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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT00492752
First received: June 26, 2007
Last updated: March 26, 2014
Last verified: March 2014
Results First Received: December 8, 2010  
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
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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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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

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
  Show All Outcome Measures

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]

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 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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.


  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:
unchecked 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.
unchecked 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.


Results Point of Contact:  
Name/Title: Therapeutic Area Head
Organization: BAYER
phone: <not disclosed>
e-mail: clinical-trials-contact@bayerhealthcare.com


Publications of Results:

Responsible Party: Bayer
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 26, 2014
Health Authority: Taiwan: National Bureau of Controlled Drugs
China: Food and Drug Administration
South Korea: Korea Food and Drug Administration (KFDA)