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A Research Study to Treat Patients With Advanced Hepatocellular Carcinoma
This study has been completed.
Study NCT00108953   Information provided by Bayer
First Received: April 21, 2005   Last Updated: April 23, 2009   History of Changes
Study Type: Interventional
Study Design: Randomized, Double-Blind, Placebo Control, Parallel Assignment
Condition: Carcinoma, Hepatocellular
Interventions: Drug: Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Drug: Doxorubicin/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
Enrollment started on 13 Apr 2005 and the last study contact occurred on 11 Apr 2008. The study was conducted at 25 active centers in 6 countries (Argentina, Canada, Hong Kong, Russia, United Kingdom, and United States.)

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
140 patients were screened, with 44 screen failures. The ITT population (primary population for efficacy analysis) includes all randomized patients (96). The Safety population includes all patients who received at least 1 dose of study drug (95). The study consists of 2 periods: treatment period (not fixed but ended by any event) and follow-up.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Participant Flow for 2 periods
Period:   Treatment
  Sorafenib + Doxorubicin Placebo + Doxorubicin
STARTED   47[1]   49[2]
COMPLETED   47[3]   49[4]
NOT COMPLETED   0     0  
[1] ITT population
[2] ITT population
[3] No patient under study medication anymore
[4] No patient under study medication anymore

Period:   Follow-up
  Sorafenib + Doxorubicin Placebo + Doxorubicin
STARTED   40[1]   45[2]
COMPLETED   11     12  
NOT COMPLETED   29     33  
      Death               18                 26  
      Lost to Follow-up               1                 1  
      Study terminated by sponsor               10                 6  
[1] 40 out of 47 patients were followed after end of double blind treatment
[2] 45 out of 49 patients were followed after end of double blind treatment



  Baseline Characteristics
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Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Baseline Measures
  Sorafenib + Doxorubicin Placebo + Doxorubicin Total
Number of Participants  
[units: participants]
 		47 49 96
Age  
[units: years]
Median ( Full Range ) 		66
( 38 to 82 )		 65
( 38 to 81 )		 65
( 38 to 82 )
Gender  
[units: participants]
 		     
Female 16 7 23
Male 31 42 73
Child Pugh Status[1]
[units: participants]
 		     
5 (Child-Pugh A) 30 28 58
6 (Child-Pugh A) 17 19 36
7 (Child-Pugh B) 0 2 2
Eastern Cooperative Group performance status (ECOG PS) at study entry[2]
[units: participants]
 		     
Grade 0 22 16 38
Grade 1 18 25 43
Grade 2 4 3 7
Grade 3 0 1 1
missing 3 4 7
Tumor burden: Extrahepatic spread[3]
[units: participants]
 		     
yes 24 32 56
no 23 17 40
Tumor burden: Macroscopic vascular invasion[4]
[units: participants]
 		     
yes 13 16 29
no 33 32 65
missing 1 1 2
[1] The Child-Pugh score is used to classify the stages of liver cirrhosis, based on clinical diagnosis and laboratory tests. Assessment of good operative risk (A) if 5 or 6 points, moderate risk (B) if 7 to 9 points, and poor operative risk (C) if 10 to 15 points. A “C” classification forecasts a survival of less than 12 months.
[2] The ECOG PS is an expert rating of cancer patients' daily living abilities, from 0 to 5. 0=Fully active, able to carry on all pre-disease performance without restriction. 3=Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. 5=dead.
[3] Tumor spread outside the liver, which describes an aggressive and advanced tumor pattern.
[4] Tumor spread into the blood vessels as determined through radiological assessment (e.g., x-ray, imaging), which describes an aggressive and advanced tumor pattern.



  Outcome Measures
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1.  Primary:   Time to Progression   [ until progression occured ]

Measure Type Primary
Measure Title Time to Progression
Measure Description Time to progression was defined as the time from randomization to radiological disease progression by independent assessment.
Time Frame until progression occured  
Safety Issue No  

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.
The ITT population, primary population for efficacy analysis, includes all randomized patients.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Measured Values
  Sorafenib + Doxorubicin Placebo + Doxorubicin
Number of Participants Analyzed
[units: participants] 		47 49
Time to Progression
[units: days]
Median ( 95% Confidence Interval ) 		263
( 146 to 384 )		 147
( 66 to 244 )


Statistical Analysis 1 for Time to Progression
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.016
Hazard Ratio, log [4] 0.6
95% Confidence Interval ( 0.33 to 0.95 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The comparison between the 2 groups is done using the log rank test stratified by tumor burden. The null hypothesis is: TTP is the same in both treatment groups.
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Hazard ratio: nexavar+doxorubicin over placebo+doxorubicin



2.  Secondary:   Overall Survival   [ until death occurred ]

Measure Type Secondary
Measure Title Overall Survival
Measure Description Overall survival was measured 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 censored at their last date of follow-up. (Censoring is a missing data problem common in survival analysis.)
Time Frame until death occurred  
Safety Issue No  

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.
The ITT population, primary population for efficacy analysis, includes all randomized patients. The table below gives the lower and upper limit of the confidence interval; 999999999 = not estimable.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Measured Values
  Sorafenib + Doxorubicin Placebo + Doxorubicin
Number of Participants Analyzed
[units: participants] 		47 49
Overall Survival
[units: days]
Median ( 95% Confidence Interval ) 		418
( 317 to 999999999 )		 199
( 148 to 302 )


Statistical Analysis 1 for Overall Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.007
Hazard Ratio (HR) [4] 0.52
95% Confidence Interval ( 0.37 to 0.74 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The comparison between the 2 groups is done using the log rank test stratified by tumor burden. The null hypothesis is: TTP is the same in both treatment groups
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Hazard ratio: nexavar+doxorubicin over placebo+doxorubicin



3.  Secondary:   Progression Free Survival   [ until progression or death occurred ]

Measure Type Secondary
Measure Title Progression Free Survival
Measure Description Progression-free survival (PFS) was defined as the time from randomization to the first documented radiological disease progression or death (if death occurred earlier than progression). For patients without documented progression or death at the time of analysis, PFS was censored at the last date of tumor evaluation.
Time Frame until progression or death occurred  
Safety Issue No  

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.
The ITT population, primary population for efficacy analysis, includes all randomized patients.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Measured Values
  Sorafenib + Doxorubicin Placebo + Doxorubicin
Number of Participants Analyzed
[units: participants] 		47 49
Progression Free Survival
[units: days]
Median ( 95% Confidence Interval ) 		242
( 140 to 312 )		 85
( 71 to 172 )


Statistical Analysis 1 for Progression Free Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.018
Hazard Ratio (HR) [4] 0.61
95% Confidence Interval ( 0.45 to 0.83 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The comparison between the 2 groups is done using the log rank test stratified by tumor burden. The null hypothesis is: TTP is the same in both treatment groups
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Hazard ratio: nexavar+doxorubicin over placebo+doxorubicin



4.  Secondary:   Overall Best Tumor Response Rate   [ achieved during treatment or within 30 days after termination of active therapy ]

Measure Type Secondary
Measure Title Overall Best Tumor Response Rate
Measure Description Overall best tumor response rate was defined as the proportion of subjects with the best tumor response (confirmed PR or CR) achieved during treatment or within 30 days after termination of active therapy and confirmed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Time Frame achieved during treatment or within 30 days after termination of active therapy  
Safety Issue No  

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.
The ITT population, primary population for efficacy analysis, includes all randomized patients.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Measured Values
  Sorafenib + Doxorubicin Placebo + Doxorubicin
Number of Participants Analyzed
[units: participants] 		47 49
Overall Best Tumor Response Rate
[units: percentage of participants with CR or PR]
 		4.3 2.0

No statistical analysis provided for Overall Best Tumor Response Rate



5.  Secondary:   Time to Symptomatic Progression   [ until first documented symptomatic progression defined by FHSI-8 assessment ]

Measure Type Secondary
Measure Title Time to Symptomatic Progression
Measure Description Time to symptomatic progression (TTSP) was defined as the time from randomization to first documented symptomatic progression. For patients who had not progressed symptomatically at the time of analysis, TTSP was censored at the date of their last Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index-8 (FHSI-8) assessment.
Time Frame until first documented symptomatic progression defined by FHSI-8 assessment  
Safety Issue No  

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.
The ITT population, primary population for efficacy analysis, includes all randomized patients.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Measured Values
  Sorafenib + Doxorubicin Placebo + Doxorubicin
Number of Participants Analyzed
[units: participants] 		47 49
Time to Symptomatic Progression
[units: days]
Median ( 95% Confidence Interval ) 		208
( 85 to 317 )		 152
( 110 to 180 )


Statistical Analysis 1 for Time to Symptomatic Progression
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.038
Hazard Ratio (HR) [4] 0.65
95% Confidence Interval ( 0.40 to 1.05 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The comparison between the 2 groups is done using the log rank test stratified by tumor burden. The null hypothesis is: TTP is the same in both treatment groups
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  Hazard ratio: nexavar+doxorubicin over placebo+doxorubicin



6.  Secondary:   Duration of Response   [ from first objective response to progression ]

Measure Type Secondary
Measure Title Duration of Response
Measure Description Duration of response is defined as the time from the first documented objective response (CR or PR) to disease progression or death, whatever occurs first.
Time Frame from first objective response to progression  
Safety Issue No  

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.
The ITT population, primary population for efficacy analysis, includes all randomized patients.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Measured Values
  Sorafenib + Doxorubicin Placebo + Doxorubicin
Number of Participants Analyzed
[units: participants] 		47 49
Duration of Response
[units: days]
Median ( Full Range ) 		199
( 97 to 301 )		 68
( 68 to 68 )

No statistical analysis provided for Duration of Response



7.  Secondary:   Time to Response   [ from randomization to first objective response ]

Measure Type Secondary
Measure Title Time to Response
Measure Description Time to response is defined as the time from randomization to the date when an objective tumor response (CR or PR) is first documented according to the RECIST criteria.
Time Frame from randomization to first objective response  
Safety Issue No  

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.
The ITT population, primary population for efficacy analysis, includes all randomized patients.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Measured Values
  Sorafenib + Doxorubicin Placebo + Doxorubicin
Number of Participants Analyzed
[units: participants] 		47 49
Time to Response
[units: days]
Median ( Full Range ) 		134
( 83 to 184 )		 40
( 40 to 40 )

No statistical analysis provided for Time to Response



8.  Secondary:   Overall Disease Control Rate (DCR)   [ from randomization to end of treatment plus 30 days ]

Measure Type Secondary
Measure Title Overall Disease Control Rate (DCR)
Measure Description Patients defined as having disease control are those who have a best response rating of CR, PR according to RECIST that is maintained for at least 28 days from the first demonstration of that rating or a SD if documented after 6-8 weeks from baseline.
Time Frame from randomization to end of treatment plus 30 days  
Safety Issue No  

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.
The ITT population, primary population for efficacy analysis, includes all randomized patients.

Reporting Groups
  Description
Sorafenib + Doxorubicin Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
Placebo + Doxorubicin Placebo plus Doxorubicin

Measured Values
  Sorafenib + Doxorubicin Placebo + Doxorubicin
Number of Participants Analyzed
[units: participants] 		47 49
Overall Disease Control Rate (DCR)
[units: percentage of participants with DCR]
 		63.8 30.6

No statistical analysis provided for Overall Disease Control Rate (DCR)




  Serious Adverse Events
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  Other Adverse Events
  Show Other Adverse Events


  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.


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
The study had been prematurely terminated by the sponsor because positive results were obtained in another Nexavar trial (Phase 3 study 100554 NCT00105443). NCI-CTC was translated to MedDRA for SOCs only.  


Results Point of Contact:  
Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com


No publications provided


Responsible Party: Bayer HealthCare AG ( Therapeutic Area Head )
Study ID Numbers: 11546, EudraCT 2004-001770-40
Study First Received: April 21, 2005
Results First Received: April 23, 2009
Last Updated: April 23, 2009
ClinicalTrials.gov Identifier: NCT00108953     History of Changes
Health Authority: United States: Food and Drug Administration





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