A Research Study to Treat Patients With Advanced Hepatocellular Carcinoma - Study Results

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

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

Hide Baseline Characteristics

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

Show All Outcome Measures

1. Primary:

Time to Progression [ until progression occured ]

Show Outcome Measure 1

2. Secondary:

Overall Survival [ until death occurred ]

Show Outcome Measure 2

3. Secondary:

Progression Free Survival [ until progression or death occurred ]

Hide Outcome Measure 3

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 ]

Show Outcome Measure 4

5. Secondary:

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

Show Outcome Measure 5

6. Secondary:

Duration of Response [ from first objective response to progression ]

Show Outcome Measure 6

7. Secondary:

Time to Response [ from randomization to first objective response ]

Show Outcome Measure 7

8. Secondary:

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

Show Outcome Measure 8

Serious Adverse Events

Show Serious Adverse Events

Other Adverse Events

Show Other Adverse Events

More Information

Hide 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 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 institution of the Coordinating Investigator (CI) has the right, consistent with academic standards, to publish any proposed publication written by the consultant as part of their services under this agreement. If the sponsor believes that any proposed publication contained any confidential information, the sponsor shall notify the CI, and the CI shall remove such confidential information.

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