Study of BAY43-9006 in Patients With Unresectable and/or Metastatic Renal Cell Cancer

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00073307
• Collaborator: Amgen (Industry)
• Enrollment: 903
• Locations: 121
• Arms: 2
• Duration (Months): 77
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate safety, efficacy (including quality of life), and pharmacokinetics of BAY43-9006 when added to Best Supportive Care in patients with unresectable and/or metastatic renal cell cancer, who have received one prior systemic regimen for advanced disease.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Renal Cell	Drug: Sorafenib (Nexavar, BAY43-9006); Drug: Placebo	Phase 3

Detailed Description

Overall Survival (OS), Patient-reported outcome (PRO)

Study Design

• Study Type: Interventional
• Actual Enrollment: 903 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Study of BAY43-9006 in Patients With Unresectable and/or Metastatic Renal Cell Cancer.
• Study Start Date: Nov 1, 2003
• Actual Primary Completion Date: Sep 1, 2006
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sorafenib (Nexavar, BAY43-9006) Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Drug: Sorafenib (Nexavar, BAY43-9006); Multi Kinase Inhibitor
Placebo Comparator: Placebo Placebo tablets matching in appearance were to be orally administered twice a day.	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Final Overall Survival (OS) - Primary Analysis in the ITT (Intent To Treat) Population [From start of randomization of the first subject (1Dec2003) until the data cut-off (8Sep2006) for the final OS analysis, approximately 33 months later]

   Overall survival determined as the time (days) from the date of randomization at start of study to the date of death, due to any cause. Outcome measure was assessed regularly, i.e. every 3 weeks for the first 24 weeks during treatment and every 4 weeks thereafter and approximately every 3 months during post-treatment.

2. Final Overall Survival - Secondary Analysis (Placebo Data Censored at 30June2005) in the ITT Population [From start of randomization of the first subject (1Dec2003) until the data cut-off (8Sep2006) for the final OS analysis, approximately 33 months later]

   Overall survival determined as the time (days) from the date of randomization at start of study to the date of death, due to any cause. Outcome measure was assessed regularly, i.e. every 3 weeks for the first 24 weeks during treatment and every 4 weeks thereafter and approximately every 3 months during post-treatment.

Secondary Outcome Measures

1. Final Progression-Free Survival (PFS) - Independent Radiological Review [From start of randomization of the first subject (1Dec2003) until the data cut-off (28Jan2005), approximately 14 months later, tumors assessed every 8 weeks.]

   PFS determined as the time (days) from the date of randomization at start of study to the actual date of disease progression (PD) (radiological or clinical) or death due to any cause, if death occurred before PD. Outcome measure was assessed approximately every 8 weeks using RECIST v1.0 criteria by independent radiologic review. Radiological PD defined as at least 20% increase in sum of longest diameter (LD) of measured lesions taking as reference smallest sum LD recorded since treatment started or appearance of new lesions.

2. Best Overall Response - Independent Radiological Review [From start of randomization of the first subject (1Dec2003) until the data cut-off (28Jan2005), approximately 14 months later, tumors assessed every 8 weeks.]

   Best overall response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 by independent radiologic review. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased) and not evaluated.

3. Health-related Quality of Life (HRQOL) by FKSI-10 (Functional Assessment of General Therapy Kidney Symptom Index 10) Assessment [From start of randomization of the first subject (1Dec2003) until the data cut-off (31May2005), approximately 18 months later, PRO data collected at Day 1 of each cycle and end of treatment.]

   Primary Analysis for FKSI-10 patient-reported outcome (PRO) measure defined as longitudinal analysis of mean score over the first 5 treatment cycles. FKSI-10 patient responses for each question range from "0=not at all" to "4=very much" and after reverse coding the range of values for FKSI-10 total score is from 0 to 40; higher score represents better HRQOL.

4. Health-related Quality of Life (HRQOL) by Physical Well-Being (PWB) Score of the FACT-G (Functional Assessment of Cancer Therapy-General Version) Assessment [From start of randomization of the first subject (1Dec2003) until the data cut-off (31May2005), approximately 18 months later, PRO data collected at Day 1 of each cycle and end of treatment.]

   Primary Analysis for FACT-G (using PWB score) patient-reported outcome (PRO) measure defined as longitudinal analysis of mean score over the first 5 treatment cycles. FACT-G (PWB score) patient responses for each question range from "0=not at all" to "4=very much" and after reverse coding the total FACT-G (PWB score) range of values is from 0 to 28; higher score represents better HRQOL.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with unresectable and/or metastatic, measurable renal cell carcinoma histologically or cytologically documented

• Patients must have had one prior systemic therapy for advanced disease, which was completed at least 30 days but no longer than 8 months prior to randomization

• Patients who have at least one uni-dimensional measurable lesion by CT-scan or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST)

• Patients who have an Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1

• Patients who have adequate coagulation, liver and kidney functions

Exclusion Criteria:

• Patients with rare subtypes of renal cell carcinoma (RCC) such as pure papillary cell tumors, mixed tumor containing predominantly sarcomatoid cells, Bellini carcinoma, medullary carcinoma, or chromophobe oncocytic tumors

• Previous malignancy (except for cervical carcinoma in situ, adequately treated basal cell carcinoma,or superficial bladder tumors, or other malignancies curatively treated

2 years prior to entry

• Cardiac arrhythmias requiring anti-arrhythmics, symptomatic coronary artery disease or ischemia or congestive heart failure

• Patients with a history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C

• Patients with a history or presence of metastatic brain or meningeal tumors

• Patients with seizure disorder requiring medication (such as anti-epileptics)

• History of organ allograft or bone marrow transplant of stem cell rescue

• Patients who are pregnant or breast-feeding Women of childbearing potential must have a negative pregnancy test prior to drug administration. Both men and women enrolled in this trial must use adequate birth control

• Patients who have three or more of the following:

• ECOG performance status greater than or equal to 2,

• Abnormally high lactate dehydrogenase,

• Abnormally high serum hemoglobin,

• Abnormally high corrected serum calcium,

• Absence of prior nephrectomy

• Excluded therapies and medications, previous and concomitant:

• Concurrent anti-cancer chemotherapy, immunotherapy or hormonal therapy except biphosphonates

• Significant surgery with 4 weeks of start of study

• Investigational drug therapy during or within 30 days

• Concomitant treatment with rifampin or St. John's Wort

• Prior use of Raf-kinase inhibitors (RKI), MEK or Farnesyl transferase inhibitors

• Prior use of Bevacizumab, and all other drugs (investigational or licensed) that target VEGF/VEGF receptors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tucson	Arizona	United States	85712
2		Los Angeles	California	United States	90033
3		Los Angeles	California	United States	90057
4		Sacramento	California	United States	95817
5		Aurora	Colorado	United States	80045
6		Hamden	Connecticut	United States	06518
7		Atlanta	Georgia	United States	30309
8		Chicago	Illinois	United States	60637
9		Louisville	Kentucky	United States	40202
10		Lafayette	Louisiana	United States	70506
11		Frederick	Maryland	United States	21701
12		Boston	Massachusetts	United States	02215
13		Minneapolis	Minnesota	United States	55455
14		Columbia	Missouri	United States	65203-3244
15		St. Louis	Missouri	United States	63110-1093
16		Bronx	New York	United States	10466-2604
17		Brooklyn	New York	United States	11220
18		New York	New York	United States	10032
19		Canton	Ohio	United States	44718
20		Cleveland	Ohio	United States	44195
21		Dayton	Ohio	United States	45429
22		Portland	Oregon	United States	97239
23		Philadelphia	Pennsylvania	United States	19107-5096
24		Spartanburg	South Carolina	United States	29303
25		Dallas	Texas	United States	75246
26		Laredo	Texas	United States	78041
27		San Antonio	Texas	United States	78212
28		Salt Lake City	Utah	United States	84132
29		Richmond	Virginia	United States	23229
30		Seattle	Washington	United States	98101
31		Milwaukee	Wisconsin	United States	53226-3596
32		Rosario	Santa Fe	Argentina	S2000DSK
33		Santa Fé	Santa Fe	Argentina	S3000FFV
34		Capital Federal-Buenos Aires		Argentina	C1426ANZ
35		Mendoza		Argentina	5500
36		Garran	Australian Capital Territory	Australia	2605
37		Camperdown	New South Wales	Australia	2050
38		Liverpool	New South Wales	Australia	2170
39		Westmead	New South Wales	Australia	2145
40		Heidelberg	Victoria	Australia	3084
41		Wodonga	Victoria	Australia	0390
42		Bruxelles - Brussel		Belgium	1000
43		Bruxelles - Brussel		Belgium	1090
44		Curitiba	Parana	Brazil	81520-060
45		Porto Alegre	Rio Grande do Sul	Brazil	90020-060
46		Porto Alegre	Rio Grande do Sul	Brazil	90619900
47		Edmonton	Alberta	Canada	T6G 1Z2
48		Hamilton	Ontario	Canada	L8V 5C2
49		London	Ontario	Canada	N6A 4L6
50		Toronto	Ontario	Canada	M5G 2M9
51		Montreal	Quebec	Canada	H3T 1E2
52		Santiago de Chile		Chile
53		Bordeaux		France	33000
54		Caen Cedex 5		France	14076
55		Lille Cedex		France	59020
56		Lyon Cedex		France	69008
57		Marseille		France	13273
58		Nantes		France	44805
59		Paris Cedex 15		France	75908
60		Strasbourg		France	67091
61		Toulouse		France	31052
62		Villejuif		France	94805
63		Mannheim	Baden-Württemberg	Germany	68167
64		Ulm	Baden-Württemberg	Germany	89075
65		München	Bayern	Germany	81377
66		Regensburg	Bayern	Germany	93042
67		Darmstadt	Hessen	Germany	64276
68		Frankfurt	Hessen	Germany	60488
69		Düsseldorf	Nordrhein-Westfalen	Germany	40225
70		Dresden	Sachsen	Germany	01307
71		Berlin		Germany	10967
72		Hamburg		Germany	20246
73		Budapest		Hungary	1032
74		Budapest		Hungary	1121
75		Debrecen		Hungary	4004
76		Zalaegerszeg		Hungary	8900
77		Haifa		Israel	3109601
78		Tel Aviv		Israel	64239
79		Milano		Italy	20133
80		Modena		Italy	41124
81		Pavia		Italy	27100
82		Perugia		Italy	06122
83		Reggio Emilia		Italy	42100
84		Roma		Italy	00144
85		Nijmegen		Netherlands	6525 GA
86		Gdansk		Poland	80-210
87		Krakow		Poland	31-115
88		Lodz		Poland	93-509
89		Lublin		Poland	20-090
90		Poznan		Poland	61-878
91		Szczecin		Poland	70-111
92		Warszawa		Poland	02-781
93		Warszawa		Poland	04-141
94		Wroclaw		Poland	50-043
95		Barnaul		Russian Federation	656049
96		Kazan		Russian Federation	420029
97		Kirov		Russian Federation	610021
98		Moscow		Russian Federation	115478
99		Moscow		Russian Federation	125284
100		Obninsk		Russian Federation	249036
101		St. Petersburg		Russian Federation	198255
102		Bloemfontein	Freestate	South Africa	9300
103		Pretoria	Gauteng	South Africa
104		Durban	Kwazulu-Natal	South Africa	4001
105		Cape Town	Western Cape	South Africa	7500
106		Cruces/Barakaldo	Bilbao	Spain	48903
107		Barcelona		Spain	08035
108		Madrid		Spain	28040
109		Valencia		Spain	46009
110		Donetsk		Ukraine	83092
111		Kharkiv		Ukraine	61024
112		Kiev		Ukraine	115
113		Lviv		Ukraine	79031
114		Poltava		Ukraine	36024
115		Northwood	Middlesex	United Kingdom	HA6 2RN
116		Cardiff	South Glamorgan	United Kingdom	CF14 2TL
117		Glasgow	Stratchclyde	United Kingdom	G11 6NT
118		Sutton	Surrey	United Kingdom	SM2 5PT
119		Newcastle Upon Tyne	Tyne and Wear	United Kingdom	NE4 6BE
120		Birmingham	West Midlands	United Kingdom	B15 2TT
121		Manchester		United Kingdom	M20 4BX

Sponsors and Collaborators

• Bayer
• Amgen

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00073307
• Other Study ID Numbers: 11213
• First Posted: Nov 21, 2003
• Last Update Posted: Feb 6, 2014
• Last Verified: Jan 1, 2014

• Keywords provided by Bayer: Renal Cell Cancer (RCC); Cancer
• Additional relevant MeSH terms: Carcinoma, Renal Cell; Sorafenib

Study Results

Participant Flow

Recruitment Details	From randomization start on 01 Dec 2003 to 31 May 2005 [last subject randomized]. One subject randomized in Placebo did not receive treatment. This study was conducted at 120 centers from 19 countries.
Pre-assignment Detail	Enrollment included outpatients with documented unresectable and/or metastatic RCC (Renal Cell Carcinoma), and subjects who had 1 prior systemic therapy for advanced disease on which the subject progressed, at least 1 unidimensional measurable lesion, intermediate or low Motzer risk score, life expectancy of 12 weeks.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo	Placebo Randomized, Switch to Sorafenib; Sorafenib Period Only
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily).	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]	Subjects received matching placebo tablets administered orally twice a day(as of ~31 May 2005) when after unblinding subjects switched over to receive Sorafenib orally administered as 2 x 200 mg tablets bid (twice daily).
Period Title: Double-Blind (DB, as of ~31May2005)
STARTED	451	452	0
Participants Received Treatment	451	451	0
COMPLETED	254	299	0
NOT COMPLETED	197	153	0
Period Title: Double-Blind (DB, as of ~31May2005)
STARTED	254	0	299
Entered OL With Sorafenib Only Phase	219	0	216
COMPLETED	120	0	143
NOT COMPLETED	134	0	156

Baseline Characteristics

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo	Total
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]	Total of all reporting groups
Overall Participants	451	452	903
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	58.0	59.0	59.0
Age, Customized (Number) [Number]
<65 years	304 67.4%	328 72.6%	632 70%
>= 65 years	147 32.6%	124 27.4%	271 30%
Sex: Female, Male (Count of Participants)
Female	136 30.2%	112 24.8%	248 27.5%
Male	315 69.8%	340 75.2%	655 72.5%
Motzer Category (Low, intermediate or high) (Number) [Number]
Low	234 51.9%	219 48.5%	453 50.2%
Intermediate	217 48.1%	232 51.3%	449 49.7%
Missing	0 0%	1 0.2%	1 0.1%
ECOG Performance Status (PS) (Participants by scale) [Number]
PS 0	219 48.6%	211 46.7%	430 47.6%
PS 1	223 49.4%	235 52%	458 50.7%
PS 2	7 1.6%	4 0.9%	11 1.2%
Missing	2 0.4%	2 0.4%	4 0.4%
TNM Classification at study entry (Number) [Number]
Stage III	18 4%	14 3.1%	32 3.5%
Stage IV	433 96%	438 96.9%	871 96.5%
Cancer Subtypes (Participants with carcinoma type) [Number]
Clear Cell	449 99.6%	447 98.9%	896 99.2%
Papillary	1 0.2%	3 0.7%	4 0.4%
Granular	1 0.2%	2 0.4%	3 0.3%

Outcome Measures

1. Primary Outcome

Title	Final Overall Survival (OS) - Primary Analysis in the ITT (Intent To Treat) Population
Description	Overall survival determined as the time (days) from the date of randomization at start of study to the date of death, due to any cause. Outcome measure was assessed regularly, i.e. every 3 weeks for the first 24 weeks during treatment and every 4 weeks thereafter and approximately every 3 months during post-treatment.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (8Sep2006) for the final OS analysis, approximately 33 months later

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population. Subjects alive at time of analysis were censored at last date of follow-up (FU) (last visit or contact or at data cut-off date). In case of incomplete date, day was missing, day 15 was used.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Measure Participants	451	452
Median (95% Confidence Interval) [days]	542	461

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	Sample size based on primary efficacy endpoint of OS. Clinically meaningful improvement defined as 33.3% improvement in median OS (i.e. HR of 0.75, Sorafenib over Placebo). With overall two-sided alpha of 0.04, 90% power and randomization of 1:1, two formal interim analyses and one final analysis were planned using O'Brien-Fleming type error spending function, and a total of approximately 540 events (deaths) were required for the final analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.146
	Comments	According to O'Brien-Fleming type alpha spending function and total actual deaths at final analysis, threshold for statistical significance was alpha=0.037 (two-sided).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	() 95%; 0.74 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Two treatment groups compared using log-rank test (Sorafenib over Placebo) stratified by country and Motzer category

2. Primary Outcome

Title	Final Overall Survival - Secondary Analysis (Placebo Data Censored at 30June2005) in the ITT Population
Description	Overall survival determined as the time (days) from the date of randomization at start of study to the date of death, due to any cause. Outcome measure was assessed regularly, i.e. every 3 weeks for the first 24 weeks during treatment and every 4 weeks thereafter and approximately every 3 months during post-treatment.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (8Sep2006) for the final OS analysis, approximately 33 months later

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population. Subjects alive at time of analysis were censored at last date of FU (last visit or contact or at data cut-off date). In case of incomplete date, missing day, day 15 was used. Placebo censored at 30June2005, approximate time of crossover of placebo subjects to sorafenib. NA - not estimable due to censored data.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Measure Participants	451	452
Median (95% Confidence Interval) [days]	542	436

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	Sample size based on primary efficacy endpoint of OS. Clinically meaningful improvement defined as 33.3% improvement in median OS (i.e. HR of 0.75, Sorafenib over Placebo). With overall two-sided alpha of 0.04, 90% power and randomization of 1:1, two formal interim analyses and one final analysis were planned using O'Brien-Fleming type error spending function, and a total of approximately 540 events (deaths) were required for the final analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0287
	Comments	According to O'Brien-Fleming type alpha spending function and total actual deaths at final analysis, threshold for statistical significance was alpha=0.037 (two-sided).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	() 95%; 0.62 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Two treatment groups compared using log-rank test (Sorafenib over Placebo) stratified by country and Motzer category

3. Secondary Outcome

Title	Final Progression-Free Survival (PFS) - Independent Radiological Review
Description	PFS determined as the time (days) from the date of randomization at start of study to the actual date of disease progression (PD) (radiological or clinical) or death due to any cause, if death occurred before PD. Outcome measure was assessed approximately every 8 weeks using RECIST v1.0 criteria by independent radiologic review. Radiological PD defined as at least 20% increase in sum of longest diameter (LD) of measured lesions taking as reference smallest sum LD recorded since treatment started or appearance of new lesions.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (28Jan2005), approximately 14 months later, tumors assessed every 8 weeks.

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population as of 28Jan2005 data cut; 769 subjects randomized at that time. PFS determined as time from randomization to actual date of disease progression (PD) (radiological or clinical) or death, if death occurred before PD. Subjects without PD or death at time of analysis were censored at last date of tumor assessment.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Placebo tablets matching in appearance were to be orally administered twice a day.
Measure Participants	384	385
Median (95% Confidence Interval) [days]	167	84

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	The planned final PFS analysis was to be performed when approximately 363 progressions or deaths (if death occurred before progression) were observed. The analysis had power of 90% to detect a 50% increase in PFS using a two-sided alpha of 0.01
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.44
	Confidence Interval	() 95%; 0.35 to 0.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Two treatment groups compared using log-rank test (Sorafenib over Placebo) stratified by country and Motzer category

4. Secondary Outcome

Title	Best Overall Response - Independent Radiological Review
Description	Best overall response was determined according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 by independent radiologic review. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased) and not evaluated.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (28Jan2005), approximately 14 months later, tumors assessed every 8 weeks.

Outcome Measure Data

Analysis Population Description

Evaluations of best overall response based on the valid for response population, where as per protocol, subjects were to have first post-baseline tumor evaluation performed at the end of Cycle 1 (6 weeks post-randomization). Of the ITT population that met this criteria as of the 28Jan2005 data cut, 672 subjects were valid for response.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Placebo tablets matching in appearance were to be orally administered twice a day.
Measure Participants	335	337
Complete Response	0.0 0%	0.0 0%
Partial Response	2.1 0.5%	0.0 0%
Stable Disease	77.9 17.3%	55.2 12.2%
Progressive Disease	8.7 1.9%	30.3 6.7%
Not Evaluated	11.3 2.5%	14.5 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in response rates (CR+PR)
	Estimated Value	-2.1
	Confidence Interval	() 95%; -3.7 to -0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	difference in response rates (CR+PR) = Placebo - Sorafenib

5. Secondary Outcome

Title	Health-related Quality of Life (HRQOL) by FKSI-10 (Functional Assessment of General Therapy Kidney Symptom Index 10) Assessment
Description	Primary Analysis for FKSI-10 patient-reported outcome (PRO) measure defined as longitudinal analysis of mean score over the first 5 treatment cycles. FKSI-10 patient responses for each question range from "0=not at all" to "4=very much" and after reverse coding the range of values for FKSI-10 total score is from 0 to 40; higher score represents better HRQOL.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (31May2005), approximately 18 months later, PRO data collected at Day 1 of each cycle and end of treatment.

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population with a PRO assessment. Day 1, Cycle 1 served as baseline assessment.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Measure Participants	451	452
Cycle 2, Day 1	27.77 (0.23)	27.78 (0.22)
Cycle 3, Day 1	27.27 (0.22)	27.28 (0.23)
Cycle 4, Day 1	26.77 (0.25)	26.78 (0.26)
Cycle 5, Day 1	26.27 (0.30)	26.28 (0.31)
Cycles 1-5 (Overall)	27.19 (0.23)	27.20 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	Approximately 200 subjects per group, assuming a 10% drop out rate, were required to detect a 2 point difference between sorafenib and placebo at approximately 80% power with a two-sided alpha of 0.05
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	random coefficient model
	Comments	Random coefficient model adjusted for baseline Motzer score, baseline FKSI-10 score and relative day of FKSI-10 completion.

6. Secondary Outcome

Title	Health-related Quality of Life (HRQOL) by Physical Well-Being (PWB) Score of the FACT-G (Functional Assessment of Cancer Therapy-General Version) Assessment
Description	Primary Analysis for FACT-G (using PWB score) patient-reported outcome (PRO) measure defined as longitudinal analysis of mean score over the first 5 treatment cycles. FACT-G (PWB score) patient responses for each question range from "0=not at all" to "4=very much" and after reverse coding the total FACT-G (PWB score) range of values is from 0 to 28; higher score represents better HRQOL.
Time Frame	From start of randomization of the first subject (1Dec2003) until the data cut-off (31May2005), approximately 18 months later, PRO data collected at Day 1 of each cycle and end of treatment.

Outcome Measure Data

Analysis Population Description

Evaluations based on ITT population with a PRO assessment. Day 1, Cycle 1 served as baseline assessment.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Placebo
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Dose modification due to toxicity was permitted.	Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]
Measure Participants	451	452
Cycle 2, Day 1	21.21 (0.17)	21.16 (0.19)
Cycle 3, Day 1	20.77 (0.17)	20.72 (0.19)
Cycle 4, Day 1	20.33 (0.19)	20.28 (0.22)
Cycle 5, Day 1	19.89 (0.24)	19.84 (0.26)
Cycles 1-5 (Overall)	20.70 (0.17)	20.65 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Placebo
	Comments	Approximately 200 subjects per group, assuming a 10% drop out rate, were required to detect a 2 point difference between sorafenib and placebo at approximately 80% power with a two-sided alpha of 0.05
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.83
	Comments
	Method	random coefficient model
	Comments	Random coefficient model adjusted for baseline Motzer score, baseline PWB score and relative day of PWB completion.

Adverse Events

Time Frame	In addition, 1 participant who was not randomized to double-blind treatment received sorafenib treatment on a compassionate-use basis in the crossover phase and was included in the safety population only.
Adverse Event Reporting Description	DIC (disseminated intravascular coagulation), AT (Atrial tachycardia), NOS (not otherwise specified), GI (gastro-intestinal), CTCAE (Common Terminology Criteria for Adverse Events), ANC (absolute neutrophil count), CNS (central nervous system), CN (cranial nerve), GU (genitourinary)
Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)-31May2005 DB		Placebo-31May2005 DB		Sorafenib (Nexavar, BAY43-9006)-30Jun2008		Placebo ~31May2005, Then Switched to Sorafenib Only-30Jun2008
Arm/Group Description	Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Double Blind period-31May2005		Subjects received matching placebo tablets administered orally twice a day. [until ~31 May 2005]		Sorafenib was to be orally administered as 2 x 200 mg tablets bid (twice daily). Double Blind-30Jun2008. In addition, 1 participant who was not randomized to double-blind treatment received sorafenib treatment on a compassionate-use basis in the open-label/Sorafenib only phase and was included in the safety population only. Participants affected may deviate from double-blind phase due to data update and cleaning.		Sorafenib period only-30Jun2008: Subjects received matching placebo tablets administered orally twice a day(as of ~31 May 2005) when after unblinding subjects switched over to receive Sorafenib orally administered as 2 x 200 mg tablets bid (twice daily). Open Label/Sorafenib only period-30Jun2008
All Cause Mortality
	Sorafenib (Nexavar, BAY43-9006)-31May2005 DB		Placebo-31May2005 DB		Sorafenib (Nexavar, BAY43-9006)-30Jun2008		Placebo ~31May2005, Then Switched to Sorafenib Only-30Jun2008
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sorafenib (Nexavar, BAY43-9006)-31May2005 DB		Placebo-31May2005 DB		Sorafenib (Nexavar, BAY43-9006)-30Jun2008		Placebo ~31May2005, Then Switched to Sorafenib Only-30Jun2008
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	154/451 (34.1%)		110/451 (24.4%)		245/452 (54.2%)		124/216 (57.4%)
Blood and lymphatic system disorders
Hemoglobin	8/451 (1.8%)		11/451 (2.4%)		16/452 (3.5%)		9/216 (4.2%)
Blood - Other	1/451 (0.2%)		1/451 (0.2%)		2/452 (0.4%)		0/216 (0%)
Platelets	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
DIC	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Edema: Limb	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Lymphatics - Other	2/451 (0.4%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Cardiac disorders
Supraventricular Arrhythmia, Atrial Fibrillation	1/451 (0.2%)		1/451 (0.2%)		3/452 (0.7%)		1/216 (0.5%)
Supraventricular Arrhythmia,supraventricular Arrhythmia NOS	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Cardiac Arrhythmia - Other	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		1/216 (0.5%)
Supraventricular Arrhythmia, ATrial Tach/Paroxysmal AT	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		1/216 (0.5%)
Supraventricular Arrhythmia, Sinus Tachycardia	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Cardiac Arrest	5/451 (1.1%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Restrictive Cardiomyopathy	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Left Ventricular Diastolic Dysfunction	2/451 (0.4%)		0/451 (0%)		2/452 (0.4%)		0/216 (0%)
Pericardial Effusion	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hypertension	5/451 (1.1%)		0/451 (0%)		6/452 (1.3%)		3/216 (1.4%)
Cardiac Ischemia/Infarction	11/451 (2.4%)		2/451 (0.4%)		18/452 (4%)		3/216 (1.4%)
Hypotension	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		0/216 (0%)
Myocarditis	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Cardiac General - Other	2/451 (0.4%)		0/451 (0%)		13/452 (2.9%)		9/216 (4.2%)
Left Ventricular Systolic Dysfunction	1/451 (0.2%)		0/451 (0%)		4/452 (0.9%)		4/216 (1.9%)
Eye disorders
Eyelid Dysfunction	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Ocular - Other	0/451 (0%)		1/451 (0.2%)		1/452 (0.2%)		0/216 (0%)
Retinal Detachment	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Retinopathy	1/451 (0.2%)		0/451 (0%)		0/452 (0%)		0/216 (0%)
Gastrointestinal disorders
Anorexia	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		0/216 (0%)
Ascites	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		2/216 (0.9%)
Colitis	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Constipation	4/451 (0.9%)		2/451 (0.4%)		5/452 (1.1%)		2/216 (0.9%)
Dehydration	4/451 (0.9%)		1/451 (0.2%)		6/452 (1.3%)		0/216 (0%)
Diarrhea	3/451 (0.7%)		0/451 (0%)		5/452 (1.1%)		3/216 (1.4%)
Dysphagia	0/451 (0%)		0/451 (0%)		4/452 (0.9%)		0/216 (0%)
Enteritis	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Esophagitis	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Fistula, GI, Colon/Cecum/Appendix	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Fistula, GI, Duodenum	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Gastritis	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Mucositis (Functional/Symptomatic), Esophagus	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Mucositis (Functional/Symptomatic), Oral Cavity	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Nausea	1/451 (0.2%)		5/451 (1.1%)		1/452 (0.2%)		1/216 (0.5%)
Ileus	0/451 (0%)		2/451 (0.4%)		0/452 (0%)		0/216 (0%)
Obstruction, GI, Colon	1/451 (0.2%)		1/451 (0.2%)		1/452 (0.2%)		1/216 (0.5%)
Obstruction, GI, Duodenum	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Obstruction, GI, Gallbladder	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Obstruction, GI, Ileum	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		0/216 (0%)
Obstruction, GI, Small Bowel NOS	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		1/216 (0.5%)
GI - Other	3/451 (0.7%)		1/451 (0.2%)		8/452 (1.8%)		4/216 (1.9%)
Perforation, GI, Colon	1/451 (0.2%)		1/451 (0.2%)		1/452 (0.2%)		2/216 (0.9%)
Perforation, GI, Small Bowel NOS	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Perforation, GI, Stomach	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Stricture, GI, Biliary Tree	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Stricture, GI, Small Bowel NOS	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Ulcer, GI, Duodenum	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		1/216 (0.5%)
Vomiting	2/451 (0.4%)		5/451 (1.1%)		4/452 (0.9%)		2/216 (0.9%)
General disorders
Death Not Associated With CTCAE Term, Death NOS	0/451 (0%)		1/451 (0.2%)		3/452 (0.7%)		0/216 (0%)
Death Not Associated With CTCAE Term, Disease Progression NOS	11/451 (2.4%)		10/451 (2.2%)		39/452 (8.6%)		32/216 (14.8%)
Death Not Associated With CTCAE Term, Multi-Organ Failure	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		1/216 (0.5%)
Death Not Associated With CTCAE Term, Sudden Death	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Fever	4/451 (0.9%)		2/451 (0.4%)		4/452 (0.9%)		2/216 (0.9%)
Fatigue	7/451 (1.6%)		4/451 (0.9%)		13/452 (2.9%)		6/216 (2.8%)
Weight Loss	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Constitutional Symptoms - Other	10/451 (2.2%)		7/451 (1.6%)		11/452 (2.4%)		6/216 (2.8%)
Pain, Back	1/451 (0.2%)		2/451 (0.4%)		5/452 (1.1%)		3/216 (1.4%)
Pain, Chest/Thorax NOS	0/451 (0%)		1/451 (0.2%)		1/452 (0.2%)		2/216 (0.9%)
Pain, Chest Wall	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Pain, Extremity-Limb	0/451 (0%)		5/451 (1.1%)		1/452 (0.2%)		1/216 (0.5%)
Pain, Tumor Pain	7/451 (1.6%)		4/451 (0.9%)		7/452 (1.5%)		2/216 (0.9%)
Pain, Abdomen NOS	4/451 (0.9%)		1/451 (0.2%)		7/452 (1.5%)		4/216 (1.9%)
Pain, Head/Headache	1/451 (0.2%)		2/451 (0.4%)		2/452 (0.4%)		0/216 (0%)
Pain, Joint	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Pain, Bone	3/451 (0.7%)		3/451 (0.7%)		6/452 (1.3%)		4/216 (1.9%)
Pain, Other	4/451 (0.9%)		1/451 (0.2%)		3/452 (0.7%)		3/216 (1.4%)
Pain, Pelvis	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Pain, Neck	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Pain, Neuralgia/Peripheral Nerve	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		2/216 (0.9%)
Pain, Pain NOS	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		0/216 (0%)
Flu-Like Syndrome	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Tumor Lysis Syndrome	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Syndromes - Other	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Not Coded Yet	1/451 (0.2%)		0/451 (0%)		0/452 (0%)		0/216 (0%)
Hepatobiliary disorders
Cholecystitis	0/451 (0%)		2/451 (0.4%)		1/452 (0.2%)		2/216 (0.9%)
Liver Dysfunction	2/451 (0.4%)		2/451 (0.4%)		3/452 (0.7%)		1/216 (0.5%)
Hepatobiliary - Other	1/451 (0.2%)		0/451 (0%)		3/452 (0.7%)		3/216 (1.4%)
Pancreatitis	2/451 (0.4%)		1/451 (0.2%)		2/452 (0.4%)		2/216 (0.9%)
Immune system disorders
Allergic Reaction	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Allergy - Other	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Infections and infestations
Infection (Documented Clinically), Blood	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		1/216 (0.5%)
Infection (Documented Clinically), Bronchus	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Infection (Documented Clinically), Catheter-Related	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Infection (Documented Clinically), Colon	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Infection (Documented Clinically), Lung (Pneumonia)	2/451 (0.4%)		0/451 (0%)		3/452 (0.7%)		0/216 (0%)
Infection (Documented Clinically), Meninges (Meningitis)	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Infection (Documented Clinically), Skin (Cellulitis)	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Infection (Documented Clinically), Urinary Tract NOS	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		1/216 (0.5%)
Infection (Documented Clinically), Vein	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Infection (Documented Clinically), Wound	0/451 (0%)		1/451 (0.2%)		1/452 (0.2%)		0/216 (0%)
Infection With Normal ANC, Appendix	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Infection With Normal ANC, Bronchus	0/451 (0%)		0/451 (0%)		0/452 (0%)		3/216 (1.4%)
Infection With Normal ANC, Catheter-Related	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Infection With Normal ANC, Lung (Pneumonia)	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		1/216 (0.5%)
Infection With Normal ANC, PANCreas	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Infection With Normal ANC, Pelvis NOS	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Infection With Normal ANC, Urinary Tract NOS	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Opportunistic Infection	1/451 (0.2%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Infection - Other	1/451 (0.2%)		1/451 (0.2%)		2/452 (0.4%)		3/216 (1.4%)
Infection With Unknown ANC, Abdomen NOS	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Infection With Unknown ANC, Bronchus	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Infection With Unknown ANC, Lung (Pneumonia)	1/451 (0.2%)		1/451 (0.2%)		2/452 (0.4%)		1/216 (0.5%)
Infection With Unknown ANC, Meninges (Meningitis)	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Infection With Unknown ANC, Upper Airway NOS	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Infection With Unknown ANC, Urinary Tract NOS	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Injury, poisoning and procedural complications
Intraop Injury, Liver	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Intraop Injury, Extremity - Upper	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Intraop Injury, Bone	2/451 (0.4%)		0/451 (0%)		0/452 (0%)		2/216 (0.9%)
Intraop Injury, Soft Tissue NOS	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Intraop Injury - Other	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		1/216 (0.5%)
Metabolism and nutrition disorders
Creatinine	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Hypercalcemia	3/451 (0.7%)		6/451 (1.3%)		3/452 (0.7%)		0/216 (0%)
Hyperkalemia	0/451 (0%)		1/451 (0.2%)		3/452 (0.7%)		1/216 (0.5%)
Hypernatremia	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hypoalbuminemia	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hypocalcemia	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		3/216 (1.4%)
Hypoglycemia	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Lipase	1/451 (0.2%)		0/451 (0%)		3/452 (0.7%)		0/216 (0%)
Hypokalemia	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hyponatremia	2/451 (0.4%)		0/451 (0%)		3/452 (0.7%)		1/216 (0.5%)
Metabolic/Lab - Other	1/451 (0.2%)		0/451 (0%)		3/452 (0.7%)		0/216 (0%)
Proteinuria	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		1/216 (0.5%)
Musculoskeletal and connective tissue disorders
Osteonecrosis	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		1/216 (0.5%)
Extremity-Upper (Function)	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Fracture	7/451 (1.6%)		5/451 (1.1%)		12/452 (2.7%)		3/216 (1.4%)
Musculoskeletal - Other	2/451 (0.4%)		4/451 (0.9%)		7/452 (1.5%)		5/216 (2.3%)
Gait/Walking	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Muscle Weakness, Extremity-Lower	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy (Possibly Related To Cancer Treatment)	2/451 (0.4%)		0/451 (0%)		3/452 (0.7%)		1/216 (0.5%)
Nervous system disorders
CNS Ischemia	1/451 (0.2%)		3/451 (0.7%)		7/452 (1.5%)		1/216 (0.5%)
Pyramidal Tract Disfunction	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Neuropathy: Cranial, CN VII Motor-Face; Sensory-Taste	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Cognitive DisturbANCe	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Confusion	1/451 (0.2%)		1/451 (0.2%)		3/452 (0.7%)		3/216 (1.4%)
Dizziness	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		2/216 (0.9%)
Speech Impairment	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		1/216 (0.5%)
Involuntary Movement	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Mood Alteration, Depression	2/451 (0.4%)		0/451 (0%)		3/452 (0.7%)		0/216 (0%)
Neuropathy: Motor	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Neurology - Other	5/451 (1.1%)		7/451 (1.6%)		11/452 (2.4%)		8/216 (3.7%)
Seizure	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Syncope	2/451 (0.4%)		2/451 (0.4%)		2/452 (0.4%)		0/216 (0%)
Tremor	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Renal and urinary disorders
Cystitis	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Urinary Electrolyte Wasting	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Renal Failure	8/451 (1.8%)		2/451 (0.4%)		9/452 (2%)		4/216 (1.9%)
Renal - Other	4/451 (0.9%)		2/451 (0.4%)		13/452 (2.9%)		6/216 (2.8%)
Obstruction, GU, Ureter	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		1/216 (0.5%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Cough	2/451 (0.4%)		0/451 (0%)		2/452 (0.4%)		0/216 (0%)
Pleural Effusion	8/451 (1.8%)		4/451 (0.9%)		11/452 (2.4%)		2/216 (0.9%)
Edema: Larynx	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Hypoxia	1/451 (0.2%)		1/451 (0.2%)		2/452 (0.4%)		0/216 (0%)
Airway Obstruction, Bronchus	2/451 (0.4%)		2/451 (0.4%)		2/452 (0.4%)		0/216 (0%)
Pulmonary - Other	5/451 (1.1%)		4/451 (0.9%)		9/452 (2%)		3/216 (1.4%)
Pneumonitis	6/451 (1.3%)		1/451 (0.2%)		7/452 (1.5%)		5/216 (2.3%)
Pneumothorax	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Dyspnea (Shortness Of Breath)	11/451 (2.4%)		8/451 (1.8%)		21/452 (4.6%)		10/216 (4.6%)
Skin and subcutaneous tissue disorders
Dermatitis, Chemoradiation	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Decubitus	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hand-Foot Skin Reaction	2/451 (0.4%)		0/451 (0%)		2/452 (0.4%)		1/216 (0.5%)
Wound Complication, Non-Infectious	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Dermatology - Other	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		1/216 (0.5%)
Dermatitis, Radiation	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Rash/Desquamation	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		3/216 (1.4%)
Skin Ulceration	0/451 (0%)		0/451 (0%)		0/452 (0%)		1/216 (0.5%)
Vascular disorders
CNS Hemorrhage	1/451 (0.2%)		1/451 (0.2%)		2/452 (0.4%)		0/216 (0%)
Hemorrhage, GI, Abdomen NOS	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hemorrhage, GI, Anus	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hemorrhage, GI, Colon	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hemorrhage, GI, Duodenum	1/451 (0.2%)		0/451 (0%)		2/452 (0.4%)		0/216 (0%)
Hemorrhage, GI, Stomach	0/451 (0%)		0/451 (0%)		3/452 (0.7%)		0/216 (0%)
Hemorrhage, GI, Jejunum	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hemorrhage, GI, Lower GI NOS	0/451 (0%)		0/451 (0%)		2/452 (0.4%)		0/216 (0%)
Hemorrhage, GI, Rectum	2/451 (0.4%)		0/451 (0%)		2/452 (0.4%)		1/216 (0.5%)
Hemorrhage, GI, Upper GI NOS	0/451 (0%)		2/451 (0.4%)		4/452 (0.9%)		0/216 (0%)
Hemorrhage With Surgery	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Hemorrhage - Other	3/451 (0.7%)		1/451 (0.2%)		4/452 (0.9%)		2/216 (0.9%)
Hemorrhage Pulmonary, Bronchopulmonary NOS	3/451 (0.7%)		2/451 (0.4%)		4/452 (0.9%)		2/216 (0.9%)
Hemorrhage Pulmonary, Bronchus	0/451 (0%)		2/451 (0.4%)		0/452 (0%)		0/216 (0%)
Hemorrhage Pulmonary, Larynx	0/451 (0%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hemorrhage Pulmonary, Lung	1/451 (0.2%)		1/451 (0.2%)		1/452 (0.2%)		0/216 (0%)
Hemorrhage Pulmonary, Nose	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		2/216 (0.9%)
Hemorrhage Pulmonary, Pleura	0/451 (0%)		1/451 (0.2%)		0/452 (0%)		0/216 (0%)
Hemorrhage Pulmonary, Respiratory Tract NOS	2/451 (0.4%)		0/451 (0%)		3/452 (0.7%)		1/216 (0.5%)
Hemorrhage, GU, Uterus	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		0/216 (0%)
Hemorrhage, GU, Urinary NOS	1/451 (0.2%)		0/451 (0%)		1/452 (0.2%)		1/216 (0.5%)
Thrombosis/Embolism (Vascular Access)	2/451 (0.4%)		0/451 (0%)		1/452 (0.2%)		2/216 (0.9%)
Vascular - Other	0/451 (0%)		0/451 (0%)		4/452 (0.9%)		1/216 (0.5%)
Thrombosis/Thrombus/Embolism	4/451 (0.9%)		5/451 (1.1%)		9/452 (2%)		6/216 (2.8%)
Other (Not Including Serious) Adverse Events
	Sorafenib (Nexavar, BAY43-9006)-31May2005 DB		Placebo-31May2005 DB		Sorafenib (Nexavar, BAY43-9006)-30Jun2008		Placebo ~31May2005, Then Switched to Sorafenib Only-30Jun2008
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	407/451 (90.2%)		346/451 (76.7%)		425/452 (94%)		200/216 (92.6%)
Blood and lymphatic system disorders
Hemoglobin	30/451 (6.7%)		29/451 (6.4%)		61/452 (13.5%)		23/216 (10.6%)
Edema: Limb	28/451 (6.2%)		22/451 (4.9%)		42/452 (9.3%)		16/216 (7.4%)
Cardiac disorders
Hypertension	74/451 (16.4%)		8/451 (1.8%)		101/452 (22.3%)		39/216 (18.1%)
Gastrointestinal disorders
Anorexia	73/451 (16.2%)		57/451 (12.6%)		111/452 (24.6%)		58/216 (26.9%)
Constipation	66/451 (14.6%)		48/451 (10.6%)		79/452 (17.5%)		31/216 (14.4%)
Diarrhea	195/451 (43.2%)		58/451 (12.9%)		244/452 (54%)		118/216 (54.6%)
Heartburn	21/451 (4.7%)		10/451 (2.2%)		27/452 (6%)		8/216 (3.7%)
Mucositis (Functional/Symptomatic), Oral Cavity	17/451 (3.8%)		11/451 (2.4%)		27/452 (6%)		26/216 (12%)
Mucositis (Clinical Exam), Oral Cavity	30/451 (6.7%)		3/451 (0.7%)		36/452 (8%)		11/216 (5.1%)
Nausea	102/451 (22.6%)		86/451 (19.1%)		121/452 (26.8%)		42/216 (19.4%)
GI - Other	25/451 (5.5%)		18/451 (4%)		37/452 (8.2%)		7/216 (3.2%)
Vomiting	72/451 (16%)		51/451 (11.3%)		89/452 (19.7%)		28/216 (13%)
General disorders
Fever	36/451 (8%)		34/451 (7.5%)		48/452 (10.6%)		16/216 (7.4%)
Insomnia	16/451 (3.5%)		20/451 (4.4%)		35/452 (7.7%)		9/216 (4.2%)
Fatigue	162/451 (35.9%)		122/451 (27.1%)		221/452 (48.9%)		86/216 (39.8%)
Weight Loss	46/451 (10.2%)		25/451 (5.5%)		102/452 (22.6%)		60/216 (27.8%)
Constitutional Symptoms - Other	38/451 (8.4%)		20/451 (4.4%)		41/452 (9.1%)		19/216 (8.8%)
Sweating	28/451 (6.2%)		17/451 (3.8%)		33/452 (7.3%)		11/216 (5.1%)
Pain, Back	33/451 (7.3%)		39/451 (8.6%)		52/452 (11.5%)		17/216 (7.9%)
Pain, Chest/Thorax NOS	18/451 (4%)		12/451 (2.7%)		26/452 (5.8%)		6/216 (2.8%)
Pain, Extremity-Limb	26/451 (5.8%)		20/451 (4.4%)		44/452 (9.7%)		16/216 (7.4%)
Pain, Tumor Pain	27/451 (6%)		20/451 (4.4%)		32/452 (7.1%)		8/216 (3.7%)
Pain, Abdomen NOS	46/451 (10.2%)		41/451 (9.1%)		69/452 (15.3%)		23/216 (10.6%)
Pain, Head/Headache	46/451 (10.2%)		26/451 (5.8%)		57/452 (12.6%)		17/216 (7.9%)
Pain, Joint	45/451 (10%)		29/451 (6.4%)		59/452 (13.1%)		12/216 (5.6%)
Pain, Muscle	41/451 (9.1%)		21/451 (4.7%)		48/452 (10.6%)		6/216 (2.8%)
Pain, Bone	33/451 (7.3%)		34/451 (7.5%)		61/452 (13.5%)		23/216 (10.6%)
Pain, Other	31/451 (6.9%)		16/451 (3.5%)		60/452 (13.3%)		28/216 (13%)
Infections and infestations
Infection - Other	35/451 (7.8%)		26/451 (5.8%)		56/452 (12.4%)		21/216 (9.7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal - Other	23/451 (5.1%)		21/451 (4.7%)		36/452 (8%)		12/216 (5.6%)
Nervous system disorders
Dizziness	17/451 (3.8%)		23/451 (5.1%)		24/452 (5.3%)		6/216 (2.8%)
Mood Alteration, Depression	12/451 (2.7%)		16/451 (3.5%)		25/452 (5.5%)		8/216 (3.7%)
Neuropathy: Sensory	59/451 (13.1%)		29/451 (6.4%)		67/452 (14.8%)		21/216 (9.7%)
Respiratory, thoracic and mediastinal disorders
Cough	59/451 (13.1%)		64/451 (14.2%)		92/452 (20.4%)		27/216 (12.5%)
Pulmonary - Other	25/451 (5.5%)		15/451 (3.3%)		38/452 (8.4%)		11/216 (5.1%)
Dyspnea (Shortness Of Breath)	58/451 (12.9%)		49/451 (10.9%)		94/452 (20.8%)		29/216 (13.4%)
Voice Changes	19/451 (4.2%)		1/451 (0.2%)		23/452 (5.1%)		6/216 (2.8%)
Skin and subcutaneous tissue disorders
Alopecia	122/451 (27.1%)		15/451 (3.3%)		143/452 (31.6%)		76/216 (35.2%)
Dry Skin	50/451 (11.1%)		18/451 (4%)		63/452 (13.9%)		22/216 (10.2%)
Hand-Foot Skin Reaction	133/451 (29.5%)		30/451 (6.7%)		156/452 (34.5%)		84/216 (38.9%)
Dermatology - Other	67/451 (14.9%)		20/451 (4.4%)		84/452 (18.6%)		30/216 (13.9%)
Pruritus	85/451 (18.8%)		29/451 (6.4%)		90/452 (19.9%)		27/216 (12.5%)
Rash/Desquamation	179/451 (39.7%)		70/451 (15.5%)		196/452 (43.4%)		70/216 (32.4%)
Flushing	33/451 (7.3%)		13/451 (2.9%)		40/452 (8.8%)		9/216 (4.2%)
Vascular disorders
Hematoma	18/451 (4%)		5/451 (1.1%)		23/452 (5.1%)		2/216 (0.9%)

Limitations/Caveats

Per final PFS data (N=769) study unblinded; placebo-randomized subjects switched to sorafenib ~31May2005 (N=216) that diluted final OS, sorafenib treatment effect. Final ITT, N=903, reported safety data include additional data and cleaning.

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Certain Agreements

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

The agreed point of publication is 12-18 months after database lock at the earliest. Bayer will have up to 30/45 days to review publications, and may request an additional publication delay of up to 60 days to allow for filing a Patent Application (if applicable). No publication of single center data should be done prior of publication if multi -center data.