A Treatment Combination for Patients With Unresectable Stage III or Stage IV Melanoma

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00111007
• Collaborator: Amgen (Industry)
• Enrollment: 270
• Locations: 66
• Arms: 2
• Duration (Months): 44.1
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The objectives of this study are to compare the anti-tumor activity as measured by Progression Free Survival (PFS) and tolerability of Sorafenib in combination with Paclitaxel and Carboplatin versus Paclitaxel and Carboplatin in combination with placebo in subjects with unresectable Stage III or Stage IV melanoma who progressed after receiving only one prior therapy containing Dacarbazine (DTIC) or Temozolomide (TMZ).

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: Sorafenib (Nexavar, BAY43-9006); Drug: Carboplatin/Paclitaxel; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 270 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Phase III Randomized, Placebo Controlled Study of Sorafenib in Repeated Cycles of 21 Days in Combination With Paclitaxel/Carboplatin Chemotherapy in Subjects With Unresectable Stage III or Stage IV Melanoma.
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Sep 1, 2006
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sorafenib (Nexavar, BAY43-9006) Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Drug: Sorafenib (Nexavar, BAY43-9006); Sorafenib, 400 mg po (per os), 2 tablets (200 mg each) bid Study Days 2-19; Drug: Carboplatin/Paclitaxel; Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1
Active Comparator: Carboplatin/Paclitaxel (C/P) Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Drug: Carboplatin/Paclitaxel; Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1; Drug: Placebo; Placebo, 2 tablets bid Study Days 2-19

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Time from randomization to documented tumor progression or death (median time of 124 days)]

   PFS was calculated as the time (days) from date of randomization to date of first observed DP (per modified Response Evaluation Criteria In Solid Tumors [RECIST] or clinical judgment, whichever was earlier: CR, PR, stable disease, progressive disease) or death due to any cause, if death occurred before progression was documented. The actual date of tumor assessments was used for this calculation. PFS for subjects without progression or death was censored at the last date of tumor evaluation. PFS for subjects who had no tumor assessments after baseline and did not die was censored at 1 day.

Secondary Outcome Measures

1. Overall Survival (OS) [Time from randomization to death (median time of 294 days)]

   Overall survival (OS) was calculated as the number of days from date of randomization to death date. Subjects who had not died at the time of analysis were censored at their last contact date.

2. Time to Progression (TTP) [Time from randomization to documented tumor progression (median time of 126 days)]

   TTP was calculated as the time (days) from date of randomization to date of first observed disease progression (DP) (per modified RECIST or clinical judgment, whichever was earlier: CR, PR, stable disease, progressive disease). The actual dates of tumor assessments were used for this calculation. TTP for subjects without disease progression at the time of analysis, including subjects with death prior to progression, was censored at the last date of tumor evaluation. TTP for subjects who had no tumor assessments after baseline was censored at 1 day.

3. Duration of Response (DOR) [Time from initial response to documented tumor progression or death (median time of 197 days)]

   Duration of response was defined as the time from the first documented objective response of Partial Response (PR: At least a 30% decrease in the sum of the longest diameter [SLD] of target lesions, taking as reference the baseline SLD or better) or Complete Response (CR: Disappearance of all target lesions), whichever was noted earlier, to disease progression or death (if death occurred before progression was documented). Duration of response for subjects who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment.

4. Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted [baseline and at visit when best response was noted (maximum treatment duration of 68.3 weeks)]

   Change in ECOG PS is defined as an improvement (increase) or worsening (decrease) of at least one grade from the baseline ECOG score (from 0 [fully active] to 5 [dead]). Change in ECOG PS was recorded at the visit at which best confirmed response (BCR) using the modified RECIST (PR, CR, stable disease or Progressive Disease (PD)) was first noted (the change was 7% for both Sorafenib and Placebo). The BCR is the BCR recorded from the start of the treatment until DP/recurrence (taking as reference for DP, the smallest measurements recorded since treatment started).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects who have a life expectancy of at least 12 weeks

• Subjects with histologically or cytologically confirmed unresectable (Stage III) or metastatic (Stage IV) melanoma

• Subjects must have progressed after receiving at least one cycle of DTIC or TMZ containing regimen

• Subjects who have an ECOG PS of 0 or 1

• Measurable disease defined as at least one lesion that can be accurately and serially measured per the modified RECIST criteria

Exclusion Criteria:

• Primary ocular or mucosal melanoma

• Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta [Noninvasive papillary carcinoma], Tis [Carcinoma in situ: "flat tumor"]& T1 [Tumor invades subepithelial connective tissue]) or any cancer curatively treated < 5 years prior to study entry

• History of cardiac disease

• Known history of human immunodeficiency virus (HIV) infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35243
2		Tucson	Arizona	United States	85724
3		Los Angeles	California	United States	90025
4		Aurora	Colorado	United States	80045
5		Tampa	Florida	United States	33612
6		Chicago	Illinois	United States	60612
7		Park Ridge	Illinois	United States	60068
8		Louisville	Kentucky	United States	40202
9		St. Louis	Missouri	United States	63110
10		Omaha	Nebraska	United States	68114
11		Montclair	New Jersey	United States	07042
12		Buffalo	New York	United States	14263
13		New York	New York	United States	10065
14		Columbus	Ohio	United States	43221
15		Pittsburgh	Pennsylvania	United States	15232
16		Nashville	Tennessee	United States	37232-6307
17		Houston	Texas	United States	77030
18		Charlottesville	Virginia	United States	22908
19		Seattle	Washington	United States	98109-1023
20		Camperdown	New South Wales	Australia	2050
21		Warartah	New South Wales	Australia	2300
22		Westmead	New South Wales	Australia	2145
23		Brisbane	Queensland	Australia	4101
24		East Melbourne	Victoria	Australia	3002
25		Heidelberg	Victoria	Australia	3084
26		Malvern	Victoria	Australia	3144
27		Melbourne	Victoria	Australia	3004
28		Nedlands	Western Australia	Australia	6009
29		Calgary	Alberta	Canada	T2N 4N2
30		Edmonton	Alberta	Canada	T6G 1Z2
31		London	Ontario	Canada	N6A 4L6
32		Toronto	Ontario	Canada	M4N 3M5
33		Toronto	Ontario	Canada	M5G 2M9
34		Montreal	Quebec	Canada	H3T 1E2
35		Bordeaux		France	33000
36		Boulogne-billancourt		France	92104
37		Brest		France	29285
38		Lyon Cedex		France	39373
39		Montpellier Cedex		France	34298
40		Paris		France	75010
41		Paris		France	75634
42		Villejuif		France	94805
43		Heidelberg	Baden-Württemberg	Germany	69112
44		Mannheim	Baden-Württemberg	Germany	68135
45		Tübingen	Baden-Württemberg	Germany	72076
46		München	Bayern	Germany	81675
47		Frankfurt	Hessen	Germany	60488
48		Frankfurt	Hessen	Germany	60590
49		Essen	Nordrhein-Westfalen	Germany	45122
50		Trier	Rheinland-Pfalz	Germany	54290
51		Homburg	Saarland	Germany	66421
52		Kiel	Schleswig-Holstein	Germany	24105
53		Berlin		Germany	12200
54		Amsterdam		Netherlands	1066 CX
55		Rotterdam		Netherlands	3075 EA
56		Utrecht		Netherlands	3584 CX
57		Southampton	Hampshire	United Kingdom	SO16 6YD
58		Leicester	Leicestershire	United Kingdom	LE1 5WW
59		Bebington	Merseyside	United Kingdom	CH63 4JY
60		Nottingham	Nottinghamshire	United Kingdom	NG5 1PB
61		Sutton	Surrey	United Kingdom	SM2 5PT
62		Leeds	West Yorkshire	United Kingdom	LS9 7TF
63		London		United Kingdom	SE1 9RT
64		London		United Kingdom	SW3 6JJ
65		Manchester		United Kingdom	M20 4BX
66		Swansea		United Kingdom	SA2 8QA

Sponsors and Collaborators

• Bayer
• Amgen

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here and search for information of Bayer products for Europe

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT00111007
• Other Study ID Numbers: 11718; 2005-000941-12; NCT00262912
• First Posted: May 17, 2005
• Last Update Posted: Oct 31, 2014
• Last Verified: Oct 1, 2014

• Additional relevant MeSH terms: Melanoma; Paclitaxel; Carboplatin; Sorafenib

Study Results

Participant Flow

Recruitment Details	The study was conducted from May 4 2005 to Jan 08 2009 (first subject's first visit to last subject's last visit) at 54 centers in 7 countries: Australia (6), Canada (6), France (6), Germany (10), Netherlands (2), United Kingdom (8), and United States (16).
Pre-assignment Detail	Of 315 screened subjects, 270 were randomized (45 failed screening) and were valid for Intent-To-Treat (ITT) analyses (135 in each treatment group). One subject in each group did not receive treatment: 1 died and 1 withdrew consent. Thus, 268 subjects received treatment (134 in each group) and were valid for the safety analyses.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Carboplatin/Paclitaxel (C/P)
Arm/Group Description	Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.
Period Title: Double-blind (DB) Treatment
STARTED	135	135
Received Treatment	134	134
COMPLETED	27	24
NOT COMPLETED	108	111
Period Title: Double-blind (DB) Treatment
STARTED	6	4
COMPLETED	0	2
NOT COMPLETED	6	2
Period Title: Double-blind (DB) Treatment
STARTED	101	107
COMPLETED	54	62
NOT COMPLETED	47	45

Baseline Characteristics

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Carboplatin/Paclitaxel (C/P)	Total
Arm/Group Description	Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Total of all reporting groups
Overall Participants	135	135	270
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.0 (12.8)	55.1 (13.0)	55.5 (57.0)
Age, Customized (participants) [Number]
<65 years	97 71.9%	92 68.1%	189 70%
65 to 74 years	29 21.5%	39 28.9%	68 25.2%
>=75 years	9 6.7%	4 3%	13 4.8%
Sex: Female, Male (Count of Participants)
Female	51 37.8%	48 35.6%	99 36.7%
Male	84 62.2%	87 64.4%	171 63.3%
American Joint Committee on Cancer (AJCC) Stage at Study Entry (participants) [Number]
Stage III or IV M1a	16 11.9%	11 8.1%	27 10%
Stage IV M1b	27 20%	31 23%	58 21.5%
Stage IV M1c	92 68.1%	93 68.9%	185 68.5%
Baseline Eastern Cooperative Oncology Group (ECOG) Performance (participants) [Number]
Status 0	76 56.3%	70 51.9%	146 54.1%
Status 1	59 43.7%	65 48.1%	124 45.9%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was calculated as the time (days) from date of randomization to date of first observed DP (per modified Response Evaluation Criteria In Solid Tumors [RECIST] or clinical judgment, whichever was earlier: CR, PR, stable disease, progressive disease) or death due to any cause, if death occurred before progression was documented. The actual date of tumor assessments was used for this calculation. PFS for subjects without progression or death was censored at the last date of tumor evaluation. PFS for subjects who had no tumor assessments after baseline and did not die was censored at 1 day.
Time Frame	Time from randomization to documented tumor progression or death (median time of 124 days)

Outcome Measure Data

Analysis Population Description

PFS was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Carboplatin/Paclitaxel (C/P)
Arm/Group Description	Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.
Measure Participants	135	135
Median (95% Confidence Interval) [days]	122	125

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Carboplatin/Paclitaxel (C/P)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.492
	Comments
	Method	log rank test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.906
	Confidence Interval	(2-Sided) 95%; 0.627 to 1.310
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) was calculated as the number of days from date of randomization to death date. Subjects who had not died at the time of analysis were censored at their last contact date.
Time Frame	Time from randomization to death (median time of 294 days)

Outcome Measure Data

Analysis Population Description

OS was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Carboplatin/Paclitaxel (C/P)
Arm/Group Description	Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.
Measure Participants	135	135
Median (95% Confidence Interval) [days]	294	294

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Carboplatin/Paclitaxel (C/P)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.979
	Comments
	Method	log rank test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.996
	Confidence Interval	(2-Sided) 95%; 0.744 to 1.333
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Time to Progression (TTP)
Description	TTP was calculated as the time (days) from date of randomization to date of first observed disease progression (DP) (per modified RECIST or clinical judgment, whichever was earlier: CR, PR, stable disease, progressive disease). The actual dates of tumor assessments were used for this calculation. TTP for subjects without disease progression at the time of analysis, including subjects with death prior to progression, was censored at the last date of tumor evaluation. TTP for subjects who had no tumor assessments after baseline was censored at 1 day.
Time Frame	Time from randomization to documented tumor progression (median time of 126 days)

Outcome Measure Data

Analysis Population Description

TTP was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Carboplatin/Paclitaxel (C/P)
Arm/Group Description	Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.
Measure Participants	135	135
Median (95% Confidence Interval) [days]	126	126

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Carboplatin/Paclitaxel (C/P)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.331
	Comments
	Method	log rank test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.863
	Confidence Interval	(2-Sided) 95%; 0.641 to 1.162
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Duration of Response (DOR)
Description	Duration of response was defined as the time from the first documented objective response of Partial Response (PR: At least a 30% decrease in the sum of the longest diameter [SLD] of target lesions, taking as reference the baseline SLD or better) or Complete Response (CR: Disappearance of all target lesions), whichever was noted earlier, to disease progression or death (if death occurred before progression was documented). Duration of response for subjects who had not progressed or died at the time of analysis was censored at the date of their last tumor assessment.
Time Frame	Time from initial response to documented tumor progression or death (median time of 197 days)

Outcome Measure Data

Analysis Population Description

DOR was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Carboplatin/Paclitaxel (C/P)
Arm/Group Description	Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.
Measure Participants	135	135
Median (Full Range) [days]	228	166

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Carboplatin/Paclitaxel (C/P)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.146
	Comments
	Method	log rank test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.398
	Confidence Interval	(2-Sided) 95%; 0.110 to 1.437
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status to the Visit When the Best Tumor Response Was Noted
Description	Change in ECOG PS is defined as an improvement (increase) or worsening (decrease) of at least one grade from the baseline ECOG score (from 0 [fully active] to 5 [dead]). Change in ECOG PS was recorded at the visit at which best confirmed response (BCR) using the modified RECIST (PR, CR, stable disease or Progressive Disease (PD)) was first noted (the change was 7% for both Sorafenib and Placebo). The BCR is the BCR recorded from the start of the treatment until DP/recurrence (taking as reference for DP, the smallest measurements recorded since treatment started).
Time Frame	baseline and at visit when best response was noted (maximum treatment duration of 68.3 weeks)

Outcome Measure Data

Analysis Population Description

Change in ECOG PS was analyzed for the intent to treat (ITT) population, defined as all subjects randomized to treatment. For the ITT population, subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)	Carboplatin/Paclitaxel (C/P)
Arm/Group Description	Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.	Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.
Measure Participants	135	135
missing	10 7.4%	4 3%
better	9 6.7%	10 7.4%
no change	70 51.9%	82 60.7%
worse	46 34.1%	39 28.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sorafenib (Nexavar, BAY43-9006), Carboplatin/Paclitaxel (C/P)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.389
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Adverse Event Reporting Description	Abbreviations used in the Adverse Events section: Absolute Neutrophil Count (ANC), Aspartate Aminotransferase (AST), Central Nervous System (CNS), Common Terminology Criteria for Adverse Events (CTCAE), Gastro-Intestinal (GI), Genito-Urinary (GU), National Cancer Institute (NCI), Not Otherwise Specified (NOS)
Arm/Group Title	Sorafenib (Nexavar, BAY43-9006)		Carboplatin/Paclitaxel (C/P)
Arm/Group Description	Sorafenib, 400 mg orally, 2 tablets (200 mg each) bid (bis in die [twice daily]) on Study Days 2 to 19 + Paclitaxel (225 mg/m^2 iv [Intravenous]) and Carboplatin (AUC [area under the curve] 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.		Placebo, 2 tablets bid on Study Days 2-19 + Paclitaxel (225 mg/m^2 iv) and Carboplatin (AUC 6 iv) on Study Day 1 (21 days per cycle) for double-blind (DB) treatment. Subjects who discontinued DB treatment with complete response (CR), partial response (PR) or stable disease (SD) entered active follow up period. Subjects who discontinued DB treatment with disease progression (DP) entered long term follow up period.
All Cause Mortality
	Sorafenib (Nexavar, BAY43-9006)		Carboplatin/Paclitaxel (C/P)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sorafenib (Nexavar, BAY43-9006)		Carboplatin/Paclitaxel (C/P)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/134 (49.3%)		65/134 (48.5%)
Blood and lymphatic system disorders
neutrophils	15/134 (11.2%)		7/134 (5.2%)
hemoglobin	3/134 (2.2%)		8/134 (6%)
platelets	0/134 (0%)		3/134 (2.2%)
leukocytes	2/134 (1.5%)		1/134 (0.7%)
Cardiac disorders
supraventricular arrhythmia, atrial flutter	1/134 (0.7%)		1/134 (0.7%)
supraventricular arrhythmia, supraventricular extrasystoles (pac; premature nodal/junction contr)	0/134 (0%)		1/134 (0.7%)
supraventricular arrhythmia, supraventricular arrhythmia NOS	1/134 (0.7%)		0/134 (0%)
tachycardia	0/134 (0%)		1/134 (0.7%)
vasovagal episode	0/134 (0%)		1/134 (0.7%)
hypotension	1/134 (0.7%)		2/134 (1.5%)
cardiac ischemia / infarction	2/134 (1.5%)		0/134 (0%)
cardiac general - other	0/134 (0%)		0/134 (0%)
left ventricular diastolic dysfunction	0/134 (0%)		1/134 (0.7%)
pericarditis	0/134 (0%)		1/134 (0.7%)
Endocrine disorders
diabetes	1/134 (0.7%)		0/134 (0%)
Gastrointestinal disorders
vomiting	1/134 (0.7%)		4/134 (3%)
diarrhea	2/134 (1.5%)		2/134 (1.5%)
dehydration	1/134 (0.7%)		2/134 (1.5%)
obstruction, GI, small bowel NOS	1/134 (0.7%)		2/134 (1.5%)
anorexia	0/134 (0%)		2/134 (1.5%)
constipation	2/134 (1.5%)		0/134 (0%)
nausea	1/134 (0.7%)		1/134 (0.7%)
colitis	0/134 (0%)		1/134 (0.7%)
esophagitis	0/134 (0%)		1/134 (0.7%)
fistula, GI, esophagus	0/134 (0%)		1/134 (0.7%)
General disorders
death not associated with CTCAE term, disease progression NOS	2/134 (1.5%)		1/134 (0.7%)
death not associated with CTCAE term, death NOS	1/134 (0.7%)		0/134 (0%)
fever	3/134 (2.2%)		5/134 (3.7%)
fatigue	2/134 (1.5%)		4/134 (3%)
constitutional symptoms - other	1/134 (0.7%)		4/134 (3%)
pain, abdomen NOS	2/134 (1.5%)		4/134 (3%)
pain, pain NOS	3/134 (2.2%)		1/134 (0.7%)
pain, chest / thorax NOS	2/134 (1.5%)		0/134 (0%)
pain, tumor pain	0/134 (0%)		1/134 (0.7%)
pain, joint	1/134 (0.7%)		0/134 (0%)
pain, muscle	0/134 (0%)		1/134 (0.7%)
no code in CTCAE	1/134 (0.7%)		0/134 (0%)
Hepatobiliary disorders
liver dysfunction	1/134 (0.7%)		1/134 (0.7%)
cholecystitis	1/134 (0.7%)		0/134 (0%)
Immune system disorders
allergic reaction	4/134 (3%)		2/134 (1.5%)
Infections and infestations
febrile neutropenia	10/134 (7.5%)		8/134 (6%)
infection with unknown ANC, lung (pneumonia)	1/134 (0.7%)		3/134 (2.2%)
infection with unknown ANC, skin (cellulitis)	2/134 (1.5%)		1/134 (0.7%)
infection with normal ANC, upper airway NOS	1/134 (0.7%)		1/134 (0.7%)
infection - other	0/134 (0%)		2/134 (1.5%)
infection (documented clinically), upper airway NOS	1/134 (0.7%)		0/134 (0%)
infection with normal ANC, blood	0/134 (0%)		1/134 (0.7%)
infection with normal ANC, lung (pneumonia)	0/134 (0%)		1/134 (0.7%)
infection with normal ANC, soft tissue NOS	0/134 (0%)		1/134 (0.7%)
infection with normal ANC, vein	1/134 (0.7%)		0/134 (0%)
infection with normal ANC, wound	0/134 (0%)		1/134 (0.7%)
Injury, poisoning and procedural complications
intraop injury, bone	0/134 (0%)		1/134 (0.7%)
Metabolism and nutrition disorders
hyperglycemia	0/134 (0%)		3/134 (2.2%)
AST	0/134 (0%)		1/134 (0.7%)
hypoglycemia	0/134 (0%)		1/134 (0.7%)
hyponatremia	1/134 (0.7%)		0/134 (0%)
Musculoskeletal and connective tissue disorders
muscle weakness, whole body / generalized	1/134 (0.7%)		0/134 (0%)
Nervous system disorders
seizure	1/134 (0.7%)		6/134 (4.5%)
confusion	0/134 (0%)		2/134 (1.5%)
neuropathy: motor	2/134 (1.5%)		0/134 (0%)
CNS ischemia	1/134 (0.7%)		0/134 (0%)
speech impairment	1/134 (0.7%)		0/134 (0%)
neurology - other	0/134 (0%)		1/134 (0.7%)
neuropathy: sensory	1/134 (0.7%)		0/134 (0%)
somnolence	1/134 (0.7%)		0/134 (0%)
syncope (fainting)	0/134 (0%)		1/134 (0.7%)
Respiratory, thoracic and mediastinal disorders
dyspnea (shortness of breath)	1/134 (0.7%)		2/134 (1.5%)
pulmonary - other	1/134 (0.7%)		1/134 (0.7%)
aspiration	1/134 (0.7%)		0/134 (0%)
pleural effusion	1/134 (0.7%)		0/134 (0%)
Skin and subcutaneous tissue disorders
erythema multiforme	2/134 (1.5%)		0/134 (0%)
hand - foot skin reaction	1/134 (0.7%)		0/134 (0%)
rash / desquamation	1/134 (0.7%)		0/134 (0%)
ulceration	1/134 (0.7%)		0/134 (0%)
Vascular disorders
CNS hemorrhage	2/134 (1.5%)		2/134 (1.5%)
hemorrhage - other	1/134 (0.7%)		1/134 (0.7%)
hemorrhage, GI, lower GI NOS	0/134 (0%)		1/134 (0.7%)
hemorrhage with surgery	1/134 (0.7%)		0/134 (0%)
hemorrhage pulmonary, respiratory tract NOS	1/134 (0.7%)		0/134 (0%)
hemorrhage, GU, bladder	0/134 (0%)		1/134 (0.7%)
hemorrhage, GU, urinary NOS	0/134 (0%)		1/134 (0.7%)
thrombosis / thrombus / embolism	3/134 (2.2%)		9/134 (6.7%)
Other (Not Including Serious) Adverse Events
	Sorafenib (Nexavar, BAY43-9006)		Carboplatin/Paclitaxel (C/P)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/134 (98.5%)		134/134 (100%)
Blood and lymphatic system disorders
neutrophils	68/134 (50.7%)		71/134 (53%)
platelets	62/134 (46.3%)		40/134 (29.9%)
hemoglobin	33/134 (24.6%)		44/134 (32.8%)
leukocytes	36/134 (26.9%)		38/134 (28.4%)
lymphopenia	8/134 (6%)		5/134 (3.7%)
edema: limb	14/134 (10.4%)		18/134 (13.4%)
Cardiac disorders
hypertension	11/134 (8.2%)		6/134 (4.5%)
Eye disorders
blurred vision	8/134 (6%)		11/134 (8.2%)
Gastrointestinal disorders
nausea	71/134 (53%)		72/134 (53.7%)
diarrhea	64/134 (47.8%)		36/134 (26.9%)
constipation	40/134 (29.9%)		42/134 (31.3%)
vomiting	33/134 (24.6%)		32/134 (23.9%)
anorexia	32/134 (23.9%)		15/134 (11.2%)
mucositis (functional / symptomatic), oral cavity	17/134 (12.7%)		11/134 (8.2%)
taste alteration	11/134 (8.2%)		13/134 (9.7%)
heartburn	12/134 (9%)		11/134 (8.2%)
GI - other	13/134 (9.7%)		6/134 (4.5%)
dry mouth	7/134 (5.2%)		3/134 (2.2%)
flatulence	7/134 (5.2%)		3/134 (2.2%)
General disorders
fatigue	102/134 (76.1%)		79/134 (59%)
insomnia	26/134 (19.4%)		25/134 (18.7%)
fever	16/134 (11.9%)		11/134 (8.2%)
sweating	10/134 (7.5%)		16/134 (11.9%)
weight loss	16/134 (11.9%)		9/134 (6.7%)
rigors / chills	10/134 (7.5%)		8/134 (6%)
constitutional symptoms - other	3/134 (2.2%)		7/134 (5.2%)
pain, joint	44/134 (32.8%)		37/134 (27.6%)
pain, muscle	35/134 (26.1%)		27/134 (20.1%)
pain, extremity - limb	25/134 (18.7%)		23/134 (17.2%)
pain, abdomen NOS	19/134 (14.2%)		23/134 (17.2%)
pain, head / headache	21/134 (15.7%)		20/134 (14.9%)
pain, back	12/134 (9%)		18/134 (13.4%)
pain, bone	13/134 (9.7%)		17/134 (12.7%)
pain, pain NOS	13/134 (9.7%)		12/134 (9%)
pain, throat / pharynx / larynx	11/134 (8.2%)		6/134 (4.5%)
pain, chest / thorax NOS	10/134 (7.5%)		5/134 (3.7%)
Immune system disorders
allergic reaction	8/134 (6%)		10/134 (7.5%)
Infections and infestations
infection - other	7/134 (5.2%)		8/134 (6%)
infection with normal ANC, upper airway NOS	7/134 (5.2%)		6/134 (4.5%)
infection with unknown ANC, skin (cellulitis)	7/134 (5.2%)		0/134 (0%)
Metabolism and nutrition disorders
hypokalemia	9/134 (6.7%)		11/134 (8.2%)
hypomagnesemia	5/134 (3.7%)		10/134 (7.5%)
hypophosphatemia	8/134 (6%)		4/134 (3%)
lipase	7/134 (5.2%)		3/134 (2.2%)
Musculoskeletal and connective tissue disorders
musculoskeletal - other	8/134 (6%)		6/134 (4.5%)
Nervous system disorders
neuropathy: sensory	89/134 (66.4%)		87/134 (64.9%)
dizziness	21/134 (15.7%)		19/134 (14.2%)
mood alteration, depression	9/134 (6.7%)		11/134 (8.2%)
neuropathy: motor	7/134 (5.2%)		5/134 (3.7%)
neurology - other	8/134 (6%)		4/134 (3%)
Respiratory, thoracic and mediastinal disorders
cough	29/134 (21.6%)		25/134 (18.7%)
dyspnea (shortness of breath)	20/134 (14.9%)		24/134 (17.9%)
voice changes	10/134 (7.5%)		4/134 (3%)
hiccoughs	9/134 (6.7%)		4/134 (3%)
pulmonary - other	4/134 (3%)		9/134 (6.7%)
Skin and subcutaneous tissue disorders
alopecia	90/134 (67.2%)		87/134 (64.9%)
rash / desquamation	79/134 (59%)		29/134 (21.6%)
hand - foot skin reaction	38/134 (28.4%)		8/134 (6%)
pruritus	34/134 (25.4%)		12/134 (9%)
dermatology - other	19/134 (14.2%)		6/134 (4.5%)
dry skin	16/134 (11.9%)		5/134 (3.7%)
erythema multiforme	12/134 (9%)		8/134 (6%)
flushing	6/134 (4.5%)		7/134 (5.2%)
injection site reaction	7/134 (5.2%)		5/134 (3.7%)
acne	1/134 (0.7%)		9/134 (6.7%)
urticaria	8/134 (6%)		1/134 (0.7%)
Vascular disorders
hemorrhage pulmonary, nose	18/134 (13.4%)		10/134 (7.5%)

Limitations/Caveats

Metastatic melanoma is notorious for its resistance to chemotherapy. Thus, it is unlikely that inhibition of a single factor or pathway would produce a sustained clinical effect in patients with previously treated, highly refractory disease.

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Certain Agreements

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

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.