RESORCE: Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01774344
• Collaborator: (none)
• Enrollment: 573
• Locations: 147
• Arms: 2
• Actual Duration (Months): 73.7
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The objective of this study was to evaluate efficacy and safety of regorafenib in patients with advanced liver cancer who had progressed after sorafenib treatment. Patients were treated with regorafenib or placebo using a 2:1 randomization scheme.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Regorafenib (Stivarga, BAY73-4506); Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 573 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, Multicenter Phase III Study of Regorafenib in Patients With Hepatocellular Carcinoma (HCC) After Sorafenib
• Actual Study Start Date: May 14, 2013
• Actual Primary Completion Date: Feb 29, 2016
• Actual Study Completion Date: Jul 5, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regorafenib 160 mg orally (p.o.) every day (qd) for 3 weeks of every 4 week cycle (i.e. 3 weeks on, 1 week off) plus BSC (Best Supportive Care)	Drug: Regorafenib (Stivarga, BAY73-4506); Regorafenib, 40 mg tablets
Placebo Comparator: Placebo 4 matching placebo tablets for 3 weeks of every 4 week cycle (i.e. 3 weeks on, 1 week off) plus BSC	Drug: Placebo; Placebo tablets matching in appearance

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [From randomization (Day 1) of the first subject until 419 days later]

   Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.

Secondary Outcome Measures

1. Time to Progression (TTP) [From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)]

   TTP was the time (days) from randomization to radiological or clinical disease progression assessed by independent radiological review. Median and 95% confidence interval were reported for the modified response evaluation criteria in solid tumors (mRECIST) and response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact.

2. Progression Free Survival (PFS) [From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks)]

   Progression Free Survival (PFS) was defined as the time (days) from date of randomization to date of disease progression (radiological or clinical) or death due to any cause, if death occurs before progression was documented. Death in the absence of progression was a PFS event only if it occurred within the 12+1 weeks for subjects who discontinued treatment prior to cycle 8 and 24+2 weeks for subjects who discontinued treatment after to cycle 8 of the last evaluable tumor assessment; PFS were censored at the date of the last evaluable tumor assessment, if it occurred later. Median and 95% confidence interval 95% were reported for the mRECIST and RECIST 1.1 analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact.

3. Objective Tumor Response Rate (ORR) [From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)]

   Objective tumor response rate (ORR) was defined as the percentage of subjects whose best tumor response CR or Partial Response (PR) observed during trial period assessed according to the mRECIST criteria and RECIST 1.1. CR= Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10 mm. PR= At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. Subjects prematurely discontinuing without an assessment were to be considered non-responders for the analysis.

4. Disease Control Rate (DCR) [From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)]

   Disease control rate (DCR) was defined as the percentage of subjects whose best response was CR (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), PR (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or stable disease (SD) (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST and RECIST 1.1 criteria. SD had to be maintained for at least 6 weeks from the first demonstration of that rating.

Other Outcome Measures

1. Overall Survival (OS) [From randomization (Day 1) of the first subject to end of follow upto 1710 days]

   Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause

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 confirmation of HCC (hepatocellular carcinoma) or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases criteria in patients with a confirmed diagnosis of cirrhosis

• Barcelona Clinic Liver Cancer stage Category B or C that cannot benefit from treatments of established efficacy with higher priority such as resection, local ablation, chemoembolization or systemic sorafenib.

• Failure to prior treatment with sorafenib (defined as documented radiological progression according to the radiology charter). Randomization needs to be performed within 10 weeks after the last treatment with sorafenib.

• Tolerability of prior treatment with sorafenib defined as not less than 20 days at a minimum daily dose of 400 mg QD within the last 28 days prior to withdrawal.

• Liver function status Child-Pugh Class A. Child Pugh status should be calculated based on clinical findings and laboratory results during the screening period.

Local or loco-regional therapy of intrahepatic tumor lesions (e.g. surgery, radiation therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) must have been completed >/=4 weeks before first dose of study medication. Note: patients who received sole intrahepatic intraarterial chemotherapy, without lipiodol or embolizing agents are not eligible.

• Eastern Cooperative Oncology Group Performance Status of 0 or 1.

• Adequate bone marrow, liver and renal function as assessed by the following laboratory tests conducted within 7 days before randomization.

• Glomerular filtration rate >/= 30 ml/min/1.73 m^2 according to the Modification of diet in renal disease study equation.

• At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST (RECIST version 1.1), and modified RECIST for HCC. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, may be considered measurable if there has been demonstrated progression in the lesion.

• Life expectancy of at least 3 months.

• Women of childbearing potential and men must agree to use adequate contraception .

Exclusion Criteria :

• Sorafenib treatment within 2 weeks of randomization.

• Prior systemic treatment for HCC, except sorafenib.

• Permanent discontinuation of prior sorafenib therapy due to sorafenib related toxicity.

• Known history or symptomatic metastatic brain or meningeal tumors (head CT or MRI at screening to confirm the absence of central nervous system [CNS] disease if patient has symptoms suggestive or consistent with CNS disease).

• Uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).

• Uncontrolled ascites (defined as not easily controlled with diuretic or paracentesis treatment).

• Ongoing infection > Grade 2 according to NCI-CTCAE (National Cancer Institute - Common Terminology Criteria for Adverse Events) v. 4.0. Hepatitis B is allowed if no active replication is present. Hepatitis C is allowed if no antiviral treatment is required.

• Clinically significant bleeding NCI-CTCAE version 4.0 Grade 3 or higher within 30 days before randomization.

• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication.

• Patients unable to swallow oral medications.

• Interstitial lung disease with ongoing signs and symptoms at the time of screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States	90048
2		Los Angeles	California	United States	90095
3		Orange	California	United States	92868-3201
4		Aurora	Colorado	United States	80045
5		Washington	District of Columbia	United States	20007-2197
6		Gainesville	Florida	United States	32610-0286
7		Tampa	Florida	United States	33606
8		Chicago	Illinois	United States	60637
9		Louisville	Kentucky	United States	40202
10		Worcester	Massachusetts	United States	01655
11		Minneapolis	Minnesota	United States	55455
12		Saint Louis	Missouri	United States	63110
13		New York	New York	United States	10029
14		Rochester	New York	United States	14642
15		Pittsburgh	Pennsylvania	United States	15232
16		Richmond	Virginia	United States	23249
17		Seattle	Washington	United States	98101
18		Pilar	Buenos Aires	Argentina	B1629ODT
19		Camperdown	New South Wales	Australia	2050
20		Liverpool	New South Wales	Australia	2170
21		Herston	Queensland	Australia	4029
22		Clayton	Victoria	Australia	3168
23		Box Hill		Australia	3128
24		Linz	Oberösterreich	Austria	4020
25		Graz	Steiermark	Austria	8036
26		Wien		Austria	1090
27		Bruxelles - Brussel		Belgium	1090
28		La Louviere		Belgium	7100
29		Salvador	Bahia	Brazil	41950-610
30		Sao Paulo		Brazil	05403-000
31		Hefei	Anhui	China	230022
32		Fuzhou	Fujian	China	350025
33		Guangzhou	Guangdong	China	510060
34		Guangzhou	Guangdong	China	510080
35		Guangzhou	Guangdong	China	510515
36		Nanning	Guangxi	China	530021
37		Harbin	Heilongjiang	China	150081
38		Wuhan	Hubei	China	430030
39		Changsha	Hunan	China	410013
40		Nanjing	Jiangsu	China	210002
41		Suzhou	Jiangsu	China	215006
42		Dalian	Liaoning	China	116011
43		Xi'an	Shaanxi	China	710032
44		Xi'an	Shaanxi	China	710038
45		Xi'an	Shaanxi	China	710061
46		Chengdu	Sichuan	China	610041
47		Beijing		China	100039
48		Beijing		China	100069
49		Beijing		China	100071
50		Beijing		China	100142
51		Chongqing		China	400038
52		Shanghai		China	200001
53		Shanghai		China	200032
54		Shanghai		China	201805
55		Tianjin		China	300060
56		Hradec Kralove		Czechia	500 05
57		Olomouc		Czechia	775 20
58		Praha 2		Czechia	128 08
59		Angers		France	49100
60		Caen		France	F-14033
61		Clichy		France	92110
62		Creteil		France	94010
63		Dijon		France	21000
64		La Tronche		France	38700
65		Lille		France	59037
66		Lyon		France	69004
67		Marseille		France	13005
68		Montpellier Cedex		France	34295
69		Nice Cedex 3		France	06202
70		Paris		France	75020
71		Paris		France	75651
72		Perpignan		France	66000
73		Reims Cedex		France	51092
74		Rennes Cedex		France	35062
75		Toulouse		France	31059
76		Vandoeuvre les Nancy		France	54500
77		Villejuif Cedex		France	94805
78		Heidelberg	Baden-Württemberg	Germany	69120
79		München	Bayern	Germany	81377
80		Frankfurt	Hessen	Germany	60590
81		Hannover	Niedersachsen	Germany	30625
82		Aachen	Nordrhein-Westfalen	Germany	52074
83		Essen	Nordrhein-Westfalen	Germany	45136
84		Köln	Nordrhein-Westfalen	Germany	50937
85		Mainz	Rheinland-Pfalz	Germany	55131
86		Magdeburg	Sachsen-Anhalt	Germany	39120
87		Berlin		Germany	13353
88		Hamburg		Germany	20246
89		Budapest		Hungary	1097
90		Debrecen		Hungary	4032
91		Kaposvar		Hungary	7400
92		Napoli	Campania	Italy	80131
93		Bologna	Emilia-Romagna	Italy	40138
94		Modena	Emilia-Romagna	Italy	41124
95		Roma	Lazio	Italy	00168
96		Genova	Liguria	Italy	16132
97		Bergamo	Lombardia	Italy	24127
98		Milano	Lombardia	Italy	20089
99		Milano	Lombardia	Italy	20122
100		Novara	Piemonte	Italy	28100
101		Torino	Piemonte	Italy	10126
102		Foggia	Puglia	Italy	71013
103		Cagliari	Sardegna	Italy	09134
104		Pisa	Toscana	Italy	56126
105		Padova	Veneto	Italy	35128
106		Chiba-shi	Chiba	Japan	260-8677
107		Kashiwa-shi	Chiba	Japan	277-8577
108		Fukuoka-shi	Fukuoka	Japan	810-8563
109		Iizuka-shi	Fukuoka	Japan	820-8505
110		Yokohama-shi	Kanagawa	Japan	232-0024
111		Kumamoto-shi	Kumamoto	Japan	860-8556
112		Osaka-shi	Osaka	Japan	541-8567
113		Osakasayama-shi	Osaka	Japan	589-8511
114		Utsunomiya-shi	Tochigi	Japan	321-0974
115		Chiyoda-ku	Tokyo	Japan	101-0062
116		Chuo-ku	Tokyo	Japan	104-0045
117		Musashino-shi	Tokyo	Japan	180-8610
118		Busan	Busan Gwang''yeogsi	Korea, Republic of	49241
119		Daegu		Korea, Republic of	700-721
120		Seoul		Korea, Republic of	06351
121		Seoul		Korea, Republic of	110-744
122		Amsterdam		Netherlands	1105 AZ
123		Leiden		Netherlands	2333 ZA
124		Barnaul		Russian Federation	656045
125		Moscow		Russian Federation	119991
126		Moscow		Russian Federation
127		Singapore		Singapore	119228
128		Oviedo	Asturias	Spain	33011
129		Alicante		Spain	03010
130		Barcelona		Spain	08035
131		Barcelona		Spain	08036
132		Córdoba		Spain	14004
133		Madrid		Spain	28007
134		Madrid		Spain	28041
135		Madrid		Spain	28050
136		Zaragoza		Spain	50009
137		Bellinzona	Ticino	Switzerland	6500
138		Bern		Switzerland	3010
139		Kaohsiung City	Kaohsiung	Taiwan	83301
140		Taipei		Taiwan	10016
141		Taipei		Taiwan	11217
142		Taoyuan		Taiwan	333
143		Birmingham	West Midlands	United Kingdom	B15 2WB
144		Leeds	West Yorkshire	United Kingdom	LS9 7TF
145		Bristol		United Kingdom	BS2 8ED
146		London		United Kingdom	SE5 9RS
147		London		United Kingdom	W12 0HS

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 AG products conducted in Europe.
• Click here to find results for studies related to Bayer Healthcare products.

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01774344
• Other Study ID Numbers: 15982; 2012-003649-14
• First Posted: Jan 24, 2013
• Last Update Posted: Aug 20, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bayer: Regorafenib; BAY73-4506
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular

Study Results

Participant Flow

Recruitment Details	The study was conducted between 14 May 2013 (first subject first visit), 29 February 2016 (primary completion date) and 05-July-2019 (Last Patient Last Visit =End of study).
Pre-assignment Detail	Overall, 843 subjects were screened, of them 270 subjects were screening failures. 573 subjects were randomized and assigned to treatment; of them 6 subjects never received treatment. 436 Entered survival Follow-up and 4 End of survival follow-up data not available.

Arm/Group Title	Placebo	Regorafenib 160 mg (BAY73-4506)
Arm/Group Description	Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.	Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
Period Title: Overall Study
STARTED	194	379
Treated	193	374
Entered Survival FU	145	291
COMPLETED	132	258
NOT COMPLETED	62	121

Baseline Characteristics

Arm/Group Title	Placebo	Regorafenib 160 mg (BAY73-4506)	Total
Arm/Group Description	Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best supportive care (BSC).	Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.	Total of all reporting groups
Overall Participants	194	379	573
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.1 (11.6)	61.8 (12.4)	61.6 (12.1)
Sex: Female, Male (Count of Participants)
Female	23 11.9%	46 12.1%	69 12%
Male	171 88.1%	333 87.9%	504 88%
Eastern cooperative oncology group (ECOG) Performance Status (PS) (data collection system-RAVE) (Count of Participants)
ECOG PS 0	130 67%	247 65.2%	377 65.8%
ECOG PS 1	64 33%	132 34.8%	196 34.2%
ECOG PS: Interactive voice response system (IVRS) (Count of Participants)
ECOG PS 0	129 66.5%	251 66.2%	380 66.3%
ECOG PS 1	65 33.5%	128 33.8%	193 33.7%
Alpha-fetoprotein (AFP) (RAVE) (Count of Participants)
less than (<) 400 nanogram per milliliter (ng/mL)	107 55.2%	217 57.3%	324 56.5%
greater than or equal to (>=) 400 ng/mL	87 44.8%	162 42.7%	249 43.5%
Alpha-fetoprotein (AFP) (IVRS) (Count of Participants)
< 400 ng/mL	105 54.1%	212 55.9%	317 55.3%
>= 400 ng/mL	89 45.9%	167 44.1%	256 44.7%
Macrovascular invasion (RAVE) (Count of Participants)
Absence	140 72.2%	269 71%	409 71.4%
Presence	54 27.8%	110 29%	164 28.6%
Macrovascular invasion (IVRS) (Count of Participants)
Absence	135 69.6%	262 69.1%	397 69.3%
Presence	59 30.4%	117 30.9%	176 30.7%
The Barcelona-Clinic Liver Cancer (BCLC) stage at study entry (Count of Participants)
Early stage	0 0%	1 0.3%	1 0.2%
Intermediate stage	22 11.3%	53 14%	75 13.1%
Advanced stage	172 88.7%	325 85.8%	497 86.7%
Extrahepatic disease (RAVE) (Count of Participants)
Absence	47 24.2%	114 30.1%	161 28.1%
Presence	147 75.8%	265 69.9%	412 71.9%
Extrahepatic disease (IVRS) (Count of Participants)
Absence	62 32%	129 34%	191 33.3%
Presence	132 68%	250 66%	382 66.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time Frame	From randomization (Day 1) of the first subject until 419 days later

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Regorafenib 160 mg (BAY73-4506)
Arm/Group Description	Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.	Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
Measure Participants	194	379
Median (95% Confidence Interval) [days]	237 (192)	323 (276)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio for OS and 95% confidence interval was calculated for stratified IVRS by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.000017
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.624
	Confidence Interval	(2-Sided) 95%; 0.498 to 0.782
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio for OS and 95% confidence interval was calculated for stratified RAVE (Sensitivity) by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.000149
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.660
	Confidence Interval	(2-Sided) 95%; 0.527 to 0.828
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio for OS and 95% confidence interval was calculated for unstratified (sensitivity) by using Cox model, stratified by the geographic region: Asia or Rest of the World (ROW), ECOG-PS: 0 versus 1, AFP level, presence versus absence of extrahepatic disease and presence versus absence of macrovascular invasion. Kaplan-Meier (KM) estimated for OS and KM survival curves were presented for each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.000107
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.674
	Confidence Interval	(2-Sided) 95%; 0.546 to 0.831
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time to Progression (TTP)
Description	TTP was the time (days) from randomization to radiological or clinical disease progression assessed by independent radiological review. Median and 95% confidence interval were reported for the modified response evaluation criteria in solid tumors (mRECIST) and response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time Frame	From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Regorafenib 160 mg (BAY73-4506)
Arm/Group Description	Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.	Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
Measure Participants	194	379
mRECIST	45 (44)	97 (87)
RECIST 1.1	45 (44)	119 (87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.439
	Confidence Interval	(2-Sided) 95%; 0.355 to 0.542
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio and its 95% CI was based on unstratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.471
	Confidence Interval	(2-Sided) 95%; 0.388 to 0.572
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.412
	Confidence Interval	(2-Sided) 95%; 0.334 to 0.509
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio and its 95% CI was based on unstratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Kaplan-Meier estimates.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.444
	Confidence Interval	(2-Sided) 95%; 0.365 to 0.539
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression Free Survival (PFS) was defined as the time (days) from date of randomization to date of disease progression (radiological or clinical) or death due to any cause, if death occurs before progression was documented. Death in the absence of progression was a PFS event only if it occurred within the 12+1 weeks for subjects who discontinued treatment prior to cycle 8 and 24+2 weeks for subjects who discontinued treatment after to cycle 8 of the last evaluable tumor assessment; PFS were censored at the date of the last evaluable tumor assessment, if it occurred later. Median and 95% confidence interval 95% were reported for the mRECIST and RECIST 1.1 analysis sets. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time Frame	From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Regorafenib 160 mg (BAY73-4506)
Arm/Group Description	Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.	Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
Measure Participants	194	379
mRECIST	45 (44)	95 (86)
RECIST 1.1	45 (44)	102 (87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.453
	Confidence Interval	(2-Sided) 95%; 0.369 to 0.555
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio and its 95% CI was based on unstratified Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.480
	Confidence Interval	(2-Sided) 95%; 0.397 to 0.580
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio and its 95% CI was based on stratified (IVRS) Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.425
	Confidence Interval	(2-Sided) 95%; 0.347 to 0.522
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Hazard ratio and its 95% CI was based on unstratified Cox Regression Model. One-sided p-value was calculated from log rank test and 95% CIs was computed by using Cox Regression Model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.454
	Confidence Interval	(2-Sided) 95%; 0.376 to 0.548
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Objective Tumor Response Rate (ORR)
Description	Objective tumor response rate (ORR) was defined as the percentage of subjects whose best tumor response CR or Partial Response (PR) observed during trial period assessed according to the mRECIST criteria and RECIST 1.1. CR= Disappearance of all clinical and radiological evidence of tumor (both target and non-target). Any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to < 10 mm. PR= At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non target lesions and no appearance of new lesions. Subjects prematurely discontinuing without an assessment were to be considered non-responders for the analysis.
Time Frame	From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Regorafenib 160 mg (BAY73-4506)
Arm/Group Description	Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.	Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
Measure Participants	194	379
mRECIST	4.1	10.8
RECIST 1.1	2.6	6.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Comparison of treatments were calculated.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.003650
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-6.88
	Confidence Interval	(2-Sided) 95%; -11.13 to -2.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Comparison of treatments were calculated.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.019991
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-4.15
	Confidence Interval	(2-Sided) 95%; -7.55 to -0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	Disease control rate (DCR) was defined as the percentage of subjects whose best response was CR (CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target).), PR (PR: at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.), or stable disease (SD) (SD: steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, no unequivocal progression of existing non-target lesions, and no appearance of new lesions.) according to RECIST and RECIST 1.1 criteria. SD had to be maintained for at least 6 weeks from the first demonstration of that rating.
Time Frame	From date of randomization until 30 days after last study treatment (assessed every 6 weeks until PD; and after 8 cycle assessed every 12 weeks) (approximately 33 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Regorafenib 160 mg (BAY73-4506)
Arm/Group Description	Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.	Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
Measure Participants	194	379
mRECIST	36.1	65.2
RECIST 1.1	34.5	65.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Comparison of treatments were calculated.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-29.31
	Confidence Interval	(2-Sided) 95%; -37.52 to -21.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regorafenib 160 mg (BAY73-4506)
	Comments	Comparison of treatments were calculated.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.000001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference
	Estimated Value	-31.39
	Confidence Interval	(2-Sided) 95%; -39.57 to -23.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Overall Survival (OS)
Description	Overall Survival (OS) was defined as the time from date of randomization (Day 1) to death due to any cause
Time Frame	From randomization (Day 1) of the first subject to end of follow upto 1710 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Regorafenib 160 mg (BAY73-4506)
Arm/Group Description	Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best best supportive care.	Subjects received regorafenib 160 milligram (mg) (4 * 40 mg coated tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
Measure Participants	194	379
Median (95% Confidence Interval) [days]	241 (196)	326 (278)

Adverse Events

Time Frame	Adverse event data were collected after start of study drug administration until 30 days after end of study treatment over a period of approximately three years
Arm/Group Title	Placebo		Regorafenib (Stivarga, BAY73-4506)
Arm/Group Description	Description: Subjects received placebo matched to regorafenib tablets orally every day for 3 weeks followed by 1 week off treatment plus best supportive care(BSC).		Description: Subjects received regorafenib 160 mg (4 *40 mg tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.
All Cause Mortality
	Placebo		Regorafenib (Stivarga, BAY73-4506)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	176/193 (91.2%)		324/374 (86.6%)
Serious Adverse Events
	Placebo		Regorafenib (Stivarga, BAY73-4506)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	92/193 (47.7%)		194/374 (51.9%)
Blood and lymphatic system disorders
Anaemia	1/193 (0.5%)	3	4/374 (1.1%)	9
Thrombocytopenia	0/193 (0%)	0	1/374 (0.3%)	7
Blood loss anaemia	1/193 (0.5%)	2	0/374 (0%)	0
Cardiac disorders
Acute coronary syndrome	0/193 (0%)	0	4/374 (1.1%)	4
Atrial fibrillation	0/193 (0%)	0	2/374 (0.5%)	2
Atrial flutter	0/193 (0%)	0	1/374 (0.3%)	1
Cardiac arrest	1/193 (0.5%)	2	0/374 (0%)	0
Myocardial infarction	0/193 (0%)	0	2/374 (0.5%)	3
Acute myocardial infarction	0/193 (0%)	0	2/374 (0.5%)	3
Angina unstable	0/193 (0%)	0	1/374 (0.3%)	1
Cardiac failure acute	0/193 (0%)	0	1/374 (0.3%)	1
Endocrine disorders
Hypothyroidism	0/193 (0%)	0	1/374 (0.3%)	1
Eye disorders
Retinal artery occlusion	0/193 (0%)	0	1/374 (0.3%)	1
Cataract	0/193 (0%)	0	1/374 (0.3%)	2
Gastrointestinal disorders
Abdominal discomfort	1/193 (0.5%)	1	0/374 (0%)	0
Abdominal distension	1/193 (0.5%)	1	0/374 (0%)	0
Abdominal pain	4/193 (2.1%)	4	2/374 (0.5%)	3
Abdominal pain lower	0/193 (0%)	0	2/374 (0.5%)	3
Abdominal pain upper	0/193 (0%)	0	1/374 (0.3%)	1
Ascites	6/193 (3.1%)	7	10/374 (2.7%)	13
Constipation	0/193 (0%)	0	1/374 (0.3%)	1
Diarrhoea	0/193 (0%)	0	3/374 (0.8%)	3
Diverticulum intestinal	0/193 (0%)	0	1/374 (0.3%)	1
Dysphagia	0/193 (0%)	0	1/374 (0.3%)	1
Duodenal perforation	0/193 (0%)	0	1/374 (0.3%)	2
Gastritis	1/193 (0.5%)	1	1/374 (0.3%)	1
Gastrointestinal haemorrhage	2/193 (1%)	3	2/374 (0.5%)	2
Haematemesis	1/193 (0.5%)	1	1/374 (0.3%)	1
Intra-abdominal haemorrhage	2/193 (1%)	4	0/374 (0%)	0
Lower gastrointestinal haemorrhage	1/193 (0.5%)	1	0/374 (0%)	0
Obstruction gastric	1/193 (0.5%)	1	0/374 (0%)	0
Oesophageal haemorrhage	1/193 (0.5%)	2	0/374 (0%)	0
Oesophageal varices haemorrhage	1/193 (0.5%)	2	6/374 (1.6%)	6
Pancreatitis	0/193 (0%)	0	3/374 (0.8%)	3
Pancreatitis acute	0/193 (0%)	0	1/374 (0.3%)	1
Rectal haemorrhage	0/193 (0%)	0	2/374 (0.5%)	2
Stomatitis	0/193 (0%)	0	1/374 (0.3%)	1
Upper gastrointestinal haemorrhage	3/193 (1.6%)	5	6/374 (1.6%)	6
Anal fistula	0/193 (0%)	0	1/374 (0.3%)	1
Duodenal ulcer	0/193 (0%)	0	1/374 (0.3%)	1
Peritoneal haemorrhage	0/193 (0%)	0	1/374 (0.3%)	1
General disorders
Asthenia	0/193 (0%)	0	4/374 (1.1%)	5
Death	0/193 (0%)	0	1/374 (0.3%)	1
Fatigue	0/193 (0%)	0	2/374 (0.5%)	3
General physical health deterioration	25/193 (13%)	32	47/374 (12.6%)	73
Malaise	0/193 (0%)	0	1/374 (0.3%)	1
Multiple organ dysfunction syndrome	1/193 (0.5%)	2	0/374 (0%)	0
Pain	2/193 (1%)	2	1/374 (0.3%)	1
Pyrexia	1/193 (0.5%)	1	6/374 (1.6%)	6
Hepatobiliary disorders
Acute hepatic failure	0/193 (0%)	0	3/374 (0.8%)	5
Bile duct stenosis	2/193 (1%)	5	0/374 (0%)	0
Cholecystitis	0/193 (0%)	0	1/374 (0.3%)	1
Cholangitis	1/193 (0.5%)	1	1/374 (0.3%)	2
Gallbladder obstruction	0/193 (0%)	0	1/374 (0.3%)	1
Hepatic cirrhosis	0/193 (0%)	0	2/374 (0.5%)	2
Hepatic failure	9/193 (4.7%)	14	9/374 (2.4%)	14
Hepatic function abnormal	3/193 (1.6%)	3	2/374 (0.5%)	2
Hepatic haemorrhage	2/193 (1%)	4	2/374 (0.5%)	3
Hepatitis acute	0/193 (0%)	0	1/374 (0.3%)	1
Hepatobiliary disease	0/193 (0%)	0	1/374 (0.3%)	1
Hepatorenal syndrome	1/193 (0.5%)	2	2/374 (0.5%)	3
Hyperbilirubinaemia	1/193 (0.5%)	3	0/374 (0%)	0
Jaundice	2/193 (1%)	2	1/374 (0.3%)	1
Jaundice cholestatic	1/193 (0.5%)	1	2/374 (0.5%)	3
Portal vein thrombosis	1/193 (0.5%)	1	0/374 (0%)	0
Cholangitis acute	0/193 (0%)	0	1/374 (0.3%)	1
Infections and infestations
Bronchitis	0/193 (0%)	0	1/374 (0.3%)	3
Abdominal infection	0/193 (0%)	0	2/374 (0.5%)	2
Candida infection	0/193 (0%)	0	1/374 (0.3%)	1
Cellulitis	0/193 (0%)	0	1/374 (0.3%)	1
Escherichia sepsis	0/193 (0%)	0	1/374 (0.3%)	1
Gastroenteritis	0/193 (0%)	0	1/374 (0.3%)	1
Liver abscess	2/193 (1%)	2	2/374 (0.5%)	2
Lower respiratory tract infection	0/193 (0%)	0	2/374 (0.5%)	5
Lung abscess	0/193 (0%)	0	1/374 (0.3%)	1
Lung infection	0/193 (0%)	0	4/374 (1.1%)	5
Peritonitis	1/193 (0.5%)	1	1/374 (0.3%)	1
Peritonitis bacterial	0/193 (0%)	0	1/374 (0.3%)	2
Pleural infection bacterial	1/193 (0.5%)	2	0/374 (0%)	0
Pneumonia	1/193 (0.5%)	1	8/374 (2.1%)	11
Sepsis	0/193 (0%)	0	3/374 (0.8%)	5
Septic shock	0/193 (0%)	0	1/374 (0.3%)	1
Streptococcal bacteraemia	0/193 (0%)	0	1/374 (0.3%)	1
Subcutaneous abscess	1/193 (0.5%)	3	1/374 (0.3%)	2
Tracheitis	0/193 (0%)	0	1/374 (0.3%)	1
Urinary tract infection	0/193 (0%)	0	1/374 (0.3%)	1
Urosepsis	0/193 (0%)	0	1/374 (0.3%)	1
Wound infection bacterial	1/193 (0.5%)	1	0/374 (0%)	0
Folliculitis	0/193 (0%)	0	1/374 (0.3%)	1
Injury, poisoning and procedural complications
Craniocerebral injury	0/193 (0%)	0	1/374 (0.3%)	2
Femur fracture	1/193 (0.5%)	1	1/374 (0.3%)	1
Pelvic fracture	0/193 (0%)	0	1/374 (0.3%)	1
Pubis fracture	1/193 (0.5%)	1	0/374 (0%)	0
Spinal compression fracture	1/193 (0.5%)	1	1/374 (0.3%)	1
Investigations
Aspartate aminotransferase increased	0/193 (0%)	0	1/374 (0.3%)	1
Blood bilirubin increased	2/193 (1%)	3	2/374 (0.5%)	3
Blood pressure decreased	0/193 (0%)	0	1/374 (0.3%)	2
General physical condition abnormal	0/193 (0%)	0	1/374 (0.3%)	1
Metabolism and nutrition disorders
Decreased appetite	3/193 (1.6%)	3	1/374 (0.3%)	3
Dehydration	0/193 (0%)	0	4/374 (1.1%)	4
Hypercalcaemia	2/193 (1%)	4	0/374 (0%)	0
Hyperglycaemia	1/193 (0.5%)	1	0/374 (0%)	0
Hypoalbuminaemia	0/193 (0%)	0	1/374 (0.3%)	1
Hypoglycaemia	0/193 (0%)	0	2/374 (0.5%)	3
Hyponatraemia	0/193 (0%)	0	2/374 (0.5%)	2
Malnutrition	0/193 (0%)	0	1/374 (0.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/193 (0.5%)	1	0/374 (0%)	0
Back pain	2/193 (1%)	2	6/374 (1.6%)	9
Bone pain	1/193 (0.5%)	1	0/374 (0%)	0
Muscular weakness	0/193 (0%)	0	1/374 (0.3%)	1
Musculoskeletal chest pain	0/193 (0%)	0	1/374 (0.3%)	2
Musculoskeletal pain	0/193 (0%)	0	1/374 (0.3%)	1
Myalgia	0/193 (0%)	0	1/374 (0.3%)	1
Neck pain	0/193 (0%)	0	1/374 (0.3%)	1
Pathological fracture	1/193 (0.5%)	1	1/374 (0.3%)	1
Pain in extremity	1/193 (0.5%)	2	1/374 (0.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric	0/193 (0%)	0	1/374 (0.3%)	1
Cancer pain	0/193 (0%)	0	1/374 (0.3%)	1
Infected neoplasm	0/193 (0%)	0	1/374 (0.3%)	1
Large intestine benign neoplasm	0/193 (0%)	0	1/374 (0.3%)	1
Metastases to lung	1/193 (0.5%)	1	0/374 (0%)	0
Thyroid neoplasm	0/193 (0%)	0	1/374 (0.3%)	1
Tumour associated fever	0/193 (0%)	0	1/374 (0.3%)	1
Tumour haemorrhage	1/193 (0.5%)	2	0/374 (0%)	0
Tumour pain	0/193 (0%)	0	4/374 (1.1%)	4
Nervous system disorders
Brain oedema	0/193 (0%)	0	1/374 (0.3%)	1
Cerebral haematoma	1/193 (0.5%)	1	0/374 (0%)	0
Cerebrovascular accident	0/193 (0%)	0	1/374 (0.3%)	1
Encephalopathy	3/193 (1.6%)	4	3/374 (0.8%)	3
Epilepsy	0/193 (0%)	0	1/374 (0.3%)	1
Haemorrhage intracranial	0/193 (0%)	0	1/374 (0.3%)	1
Headache	1/193 (0.5%)	1	0/374 (0%)	0
Hemiparesis	1/193 (0.5%)	1	0/374 (0%)	0
Hepatic encephalopathy	3/193 (1.6%)	6	9/374 (2.4%)	14
Meningorrhagia	0/193 (0%)	0	1/374 (0.3%)	2
Myasthenia gravis	0/193 (0%)	0	1/374 (0.3%)	1
Paraesthesia	0/193 (0%)	0	1/374 (0.3%)	1
Quadriparesis	0/193 (0%)	0	1/374 (0.3%)	2
Sciatica	1/193 (0.5%)	2	0/374 (0%)	0
Seizure	0/193 (0%)	0	2/374 (0.5%)	2
Status epilepticus	0/193 (0%)	0	1/374 (0.3%)	1
Syncope	0/193 (0%)	0	1/374 (0.3%)	1
Diplegia	0/193 (0%)	0	1/374 (0.3%)	1
Intracranial pressure increased	0/193 (0%)	0	1/374 (0.3%)	2
Intracranial venous sinus thrombosis	0/193 (0%)	0	1/374 (0.3%)	1
Psychiatric disorders
Anxiety	0/193 (0%)	0	1/374 (0.3%)	2
Renal and urinary disorders
Acute kidney injury	2/193 (1%)	2	2/374 (0.5%)	2
Calculus urinary	0/193 (0%)	0	1/374 (0.3%)	1
Cystitis noninfective	0/193 (0%)	0	1/374 (0.3%)	1
Renal failure	1/193 (0.5%)	1	3/374 (0.8%)	3
Ureterolithiasis	0/193 (0%)	0	1/374 (0.3%)	1
Reproductive system and breast disorders
Pelvic pain	1/193 (0.5%)	1	0/374 (0%)	0
Scrotal oedema	0/193 (0%)	0	1/374 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/193 (0.5%)	1	0/374 (0%)	0
Bronchial obstruction	0/193 (0%)	0	1/374 (0.3%)	2
Dyspnoea	2/193 (1%)	3	5/374 (1.3%)	7
Haemoptysis	2/193 (1%)	2	3/374 (0.8%)	6
Interstitial lung disease	0/193 (0%)	0	1/374 (0.3%)	2
Pleural effusion	1/193 (0.5%)	2	4/374 (1.1%)	4
Pneumonia aspiration	0/193 (0%)	0	1/374 (0.3%)	1
Pulmonary oedema	0/193 (0%)	0	1/374 (0.3%)	1
Pneumonitis	0/193 (0%)	0	2/374 (0.5%)	2
Respiratory distress	0/193 (0%)	0	1/374 (0.3%)	1
Respiratory failure	3/193 (1.6%)	6	1/374 (0.3%)	2
Tracheal disorder	0/193 (0%)	0	1/374 (0.3%)	2
Cough	0/193 (0%)	0	1/374 (0.3%)	1
Pulmonary venous thrombosis	0/193 (0%)	0	1/374 (0.3%)	1
Skin and subcutaneous tissue disorders
Blister	0/193 (0%)	0	1/374 (0.3%)	1
Palmar-plantar erythrodysaesthesia syndrome	0/193 (0%)	0	2/374 (0.5%)	3
Skin ulcer	0/193 (0%)	0	1/374 (0.3%)	1
Precancerous skin lesion	1/193 (0.5%)	1	0/374 (0%)	0
Vascular disorders
Deep vein thrombosis	1/193 (0.5%)	1	0/374 (0%)	0
Embolism	0/193 (0%)	0	1/374 (0.3%)	1
Hypovolaemic shock	0/193 (0%)	0	1/374 (0.3%)	2
Hypertensive crisis	0/193 (0%)	0	1/374 (0.3%)	1
Shock haemorrhagic	0/193 (0%)	0	3/374 (0.8%)	5
Orthostatic hypotension	1/193 (0.5%)	1	0/374 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Regorafenib (Stivarga, BAY73-4506)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	162/193 (83.9%)		366/374 (97.9%)
Blood and lymphatic system disorders
Anaemia	21/193 (10.9%)	40	57/374 (15.2%)	114
Endocrine disorders
Hypothyroidism	1/193 (0.5%)	1	29/374 (7.8%)	33
Gastrointestinal disorders
Abdominal distension	10/193 (5.2%)	13	20/374 (5.3%)	24
Abdominal pain upper	18/193 (9.3%)	22	52/374 (13.9%)	85
Abdominal pain	29/193 (15%)	43	85/374 (22.7%)	127
Ascites	31/193 (16.1%)	57	61/374 (16.3%)	91
Constipation	21/193 (10.9%)	24	67/374 (17.9%)	79
Diarrhoea	31/193 (16.1%)	44	163/374 (43.6%)	348
Dry mouth	12/193 (6.2%)	15	22/374 (5.9%)	24
Nausea	26/193 (13.5%)	38	72/374 (19.3%)	106
Stomatitis	4/193 (2.1%)	4	31/374 (8.3%)	44
Vomiting	13/193 (6.7%)	17	50/374 (13.4%)	73
General disorders
Asthenia	19/193 (9.8%)	34	56/374 (15%)	97
Fatigue	50/193 (25.9%)	67	110/374 (29.4%)	205
Malaise	5/193 (2.6%)	5	23/374 (6.1%)	33
Oedema peripheral	26/193 (13.5%)	32	63/374 (16.8%)	81
Pyrexia	13/193 (6.7%)	15	79/374 (21.1%)	113
Investigations
Alanine aminotransferase increased	21/193 (10.9%)	37	56/374 (15%)	102
Blood alkaline phosphatase increased	9/193 (4.7%)	21	23/374 (6.1%)	43
Aspartate aminotransferase increased	40/193 (20.7%)	89	99/374 (26.5%)	234
Blood bilirubin increased	30/193 (15.5%)	59	94/374 (25.1%)	258
Gamma-glutamyltransferase increased	14/193 (7.3%)	32	24/374 (6.4%)	73
Lipase increased	7/193 (3.6%)	15	27/374 (7.2%)	62
Platelet count decreased	2/193 (1%)	8	39/374 (10.4%)	129
Weight decreased	9/193 (4.7%)	11	55/374 (14.7%)	132
White blood cell count decreased	2/193 (1%)	7	20/374 (5.3%)	40
Metabolism and nutrition disorders
Decreased appetite	29/193 (15%)	37	122/374 (32.6%)	186
Hypoalbuminaemia	14/193 (7.3%)	19	56/374 (15%)	152
Hypokalaemia	6/193 (3.1%)	22	28/374 (7.5%)	62
Hyponatraemia	7/193 (3.6%)	17	20/374 (5.3%)	30
Hypophosphataemia	5/193 (2.6%)	11	36/374 (9.6%)	96
Musculoskeletal and connective tissue disorders
Arthralgia	11/193 (5.7%)	12	15/374 (4%)	17
Back pain	16/193 (8.3%)	18	50/374 (13.4%)	73
Musculoskeletal pain	11/193 (5.7%)	19	18/374 (4.8%)	22
Muscle spasms	4/193 (2.1%)	5	38/374 (10.2%)	48
Pain in extremity	5/193 (2.6%)	6	31/374 (8.3%)	51
Nervous system disorders
Headache	12/193 (6.2%)	12	25/374 (6.7%)	33
Psychiatric disorders
Insomnia	8/193 (4.1%)	8	30/374 (8%)	35
Renal and urinary disorders
Proteinuria	2/193 (1%)	6	34/374 (9.1%)	96
Respiratory, thoracic and mediastinal disorders
Cough	13/193 (6.7%)	15	45/374 (12%)	50
Dyspnoea	15/193 (7.8%)	15	26/374 (7%)	42
Dysphonia	5/193 (2.6%)	7	68/374 (18.2%)	85
Pleural effusion	10/193 (5.2%)	11	13/374 (3.5%)	14
Skin and subcutaneous tissue disorders
Alopecia	6/193 (3.1%)	6	27/374 (7.2%)	27
Palmar-plantar erythrodysaesthesia syndrome	15/193 (7.8%)	27	194/374 (51.9%)	554
Pruritus	14/193 (7.3%)	19	22/374 (5.9%)	34
Rash	14/193 (7.3%)	15	21/374 (5.6%)	28
Vascular disorders
Hypertension	14/193 (7.3%)	30	119/374 (31.8%)	327

Limitations/Caveats

Decimal places were automatically truncated if last decimal equals zero.

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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.