Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01103323
• Collaborator: (none)
• Enrollment: 760
• Locations: 171
• Arms: 2
• Duration (Months): 45
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a randomized, double-blind, placebo-controlled multi-center phase III study to evaluate efficacy and safety of regorafenib in patients with metastatic colorectal cancer (CRC) who have progressed on/after all approved drugs for CRC

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: Regorafenib (Stivarga, BAY73-4506); Drug: Placebo; Other: Best Supportive Care (BSC)	Phase 3

Detailed Description

All participants received Best Supportive Care. Acronyms used in Adverse events section:

Gastrointestinal (GI), Genitourinary (GU), Not Otherwise Specified (NOS), Absolute Neutrophil Count (ANC), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Common Terminology Criteria for Adverse Events (CTCAE), International Normalized Ratio (INR), Central nervous system (CNS), Acute respiratory distress syndrome (ARDS), Cranial nerves (CN), Disseminated Intravascular Coagulation (DIC), Cardiac troponin T (cTnT).

Abbreviation used in Results section: Data Monitoring Committee (DMC). Adverse event collection will be covered in Adverse events section.

Study Design

• Study Type: Interventional
• Actual Enrollment: 760 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Phase III Study of Regorafenib Plus BSC Versus Placebo Plus BSC in Patients With Metastatic Colorectal Cancer (CRC) Who Have Progressed After Standard Therapy
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regorafenib (Stivarga, BAY73-4506)+BSC Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus Best Supportive Care(BSC).	Drug: Regorafenib (Stivarga, BAY73-4506); 160 mg per oral once daily for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off); Other: Best Supportive Care (BSC); BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.
Placebo Comparator: Placebo+BSC Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus Best Supportive Care (BSC).	Drug: Placebo; matching placebo tablets for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off); Other: Best Supportive Care (BSC); BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA).]

   Overall survival (OS) was defined as the time (days) from randomization to death due to any cause. Patients alive at the time of analysis were censored at the last date known to be alive. If a patient was lost to follow-up and there was no contact after randomization, this patient was censored at Day 1.

Secondary Outcome Measures

1. Progression-free Survival (Based on Investigator's Assessment) [From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.]

   Progression-free survival was defined as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented.

2. Objective Tumor Response [From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.]

   The objective tumor response was defined as the percentage of patients with complete response (CR, tumor disappears) or partial response (PR, sum of lesion sizes decreased at least 30% from baseline) as best overall response. A best overall response was defined for all patients, using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. Patients whose best overall response was not CR or PR, and any patients with no post-baseline assessments were considered nonresponders for the analysis.

3. Disease Control [From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.]

   Disease control was defined as the percentage of patients whose best response was not PD [sum of lesion sizes increased at least 20% from smallest sum on study or new lesions] (ie, CR [tumor disappears], PR [sum of lesion sizes decreased at least 30% from baseline] or SD (stable disease)). SD included if at least 6 weeks after randomization.

4. Tumor Response [From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.]

   A tumor response (best overall response) was defined for all patients, using the RECIST criteria, version 1.1. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased at least 30% from baseline), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased at least 20% from smallest sum on study or new lesions). Clinical PD considered when radiographic imaging not possible.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histological or cytological documentation of adenocarcinoma of the colon or rectum

• Progression during or within 3 months following the last administration of approved standard therapies. Patients treated with oxaliplatin in an adjuvant setting should have progressed during or within 6 months of completion of adjuvant therapy

• Patients with measurable or non measurable disease

• Eastern Cooperative Oncology Group (ECOG) Performance Status of </= 1

• Life expectancy of at least 3 months

• Adequate bone marrow, liver and renal function

Exclusion Criteria:

• Unstable/uncontrolled cardiac disease

• History of arterial or venous thrombotic or embolic events

• Symptomatic metastatic brain or meningeal tumors

• Patients with evidence or history of bleeding diathesis

• Interstitial lung disease - Persistent proteinuria >/= grade 3

• Unresolved toxicity > grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity </= Grade 2

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Beverly Hills	California	United States	90211
2		Los Angeles	California	United States	90033
3		Los Angeles	California	United States	90036
4		Mission Hills	California	United States	91345
5		Orange	California	United States	92868
6		Redlands	California	United States	92374
7		Santa Maria	California	United States	93454
8		Aventura	Florida	United States	33180
9		Jacksonville	Florida	United States	32224
10		Peoria	Illinois	United States	61615-7828
11		Cedar Rapids	Iowa	United States	52403
12		New Orleans	Louisiana	United States	70121
13		Ann Arbor	Michigan	United States	48106
14		Rochester	Minnesota	United States	55905
15		St. Cloud	Minnesota	United States	56303
16		Jefferson City	Missouri	United States	65109
17		Neptune	New Jersey	United States	07754
18		New York	New York	United States	10011
19		Fargo	North Dakota	United States	58122
20		Toledo	Ohio	United States	43623
21		Scranton	Pennsylvania	United States	18510
22		Charleston	South Carolina	United States	29414
23		Sumter	South Carolina	United States	29150
24		Dallas	Texas	United States	75390-9110
25		Salt Lake City	Utah	United States	84106
26		Green Bay	Wisconsin	United States	54303
27		Buenos Aires	Ciudad Auton. de Buenos Aires	Argentina	C1122AAL
28		Buenos Aires	Ciudad Auton. de Buenos Aires	Argentina	C1264AAA
29		Rosario	Santa Fe	Argentina	S2000PBJ
30		San Miguel de Tucumán	Tucuman	Argentina	T4000GTB
31		Capital Federal-Buenos Aires		Argentina	C1426ANZ
32		Concord	New South Wales	Australia	2139
33		St Leonards	New South Wales	Australia	2065
34		Woolloogabba	Queensland	Australia	4102
35		Woodville South	South Australia	Australia	5011
36		Footscray	Victoria	Australia	3011
37		Parkville	Victoria	Australia	3050
38		Bruxelles - Brussel		Belgium	1000
39		Bruxelles - Brussel		Belgium	1070
40		Bruxelles - Brussel		Belgium	1200
41		Edegem		Belgium	2650
42		Leuven		Belgium	3000
43		Roeselare		Belgium	8800
44		Salvador	Bahia	Brazil	41830-492
45		Fortaleza	Ceará	Brazil	60160-230
46		Belo Horizonte	Minas Gerais	Brazil	30110-090
47		Ijuí	Rio Grande do Sul	Brazil	98700-000
48		Vancouver	British Columbia	Canada	V5Z 4E6
49		Winnipeg	Manitoba	Canada	R2H 2A6
50		Moncton	New Brunswick	Canada	E1C 6Z8
51		London	Ontario	Canada	N6A 4L6
52		Mississauga	Ontario	Canada	L5M 2N1
53		Oshawa	Ontario	Canada	L1G 2B9
54		Toronto	Ontario	Canada	M4N 3M5
55		Montreal	Quebec	Canada	H3T 1E2
56		Quebec		Canada	G1R 2J6
57		Guangzhou	Guangdong	China	510060
58		Guangzhou	Guangdong	China	510515
59		Nanjing	Jiangsu	China	210003
60		Nanjing	Jiangsu	China	210009
61		Qingdao	Shandong	China	266100
62		Beijing		China	100021
63		Beijing		China	100071
64		Changchun		China	130021
65		Chongqing		China	400038
66		Chongqing		China	400042
67		Fuzhou		China	350014
68		Fuzhou		China	350025
69		Ha'erbin		China	150040
70		Hanghzou		China	310009
71		Shanghai		China	200001
72		Shanghai		China	200030
73		Tianjin		China	300060
74		Brno		Czech Republic	65 653
75		Hradec Kralove		Czech Republic	500 05
76		Olomouc		Czech Republic	775 20
77		Praha		Czech Republic	18081
78		Avignon		France	84000
79		Le Mans Cedex 2		France	72015
80		Lille Cedex		France	59020
81		Lille Cedex		France	59037
82		Marseille		France	13005
83		Montpellier		France	34298
84		Paris		France	75651
85		Reims		France	51092
86		Rennes		France	35042
87		Strasbourg Cedex		France	67085
88		Freiburg	Baden-Württemberg	Germany	79106
89		Karlsruhe	Baden-Württemberg	Germany	76137
90		Mannheim	Baden-Württemberg	Germany	68167
91		Stuttgart	Baden-Württemberg	Germany	70199
92		München	Bayern	Germany	81377
93		München	Bayern	Germany	81737
94		München	Bayern	Germany	81925
95		Hannover	Niedersachsen	Germany	30625
96		Oldenburg	Niedersachsen	Germany	26133
97		Essen	Nordrhein-Westfalen	Germany	45122
98		Köln	Nordrhein-Westfalen	Germany	50924
99		Leverkusen	Nordrhein-Westfalen	Germany	51375
100		Porta Westfalica	Nordrhein-Westfalen	Germany	32457
101		Trier	Rheinland-Pfalz	Germany	54290
102		Halle	Sachsen-Anhalt	Germany	06120
103		Magdeburg	Sachsen-Anhalt	Germany	39104
104		Dresden	Sachsen	Germany	01307
105		Berlin		Germany	13125
106		Budapest		Hungary	1082
107		Debrecen		Hungary	4032
108		Nyiregyhaza		Hungary	4400
109		Szeged		Hungary	6725
110		Ashkelon		Israel	7830604
111		Beer Sheva		Israel	8410101
112		Haifa		Israel	3109601
113		Holon		Israel
114		Jerusalem		Israel	9112001
115		Petach Tikva		Israel	4941492
116		Rehovot		Israel	7610001
117		Tel Aviv		Israel	6423906
118		Tel Hashomer		Israel	5262000
119		Zrifin		Israel	6093000
120		Brescia		Italy	25124
121		Genova		Italy	16132
122		Milano		Italy	20133
123		Milano		Italy	20162
124		Modena		Italy	41124
125		Napoli		Italy	80131
126		Pisa		Italy	56126
127		Reggio Emilia		Italy	42100
128		Roma		Italy	00168
129		Nagoya	Aichi	Japan	464-8681
130		Kashiwa	Chiba	Japan	277-8577
131		Matsuyama	Ehime	Japan	791-0280
132		Sapporo	Hokkaido	Japan	060-8648
133		Osakasayama	Osaka	Japan	589-8511
134		Takatsuki	Osaka	Japan	569-8686
135		Hidaka	Saitama	Japan	350-1298
136		Kita-Adachigun	Saitama	Japan	362-0806
137		Sunto	Shizuoka	Japan	411-8777
138		Shimotsuke	Tochigi	Japan	329-0498
139		Utsunomiya	Tochigi	Japan	320-0834
140		Bunkyo-ku	Tokyo	Japan	113-8519
141		Chuo-ku	Tokyo	Japan	104-0045
142		Koto-ku	Tokyo	Japan	135-8550
143		Mitaka	Tokyo	Japan	181-8611
144		Chiba		Japan	260-8717
145		Fukuoka		Japan	812-8582
146		Kochi		Japan	781-8555
147		Kumamoto		Japan	860-8556
148		Osaka		Japan	540-0006
149		Amsterdam		Netherlands	1081 HV
150		Hoofddorp		Netherlands	2134 TM
151		Leeuwarden		Netherlands	8901 BR
152		Leiden		Netherlands	2333 ZA
153		Aveiro		Portugal	3810-096
154		Coimbra		Portugal	3030-075
155		Lisboa		Portugal	1649-035
156		Porto		Portugal	4099-001
157		Porto		Portugal	4200-072
158		Hospitalet de Llobregat	Barcelona	Spain	08907
159		Sabadell	Barcelona	Spain	08208
160		Barcelona		Spain	08035
161		Madrid		Spain	28040
162		Madrid		Spain	28041
163		Madrid		Spain	28046
164		Málaga		Spain	29010
165		Sevilla		Spain	41013
166		Chur	Graubünden	Switzerland	7000
167		Genève		Switzerland	1211
168		Ankara		Turkey	06500
169		Instanbul		Turkey	34662
170		Istanbul		Turkey	34390
171		Izmir		Turkey	35100

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01103323
• Other Study ID Numbers: 14387; 2009-012787-14
• First Posted: Apr 14, 2010
• Last Update Posted: Jun 24, 2015
• Last Verified: May 1, 2015

• Keywords provided by Bayer: Metastatic Colorectal Cancer
• Additional relevant MeSH terms: Colorectal Neoplasms

Study Results

Participant Flow

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
Arm/Group Description	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). Period 1 is placebo and placebo-regorafenib with placebo period only before unblinding. Period 2 is placebo-regorafenib with regorafenib period only.
Period Title: Without/Before Drug Switch
STARTED	505	255
Participants Received Treatment	500	253
COMPLETED	429	237
NOT COMPLETED	76	18
Period Title: Without/Before Drug Switch
STARTED	0	4
COMPLETED	0	3
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC	Total
Arm/Group Description	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).	Total of all reporting groups
Overall Participants	505	255	760
Age (Years) [Mean (Full Range) ]
Mean (Full Range) [Years]	60.7	60.1	60.5
Sex: Female, Male (Count of Participants)
Female	194 38.4%	102 40%	296 38.9%
Male	311 61.6%	153 60%	464 61.1%
Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment (Number) [Number]
0	265 52.5%	146 57.3%	411 54.1%
1	240 47.5%	109 42.7%	349 45.9%
KRAS mutation (Number) [Number]
No	205 40.6%	94 36.9%	299 39.3%
Yes	273 54.1%	157 61.6%	430 56.6%
Unknown	27 5.3%	4 1.6%	31 4.1%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall survival (OS) was defined as the time (days) from randomization to death due to any cause. Patients alive at the time of analysis were censored at the last date known to be alive. If a patient was lost to follow-up and there was no contact after randomization, this patient was censored at Day 1.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA).

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT)

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
Arm/Group Description	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Measure Participants	505	255
Median (95% Confidence Interval) [Days]	196	151

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506)+BSC, Placebo+BSC
	Comments	Sample size based on primary efficacy endpoint of OS. The study was designed to have 90% power to detect 33.3% increase in median OS (i.e. hazard ratio of 0.75, Regorafenib / Placebo). Assuming 1-sided overall alpha of 0.025, randomization ratio of 2:1 for Regorafenib and Placebo, and 2 formal interim analyses of OS using an O'Brien-Fleming-type error spending function, a total of 582 death events were required for primary completion. Results based on 2nd planned formal IA with 432 total events.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.005178
	Comments	According to protocol specified O'Brien-Fleming type alpha spending function and 432 death events at 2nd IA, the pre-specified alpha (false positive rate) for this analysis was 0.009279 (1-sided).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.774
	Confidence Interval	() 95%; 0.636 to 0.942
	Parameter Dispersion	Type: Value:
	Estimation Comments	Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.

2. Secondary Outcome

Title	Progression-free Survival (Based on Investigator's Assessment)
Description	Progression-free survival was defined as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
Arm/Group Description	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Measure Participants	505	255
Median (95% Confidence Interval) [Days]	59	52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506)+BSC, Placebo+BSC
	Comments	Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.000001
	Comments	Comparison based on pre-specified alpha level of 0.025 (1-sided).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.494
	Confidence Interval	() 95%; 0.419 to 0.582
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (Regorafenib / Placebo)

3. Secondary Outcome

Title	Objective Tumor Response
Description	The objective tumor response was defined as the percentage of patients with complete response (CR, tumor disappears) or partial response (PR, sum of lesion sizes decreased at least 30% from baseline) as best overall response. A best overall response was defined for all patients, using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. Patients whose best overall response was not CR or PR, and any patients with no post-baseline assessments were considered nonresponders for the analysis.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
Arm/Group Description	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Measure Participants	505	255
Number [Percentage of participants]	1.0 0.2%	0.4 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506)+BSC, Placebo+BSC
	Comments	Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.188432
	Comments	Comparison based on pre-specified alpha level of 0.025 (1-sided).
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-0.60
	Confidence Interval	() 95%; -1.74 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Placebo - Regorafenib 160 mg

4. Secondary Outcome

Title	Disease Control
Description	Disease control was defined as the percentage of patients whose best response was not PD [sum of lesion sizes increased at least 20% from smallest sum on study or new lesions] (ie, CR [tumor disappears], PR [sum of lesion sizes decreased at least 30% from baseline] or SD (stable disease)). SD included if at least 6 weeks after randomization.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
Arm/Group Description	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Measure Participants	505	255
Number [Percentage of participants]	41.0 8.1%	14.9 5.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regorafenib (Stivarga, BAY73-4506)+BSC, Placebo+BSC
	Comments	Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.000001
	Comments	Comparison based on pre-specified alpha level of 0.025 (1-sided).
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-25.94
	Confidence Interval	() 95%; -32.06 to -19.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference = Placebo - Regorafenib 160 mg

5. Secondary Outcome

Title	Tumor Response
Description	A tumor response (best overall response) was defined for all patients, using the RECIST criteria, version 1.1. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased at least 30% from baseline), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased at least 20% from smallest sum on study or new lesions). Clinical PD considered when radiographic imaging not possible.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Regorafenib (Stivarga, BAY73-4506)+BSC	Placebo+BSC
Arm/Group Description	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC)
Measure Participants	505	255
Complete Response (CR)	0 0%	0 0%
Partial Response (PR)	1.0 0.2%	0.4 0.2%
Stable Disease (SD)	42.8 8.5%	14.5 5.7%
Progressive Disease (PD)	49.5 9.8%	80.0 31.4%
Non CR/Non PD	0.8 0.2%	0.4 0.2%
Not applicable	0.2 0%	0 0%
Not assessed	5.7 1.1%	4.7 1.8%

Adverse Events

Time Frame	AE was collected up to 30 days after end of study treatment (per protocol) over a period of approximately 3.7 years.
Adverse Event Reporting Description	Disseminated Intravascular Coagulation (DIC), International Normalized Ratio (INR), Cardiac Troponin T (cTnT), Gastroihntestina (GI), Not Otherwise Specified (NOS), Aspartate Aminotransferase (AST), Genitourinary (GU), Alanine Aminotransferase (ALT), Acute Respiratory Distress Syndrome (ARDS), Absolute Neutrophil Count (ANC)
Arm/Group Title	Regorafenib (BAY73-4506)+BSC		Placebo+BSC		Placebo - Regorafenib After Unblinding
Arm/Group Description	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC).		Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). It is for placebo period only before unblinding.		Participants in the placebo+BSC group switched to treatment with Regorafenib after unblinding. It is for Regorafenib treatment period only
All Cause Mortality
	Regorafenib (BAY73-4506)+BSC		Placebo+BSC		Placebo - Regorafenib After Unblinding
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Regorafenib (BAY73-4506)+BSC		Placebo+BSC		Placebo - Regorafenib After Unblinding
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	232/500 (46.4%)		103/253 (40.7%)		2/4 (50%)
Blood and lymphatic system disorders
DIC	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Edema: Limb	1/500 (0.2%)	1	1/253 (0.4%)	1	0/4 (0%)	0
Edema: Trunk/Genital	0/500 (0%)	0	2/253 (0.8%)	4	0/4 (0%)	0
Edema: Viscera	0/500 (0%)	0	1/253 (0.4%)	3	0/4 (0%)	0
Hemoglobin	4/500 (0.8%)	8	2/253 (0.8%)	2	0/4 (0%)	0
INR	2/500 (0.4%)	5	0/253 (0%)	0	0/4 (0%)	0
Neutrophils	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Platelets	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Thrombotic microangiopathy	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Cardiac disorders
Cardiac arrhythmia - Other	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Cardiac ischemia/infarction	6/500 (1.2%)	6	1/253 (0.4%)	2	0/4 (0%)	0
Hypertension	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hypotension	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Left ventricular systolic dysfunction	1/500 (0.2%)	3	0/253 (0%)	0	0/4 (0%)	0
Supraventricular arrhythmia, Atrial fibrillation	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
cTnT	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Eye disorders
Diplopia	1/500 (0.2%)	1	1/253 (0.4%)	1	0/4 (0%)	0
Ocular - Other	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Anorexia	5/500 (1%)	8	2/253 (0.8%)	2	0/4 (0%)	0
Ascites	1/500 (0.2%)	2	2/253 (0.8%)	2	1/4 (25%)	1
Constipation	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Dehydration	3/500 (0.6%)	3	2/253 (0.8%)	2	0/4 (0%)	0
Diarrhea	8/500 (1.6%)	9	0/253 (0%)	0	0/4 (0%)	0
Distension	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Enteritis	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Fistula, GI, Abdomen NOS	1/500 (0.2%)	2	1/253 (0.4%)	1	0/4 (0%)	0
Fistula, GI, Anus	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Fistula, GI, Small bowel NOS	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
GI - Other	1/500 (0.2%)	1	1/253 (0.4%)	1	0/4 (0%)	0
Hemorrhoids	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Ileus	2/500 (0.4%)	3	3/253 (1.2%)	3	0/4 (0%)	0
Mucositis (functional/symptomatic), Small bowel	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Necrosis, GI, Peritoneal cavity	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Obstruction, GI, Colon	9/500 (1.8%)	11	6/253 (2.4%)	8	0/4 (0%)	0
Obstruction, GI, Ileum	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Obstruction, GI, Small bowel NOS	4/500 (0.8%)	5	7/253 (2.8%)	9	0/4 (0%)	0
Obstruction, GI, Stomach	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Perforation, GI, Colon	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Stricture, GI, Biliary tree	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Ulcer, GI, Duodenum	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Vomiting	3/500 (0.6%)	3	0/253 (0%)	0	1/4 (25%)	1
General disorders
Constitutional symptoms - Other	34/500 (6.8%)	49	23/253 (9.1%)	39	0/4 (0%)	0
Death not associated with CTCAE term, Disease progression NOS	16/500 (3.2%)	17	6/253 (2.4%)	6	1/4 (25%)	1
Death not associated with CTCAE term, Multi-Organ Failure	4/500 (0.8%)	4	1/253 (0.4%)	1	0/4 (0%)	0
Death not associated with CTCAE term, Sudden death	2/500 (0.4%)	2	2/253 (0.8%)	2	0/4 (0%)	0
Fatigue	5/500 (1%)	6	5/253 (2%)	5	0/4 (0%)	0
Fever	17/500 (3.4%)	21	2/253 (0.8%)	2	0/4 (0%)	0
Pain, Abdomen NOS	13/500 (2.6%)	21	2/253 (0.8%)	2	0/4 (0%)	0
Pain, Back	4/500 (0.8%)	6	4/253 (1.6%)	5	0/4 (0%)	0
Pain, Buttock	2/500 (0.4%)	4	0/253 (0%)	0	0/4 (0%)	0
Pain, Cardiac/Heart	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Pain, Chest wall	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Pain, Chest/Thorax NOS	4/500 (0.8%)	4	1/253 (0.4%)	1	0/4 (0%)	0
Pain, Extremity - limb	2/500 (0.4%)	6	0/253 (0%)	0	0/4 (0%)	0
Pain, Head/Headache	2/500 (0.4%)	2	1/253 (0.4%)	1	0/4 (0%)	0
Pain, Joint	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Pain, Liver	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Pain, Neuralgia/Peripheral nerve	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Pain, Pain NOS	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Pain, Tumor pain	3/500 (0.6%)	3	1/253 (0.4%)	1	0/4 (0%)	0
Syndromes - Other	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Tumor flare	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Weight loss	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Hepatobiliary disorders
Cholecystitis	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Hepatobiliary - Other	2/500 (0.4%)	2	1/253 (0.4%)	1	0/4 (0%)	0
Liver dysfunction	17/500 (3.4%)	28	5/253 (2%)	11	0/4 (0%)	0
Immune system disorders
Allergic reaction	2/500 (0.4%)	4	0/253 (0%)	0	0/4 (0%)	0
Infections and infestations
Infection (documented clinically), Abdomen NOS	4/500 (0.8%)	4	0/253 (0%)	0	0/4 (0%)	0
Infection (documented clinically), Anal/perianal	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection (documented clinically), Appendix	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection (documented clinically), Bladder (urinary)	2/500 (0.4%)	2	1/253 (0.4%)	1	0/4 (0%)	0
Infection (documented clinically), Blood	3/500 (0.6%)	5	2/253 (0.8%)	2	0/4 (0%)	0
Infection (documented clinically), Bronchus	3/500 (0.6%)	3	0/253 (0%)	0	0/4 (0%)	0
Infection (documented clinically), Catheter-related	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Infection (documented clinically), Kidney	1/500 (0.2%)	1	1/253 (0.4%)	1	0/4 (0%)	0
Infection (documented clinically), Lung (Pneumonia)	9/500 (1.8%)	11	3/253 (1.2%)	4	0/4 (0%)	0
Infection (documented clinically), Skin (Cellulitis)	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection (documented clinically), Soft tissue NOS	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection (documented clinically), Urinary tract NOS	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Infection (documented clinically), Wound	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection - Other	5/500 (1%)	6	1/253 (0.4%)	2	0/4 (0%)	0
Infection with normal ANC, Blood	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Infection with normal ANC, Catheter-related	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection with normal ANC, Colon	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection with normal ANC, Gallbladder (Cholecystitis)	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection with normal ANC, Kidney	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection with normal ANC, Lung (Pneumonia)	1/500 (0.2%)	1	1/253 (0.4%)	1	0/4 (0%)	0
Infection with normal ANC, Soft tissue NOS	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Infection with unknown ANC, Kidney	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Infection with unknown ANC, Lung (Pneumonia)	1/500 (0.2%)	1	1/253 (0.4%)	1	0/4 (0%)	0
Metabolism and nutrition disorders
AST	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Bilirubin (Hyperbilirubinemia)	8/500 (1.6%)	11	3/253 (1.2%)	3	0/4 (0%)	0
Hypoalbuminemia	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hypocalcemia	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Hyponatremia	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Metabolic/Lab - Other	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Fracture	4/500 (0.8%)	4	2/253 (0.8%)	3	0/4 (0%)	0
Gait/Walking	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Muscle weakness left-sided	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Muscle weakness, Extremity - lower	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Muscle weakness, Whole body/generalized	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Musculoskeletal - Other	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Myositis	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy (possibly related to cancer treatment)	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Nervous system disorders
Ataxia	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
CNS ischemia	1/500 (0.2%)	2	2/253 (0.8%)	2	0/4 (0%)	0
Cognitive disturbance	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Confusion	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Dizziness	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Encephalopathy	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Mood Alteration, Anxiety	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Neurology - Other	3/500 (0.6%)	4	2/253 (0.8%)	2	0/4 (0%)	0
Neuropathy: Cranial, CN III Pupil, upper eyelid, extra ocular mov	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Neuropathy: motor	3/500 (0.6%)	3	0/253 (0%)	0	0/4 (0%)	0
Seizure	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Somnolence	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Speech impairment	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Syncope (Fainting)	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Renal and urinary disorders
Cystitis	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Fistula, GU, Bladder	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Obstruction, GU, Ureter	2/500 (0.4%)	2	1/253 (0.4%)	1	0/4 (0%)	0
Renal - Other	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Renal failure	5/500 (1%)	6	3/253 (1.2%)	5	0/4 (0%)	0
Urinary retention	0/500 (0%)	0	2/253 (0.8%)	2	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
ARDS	1/500 (0.2%)	1	1/253 (0.4%)	1	0/4 (0%)	0
Cough	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Dyspnea (Shortness of breath)	12/500 (2.4%)	18	4/253 (1.6%)	4	0/4 (0%)	0
Pleural effusion	1/500 (0.2%)	2	4/253 (1.6%)	4	0/4 (0%)	0
Pneumonitis	1/500 (0.2%)	2	1/253 (0.4%)	1	0/4 (0%)	0
Pneumothorax	2/500 (0.4%)	3	0/253 (0%)	0	0/4 (0%)	0
Pulmonary - Other	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Dermatology - Other	1/500 (0.2%)	2	2/253 (0.8%)	3	0/4 (0%)	0
Erythema multiforme	2/500 (0.4%)	2	0/253 (0%)	0	0/4 (0%)	0
Hand-foot skin reaction	1/500 (0.2%)	3	0/253 (0%)	0	0/4 (0%)	0
Rash/Desquamation	4/500 (0.8%)	7	1/253 (0.4%)	1	0/4 (0%)	0
Wound complication, non-infectious	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Vascular disorders
Hematoma	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Hemorrhage - Other	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage pulmonary, Bronchus	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage pulmonary, Mediastinum	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, Abdomen NOS	2/500 (0.4%)	4	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, Anus	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, Lower GI NOS	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, Rectum	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, Stoma	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, Upper GI NOS	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage, GI, Varices (esophageal)	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Hemorrhage, GI, Varices (rectal)	1/500 (0.2%)	1	0/253 (0%)	0	0/4 (0%)	0
Hemorrhage, GU, Vagina	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Thrombosis/Embolism (vascular access)	0/500 (0%)	0	1/253 (0.4%)	1	0/4 (0%)	0
Thrombosis/Thrombus/Embolism	6/500 (1.2%)	6	3/253 (1.2%)	5	0/4 (0%)	0
Vascular - Other	1/500 (0.2%)	2	0/253 (0%)	0	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	Regorafenib (BAY73-4506)+BSC		Placebo+BSC		Placebo - Regorafenib After Unblinding
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	489/500 (97.8%)		229/253 (90.5%)		4/4 (100%)
Blood and lymphatic system disorders
Edema: Limb	49/500 (9.8%)	57	16/253 (6.3%)	19	0/4 (0%)	0
Hemoglobin	76/500 (15.2%)	142	29/253 (11.5%)	46	0/4 (0%)	0
Platelets	79/500 (15.8%)	136	6/253 (2.4%)	9	1/4 (25%)	2
Cardiac disorders
Hypertension	155/500 (31%)	213	21/253 (8.3%)	23	1/4 (25%)	1
Endocrine disorders
Hypothyroidism	27/500 (5.4%)	29	1/253 (0.4%)	1	1/4 (25%)	1
Eye disorders
Ocular - Other	5/500 (1%)	5	0/253 (0%)	0	1/4 (25%)	1
Gastrointestinal disorders
Anorexia	239/500 (47.8%)	388	73/253 (28.9%)	96	0/4 (0%)	0
Ascites	23/500 (4.6%)	24	6/253 (2.4%)	8	1/4 (25%)	1
Constipation	119/500 (23.8%)	147	48/253 (19%)	58	0/4 (0%)	0
Diarrhea	218/500 (43.6%)	514	44/253 (17.4%)	57	2/4 (50%)	2
Fistula, GI, Colon/Cecum/Appendix	0/500 (0%)	0	0/253 (0%)	0	1/4 (25%)	1
Mucositis (functional/symptomatic), Oral cavity	145/500 (29%)	267	12/253 (4.7%)	12	0/4 (0%)	0
Nausea	115/500 (23%)	162	55/253 (21.7%)	67	1/4 (25%)	1
Taste alteration	39/500 (7.8%)	44	6/253 (2.4%)	6	0/4 (0%)	0
Vomiting	85/500 (17%)	144	41/253 (16.2%)	50	1/4 (25%)	3
General disorders
Constitutional symptoms - Other	30/500 (6%)	33	17/253 (6.7%)	19	0/4 (0%)	0
Fatigue	318/500 (63.6%)	612	115/253 (45.5%)	168	0/4 (0%)	0
Fever	136/500 (27.2%)	189	40/253 (15.8%)	48	2/4 (50%)	3
Flu-like syndrome	27/500 (5.4%)	30	6/253 (2.4%)	8	1/4 (25%)	1
Insomnia	39/500 (7.8%)	43	14/253 (5.5%)	15	0/4 (0%)	0
Pain, Abdomen NOS	121/500 (24.2%)	239	47/253 (18.6%)	53	0/4 (0%)	0
Pain, Back	79/500 (15.8%)	114	25/253 (9.9%)	27	0/4 (0%)	0
Pain, Buttock	4/500 (0.8%)	5	0/253 (0%)	0	1/4 (25%)	1
Pain, Chest/Thorax NOS	26/500 (5.2%)	29	12/253 (4.7%)	14	0/4 (0%)	0
Pain, Extremity - limb	51/500 (10.2%)	83	14/253 (5.5%)	19	0/4 (0%)	0
Pain, Head/Headache	50/500 (10%)	65	18/253 (7.1%)	23	0/4 (0%)	0
Pain, Joint	32/500 (6.4%)	34	13/253 (5.1%)	14	0/4 (0%)	0
Pain, Muscle	50/500 (10%)	64	14/253 (5.5%)	16	0/4 (0%)	0
Pain, Throat/Pharynx/Larynx	9/500 (1.8%)	12	1/253 (0.4%)	1	1/4 (25%)	1
Weight loss	167/500 (33.4%)	240	30/253 (11.9%)	34	2/4 (50%)	7
Hepatobiliary disorders
Hepatobiliary - Other	8/500 (1.6%)	9	4/253 (1.6%)	4	1/4 (25%)	3
Metabolism and nutrition disorders
ALT	28/500 (5.6%)	53	7/253 (2.8%)	8	0/4 (0%)	0
AST	37/500 (7.4%)	72	12/253 (4.7%)	13	0/4 (0%)	0
Alkaline phosphatase	35/500 (7%)	49	8/253 (3.2%)	12	0/4 (0%)	0
Bilirubin (Hyperbilirubinemia)	97/500 (19.4%)	160	22/253 (8.7%)	37	1/4 (25%)	3
Creatinine	15/500 (3%)	19	7/253 (2.8%)	8	1/4 (25%)	2
GFR	4/500 (0.8%)	9	1/253 (0.4%)	2	1/4 (25%)	1
Hyperuricemia	12/500 (2.4%)	13	1/253 (0.4%)	1	1/4 (25%)	1
Hypocalcemia	34/500 (6.8%)	57	1/253 (0.4%)	1	0/4 (0%)	0
Hypokalemia	50/500 (10%)	84	6/253 (2.4%)	7	0/4 (0%)	0
Hyponatremia	32/500 (6.4%)	43	6/253 (2.4%)	10	0/4 (0%)	0
Hypophosphatemia	32/500 (6.4%)	62	2/253 (0.8%)	3	1/4 (25%)	2
Lipase	32/500 (6.4%)	74	3/253 (1.2%)	4	0/4 (0%)	0
Metabolic/Lab - Other	42/500 (8.4%)	69	8/253 (3.2%)	15	0/4 (0%)	0
Proteinuria	40/500 (8%)	109	6/253 (2.4%)	11	0/4 (0%)	0
Nervous system disorders
Dizziness	28/500 (5.6%)	31	13/253 (5.1%)	13	0/4 (0%)	0
Neuropathy: sensory	51/500 (10.2%)	68	25/253 (9.9%)	27	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	56/500 (11.2%)	77	28/253 (11.1%)	32	1/4 (25%)	1
Dyspnea (Shortness of breath)	89/500 (17.8%)	110	34/253 (13.4%)	46	0/4 (0%)	0
Voice changes	160/500 (32%)	211	16/253 (6.3%)	17	1/4 (25%)	1
Skin and subcutaneous tissue disorders
Alopecia	39/500 (7.8%)	43	4/253 (1.6%)	4	0/4 (0%)	0
Cheilitis	4/500 (0.8%)	4	0/253 (0%)	0	1/4 (25%)	3
Dermatology - Other	30/500 (6%)	45	7/253 (2.8%)	10	0/4 (0%)	0
Dry skin	50/500 (10%)	59	10/253 (4%)	11	0/4 (0%)	0
Hand-foot skin reaction	235/500 (47%)	720	19/253 (7.5%)	21	1/4 (25%)	3
Pruritus	29/500 (5.8%)	39	11/253 (4.3%)	11	0/4 (0%)	0
Rash/Desquamation	145/500 (29%)	211	13/253 (5.1%)	17	1/4 (25%)	2
Vascular disorders
Hemorrhage pulmonary, Nose	45/500 (9%)	55	6/253 (2.4%)	6	0/4 (0%)	0

Limitations/Caveats

At 2nd IA, pre-specified O'Brien-Fleming-type efficacy boundary was crossed. DMC concluded OS result positive and after positive risk benefit assessment, recommended unblinding of study. OS from 2nd IA are the final formal and definitive results.

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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 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.