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

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Carcinoma, Hepatocellular
Interventions:	Drug: Sorafenib (Nexavar, BAY43-9006) Drug: Placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
A1) Sorafenib (Nexavar, BAY43-9006) - no Open Label Phase	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.
A2) Sorafenib (Nexavar, BAY43-9006) - With Open Label Phase	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.
B1) Placebo - no Open Label Phase	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.
B2) Placebo First - Then Open Label Sorafenib Treatment Phase	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.

Participant Flow for 2 periods

Period 1: Double Blind Treatment

	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
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
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 2: Follow-up and/or Open Label Sorafenib

	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
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
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

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Reporting Groups

	Description
Sorafenib (Nexavar, BAY43-9006)	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	Placebo tablets matching in appearance were orally administered bid (twice daily).
Total	Total of all reporting groups

Baseline Measures

	Sorafenib (Nexavar, BAY43-9006)	Placebo	Total
Number of Participants [units: participants]	150	76	226
Age [units: Years] Median ( Full Range )	51 ( 23 to 86 )	52 ( 25 to 79 )	51 ( 23 to 86 )
Age, Customized [units: Participants]
<65 years	131	63	194
>=65 years	19	13	32
Gender [units: Participants]
Female	127	66	193
Male	23	10	33
Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ^[1] [units: Participants]
0	33	22	55
1	108	50	158
2	9	4	13
Tumor burden ^[2] [units: Participants]
Absent	32	15	47
Present	118	61	179

[1]	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.
[2]	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

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1. Primary:

Overall Survival [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ]

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2. Secondary:

Time to Symptomatic Progression (TTSP) [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ]

Show Outcome Measure 2

3. Secondary:

Time to Progression (TTP) [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ]

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4. Secondary:

Disease Control [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ]

Show Outcome Measure 4

5. Secondary:

Change in Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index-8 (FHSI-8) Score From Baseline to Cycle 1 and Cycle 3 [ 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 ]

Show Outcome Measure 5

6. Secondary:

Change in Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Score From Baseline to Cycle 3 and End of Treatment [ 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 ]

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7. Secondary:

Number of Participants With Different Tumor Response [ 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 ]

Show Outcome Measure 7

8. Secondary:

Duration of Response [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ]

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9. Secondary:

Time to Response [ Time Frame: From randomization of the first subject until the data cut-off date approximately 23 months after start of randomization ]

Show Outcome Measure 9

10. Secondary:

Area Under the Curve From Time 0 to 12 Hours Post-dose (AUC 0-12) After 21 Days of Sorafenib Treatment [ 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 ]

Show Outcome Measure 10

11. Secondary:

Normalized Area Under the Curve (AUC Norm) After 21 Days of Sorafenib Treatment [ 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 ]

Show Outcome Measure 11

12. Secondary:

Maximum Concentration (Cmax) After 21 Days of Sorafenib Treatment [ 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 ]

Show Outcome Measure 12

13. Secondary:

Normalized Maximum Concentration (Cmaxnorm) After 21 Days of Sorafenib Treatment [ 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 ]

Show Outcome Measure 13

14. Secondary:

Time of Maximum Concentration (Tmax) After 21 Days of Sorafenib Treatment [ 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 ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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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 agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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.

Results Point of Contact:

Name/Title: Therapeutic Area Head
Organization: BAYER
phone: <not disclosed>
e-mail: 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. 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 Jan 10. [Epub ahead of print]

Responsible Party:	Therapeutic Area Head, Bayer HealthCare AG
ClinicalTrials.gov Identifier:	NCT00492752 History of Changes
Other Study ID Numbers:	11849
Study First Received:	June 26, 2007
Results First Received:	December 8, 2010
Last Updated:	March 21, 2013
Health Authority:	Taiwan: National Bureau of Controlled Drugs China: Food and Drug Administration South Korea: Korea Food and Drug Administration (KFDA)