0.00%)
Hypocalcemia * 1	12/149 (8.05%)	3/75 (4.00%)	0/6 (0.00%)
Hypokalemia * 1	11/149 (7.38%)	2/75 (2.67%)	0/6 (0.00%)
Hyponatremia * 1	23/149 (15.44%)	10/75 (13.33%)	0/6 (0.00%)
Hypophosphatemia * 1	17/149 (11.41%)	4/75 (5.33%)	1/6 (16.67%)
Lipase * 1	19/149 (12.75%)	4/75 (5.33%)	0/6 (0.00%)
Metabolic / Lab - Other * 1	33/149 (22.15%)	9/75 (12.00%)	0/6 (0.00%)
Nervous system disorders
Dizziness * 1	4/149 (2.68%)	5/75 (6.67%)	1/6 (16.67%)
Memory Impairment * 1	0/149 (0.00%)	0/75 (0.00%)	1/6 (16.67%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	29/149 (19.46%)	12/75 (16.00%)	2/6 (33.33%)
Dyspnea (Shortness of Breath) * 1	17/149 (11.41%)	12/75 (16.00%)	0/6 (0.00%)
Pulmonary - Other * 1	11/149 (7.38%)	7/75 (9.33%)	0/6 (0.00%)
Skin and subcutaneous tissue disorders
Alopecia * 1	40/149 (26.85%)	1/75 (1.33%)	0/6 (0.00%)
Dermatology - Other * 1	15/149 (10.07%)	3/75 (4.00%)	0/6 (0.00%)
Hand - Foot Skin Reaction * 1	69/149 (46.31%)	2/75 (2.67%)	2/6 (33.33%)
Pruritus * 1	19/149 (12.75%)	9/75 (12.00%)	0/6 (0.00%)
Rash / Desquamation * 1	33/149 (22.15%)	7/75 (9.33%)	0/6 (0.00%)
Vascular disorders
Hemorrhage Pulmonary, Respiratory Tract NOS * 1	2/149 (1.34%)	1/75 (1.33%)	1/6 (16.67%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, NCI-CTCAE v. 3.0

Limitations and Caveats

On review of unblinded data, up to 19 Mar. 2007, the independent Data Monitoring Committee concluded the efficacy results can be considered positive, recommended subjects under placebo to cross over to Sorafenib; study continued to extension phase.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Investigator must send a draft manuscript to be submitted for publication or to be presented or abstract to Bayer at least 60 days in advance of submission in order to obtain approval prior to submission of the final version for publication or presentation. In case of a difference of opinion between Bayer and the Investigator(s), the contents of the publication will be discussed in order to find a solution, which satisfies both parties.

Results Point of Contact

• Name/Title: Therapeutic Area Head
• Organization: BAYER
• Phone: <not disclosed>
• EMail: clinical-trials-contact@bayerhealthcare.com

Publications of Results:

Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jan;10(1):25-34. doi: 10.1016/S1470-2045(08)70285-7. Epub 2008 Dec 16.

Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Yang TS, Tak WY, Pan H, Yu S, Xu J, Fang F, Zou J, Lentini G, Voliotis D, Kang YK. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer. 2012 Jul;48(10):1452-65. doi: 10.1016/j.ejca.2011.12.006. Epub 2012 Jan 10.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bruix J, Cheng AL, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies. J Hepatol. 2017 Nov;67(5):999-1008. doi: 10.1016/j.jhep.2017.06.026. Epub 2017 Jul 4. Erratum In: J Hepatol. 2018 Oct;69(4):990-991.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00492752
• Other Study ID Numbers: 11849
• First Submitted: June 26, 2007
• First Posted: June 27, 2007
• Results First Submitted: December 8, 2010
• Results First Posted: January 13, 2011
• Last Update Posted: April 16, 2014