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Clinical Trial Results:
A randomized, double blind, placebo-controlled, multicenter phase III study of regorafenib in patients with hepatocellular carcinoma (HCC) after sorafenib

Summary
EudraCT number	2012-003649-14
Trial protocol	DE BE GB AT ES CZ FR HU NL IT
Global end of trial date

Results information
Results version number	v1
This version publication date	25 Feb 2017
First version publication date	25 Feb 2017
Other versions	v2 , v3

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

BAY73-4506/15982

ISRCTN number

-

US NCT number

NCT01774344

WHO universal trial number (UTN)

-

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,

Public contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Interim

Date of interim/final analysis

29 Feb 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

29 Feb 2016

Global end of trial reached?

No

Main objective of the trial

The objective of this study was to evaluate efficacy and safety of regorafenib in subjects with hepatocellular carcinoma (HCC) who had progressed after sorafenib.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

14 May 2013

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Brazil: 4

Country: Number of subjects enrolled

Switzerland: 3

Country: Number of subjects enrolled

China: 137

Country: Number of subjects enrolled

Czech Republic: 8

Country: Number of subjects enrolled

Germany: 35

Country: Number of subjects enrolled

Spain: 34

Country: Number of subjects enrolled

France: 118

Country: Number of subjects enrolled

United Kingdom: 20

Country: Number of subjects enrolled

Hungary: 17

Country: Number of subjects enrolled

Italy: 53

Country: Number of subjects enrolled

Japan: 40

Country: Number of subjects enrolled

Korea, Republic of: 19

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Russian Federation: 11

Country: Number of subjects enrolled

Singapore: 1

Country: Number of subjects enrolled

Taiwan: 19

Country: Number of subjects enrolled

United States: 31

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

Austria: 8

Country: Number of subjects enrolled

Belgium: 2

Worldwide total number of subjects

573

EEA total number of subjects

297

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

315

From 65 to 84 years

258

85 years and over

0

Subject disposition

Top of page

Recruitment details

The study was conducted at multiple centers in North America, South America, Europe, Asia, and Australia between 14 May 2013 (first subject first visit) and 29 February 2016 (primary completion date).

Screening details

Overall, 843 subjects were enrolled, of them 270 were screen failures. The remaining 573 subjects were randomized and assigned to treatment; of them 6 subjects never received treatment.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm 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.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo matched to regorafenib coated tablets orally every day for 3 weeks followed by 1 week off treatment plus best BSC.

Regorafenib 160 mg (BAY73-4506)

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received regorafenib 160 mg coated tablets orally every day for 3 weeks followed by 1 week off treatment plus BSC.

Number of subjects in period 1	Placebo	Regorafenib 160 mg (BAY73-4506)
Started	194	379
Treated	193	374
Completed	162	231
Not completed	32	148
Physician decision	-	1
Protocol violation	3	1
Study drug never administered	1	5
Ongoing with treatment	10	65
Non-compliance with study drug	-	2
Unspecified	1	-
Adverse event (AE)	-	1
AE un-associated with clinical disease progression	12	47
Withdrawal by subject	5	26

Baseline characteristics

Top of page

Reporting group title

Placebo

Reporting 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.

Reporting group title

Regorafenib 160 mg (BAY73-4506)

Reporting group description

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.

Reporting group values	Placebo	Regorafenib 160 mg (BAY73-4506)	Total
Number of subjects	194	379	573
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	61.1 ( 11.6 )	61.8 ( 12.4 )	-
Gender categorical
Units: Subjects
Female	23	46	69
Male	171	333	504
Eastern cooperative oncology group (ECOG) Performance Status (PS) (data collection system-RAVE)
ECOG PS was measured in a scale from 0 (best) to grade 4 (worst), where 0= Fully active, able to carry on all pre-diseases performance without restriction, 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50 percent (%) waking hours (h), 3= Capable of only limited self-care, confined to bed/chair, more than 50% waking hours, and 4= Completely disabled, cannot carry on any self-care, totally confined to bed/chair.
Units: Subjects
Grade 0	130	247	377
Grade 1	64	132	196
ECOG PS: Interactive voice response system (IVRS)
ECOG PS was measured in a scale from 0 (best) to grade 4 (worst), where 0= Fully active, able to carry on all pre-diseases performance without restriction, 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2= Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50 % waking h, 3= Capable of only limited self-care, confined to bed/chair, more than 50% waking hours, and 4= Completely disabled, cannot carry on any self-care, totally confined to bed/chair.
Units: Subjects
Grade 0	129	251	380
Grade 1	65	128	193
Alpha-fetoprotein (AFP) (RAVE)
Alpha-Fetoprotein blood test was performed and baseline data were reported.
Units: Subjects
less than (<) 400 nanogram per milliliter (ng/mL)	107	217	324
greater than or equal to (>=) 400 ng/mL	87	162	249
Alpha-fetoprotein (AFP) (IVRS)
AFP blood test was performed and baseline data were reported.
Units: Subjects
< 400 ng/mL	105	212	317
>= 400 ng/mL	89	167	256
Macrovascular invasion (RAVE)
Macrovascular invasion was defined as presence or absence of invasion of portal or hepatic vasculature by tumor.
Units: Subjects
Absence	140	269	409
Presence	54	110	164
Macrovascular invasion (IVRS)
Macrovascular invasion was defined as presence or absence of invasion of portal or hepatic vasculature by tumor.
Units: Subjects
Absence	135	262	397
Presence	59	117	176
The Barcelona-Clinic Liver Cancer (BCLC) stage at study entry
BCLC classification divides HCC subjects in 5 stages (0=very early stage, A=early stage, B=intermediate stage, C=advanced stage and D=terminal stage) according to pre-established prognostic variables, and allocates therapies according to treatment-related status. Thus, it provides information on both prognostic prediction and treatment allocation.
Units: Subjects
Early stage	0	1	1
Intermediate stage	22	53	75
Advanced stage	172	325	497
Extrahepatic disease (RAVE)
Extrahepatic disease defined as presence or absence of tumor outside the liver.
Units: Subjects
Absence	47	114	161
Presence	147	265	412
Extrahepatic disease (IVRS)
Extrahepatic disease defined as presence or absence of tumor outside the liver.
Units: Subjects
Absence	62	129	191
Presence	132	250	382

End points

Top of page

Reporting group title

Placebo

Reporting 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.

Reporting group title

Regorafenib 160 mg (BAY73-4506)

Reporting group description

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.

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

FAS (N=573) included all randomized subjects.

Primary: Overall Survival (OS)

Top of page

End point title

Overall Survival (OS)

End point 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.

End point type

Primary

End point timeframe

From randomization (Day 1) of the first subject until 419 days later

End point values	Placebo	Regorafenib 160 mg (BAY73-4506)
Number of subjects analysed	194 ^[1]	379 ^[2]
Units: days
median (confidence interval 95%)	237 (192 to 269)	323 (276 to 369)

Notes
[1] - FAS
[2] - FAS

Regorafenib v Placebo: Stratified (IVRS)

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.00002 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.627

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

0.785

Notes
[3] - One-sided p-value was analyzed from log rank test.

Regorafenib v Placebo: Stratified (RAVE)

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.000155 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.661

Confidence interval

level

95%

sides

2-sided

lower limit

0.527

upper limit

0.829

Notes
[4] - One-sided p-value was analyzed from log rank test.

Regorafenib v Placebo: Unstratified (Sensitivity)

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.000107 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.673

Confidence interval

level

95%

sides

2-sided

lower limit

0.545

upper limit

0.831

Notes
[5] - One-sided p-value was analyzed from log rank test.

Secondary: Time to Progression (TTP)

Top of page

End point title

Time to Progression (TTP)

End point 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.

End point type

Secondary

End point timeframe

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)

End point values	Placebo	Regorafenib 160 mg (BAY73-4506)
Number of subjects analysed	194 ^[6]	379 ^[7]
Units: days
median (confidence interval 95%)
mRECIST	45 (44 to 49)	97 (87 to 128)
RECIST 1.1	45 (44 to 49)	119 (87 to 128)

Notes
[6] - FAS
[7] - FAS

Regorafenib v Placebo-mRECIST: Stratified (IVRS)

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.442

Confidence interval

level

95%

sides

2-sided

lower limit

0.358

upper limit

0.545

Regorafenib v Placebo-mRECIST: Unstratified

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.472

Confidence interval

level

95%

sides

2-sided

lower limit

0.389

upper limit

0.573

Regorafenib v Placebo-RECIST 1.1:Stratified (IVRS)

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.414

Confidence interval

level

95%

sides

2-sided

lower limit

0.335

upper limit

0.511

Regorafenib v Placebo-RECIST 1.1: Unstratified

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.443

Confidence interval

level

95%

sides

2-sided

lower limit

0.365

upper limit

0.539

Secondary: Progression Free Survival (PFS)

Top of page

End point title

Progression Free Survival (PFS)

End point 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.

End point type

Secondary

End point timeframe

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)

End point values	Placebo	Regorafenib 160 mg (BAY73-4506)
Number of subjects analysed	194 ^[8]	379 ^[9]
Units: days
median (confidence interval 95%)
mRECIST	45 (44 to 49)	95 (86 to 127)
RECIST 1.1	45 (44 to 47)	102 (87 to 127)

Notes
[8] - FAS
[9] - FAS

Regorafenib v Placebo-mRECIST: Stratified (IVRS)

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.455

Confidence interval

level

95%

sides

2-sided

lower limit

0.371

upper limit

0.558

Regorafenib v Placebo-mRECIST: Unstratified

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.481

Confidence interval

level

95%

sides

2-sided

lower limit

0.398

upper limit

0.581

Regorafenib v Placebo-RECIST 1.1:Stratified (IVRS)

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.427

Confidence interval

level

95%

sides

2-sided

lower limit

0.348

upper limit

0.524

Regorafenib v Placebo-RECIST 1.1: Unstratified

Statistical analysis description

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.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.453

Confidence interval

level

95%

sides

2-sided

lower limit

0.375

upper limit

0.548

Secondary: Objective Tumor Response Rate (ORR)

Top of page

End point title

Objective Tumor Response Rate (ORR)

End point 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.

End point type

Secondary

End point timeframe

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)

End point values	Placebo	Regorafenib 160 mg (BAY73-4506)
Number of subjects analysed	194 ^[10]	379 ^[11]
Units: percentage of subjects
number (not applicable)
mRECIST	4.1	10.6
RECIST 1.1	2.6	6.6

Notes
[10] - FAS
[11] - FAS

Regorafenib v Placebo-mRECIST

Statistical analysis description

Comparison of treatments were calculated.

Comparison groups

Placebo v Regorafenib 160 mg (BAY73-4506)

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004728

Method

Cochran-Mantel-Haenszel

Parameter type

Difference

Point estimate

-6.61

Confidence interval

level

95%

sides

2-sided

lower limit

-10.84

upper limit

-2.39

Regorafenib v Placebo-RECIST 1.1

Statistical analysis description

Comparison of treatments were calculated.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.019991

Method

Cochran-Mantel-Haenszel

Parameter type

Difference

Point estimate

-4.15

Confidence interval

level

95%

sides

2-sided

lower limit

-7.55

upper limit

-0.75

Secondary: Disease Control Rate (DCR)

Top of page

End point title

Disease Control Rate (DCR)

End point 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.

End point type

Secondary

End point timeframe

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)

End point values	Placebo	Regorafenib 160 mg (BAY73-4506)
Number of subjects analysed	194 ^[12]	379 ^[13]
Units: percentage of subjects
number (not applicable)
mRECIST	36.1	65.2
RECIST 1.1	34.5	65.7

Notes
[12] - FAS
[13] - FAS

Regorafenib v Placebo-mRECIST

Statistical analysis description

Comparison of treatments were calculated.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference

Point estimate

-29.31

Confidence interval

level

95%

sides

2-sided

lower limit

-37.52

upper limit

-21.11

Regorafenib v Placebo-RECIST 1.1

Statistical analysis description

Comparison of treatments were calculated.

Comparison groups

Regorafenib 160 mg (BAY73-4506) v Placebo

Number of subjects included in analysis

573

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001

Method

Cochran-Mantel-Haenszel

Parameter type

Difference

Point estimate

-31.39

Confidence interval

level

95%

sides

2-sided

lower limit

-39.57

upper limit

-23.22

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse event data were collected after signing the informed consent until 30 days after end of study treatment over a period of approximately three years

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Placebo

Reporting group description

Subjects received placebo matched to regorafenib tablets orally every day for 3 weeks followed by 1 week off treatment plus BSC.

Reporting group title

Regorafenib 160mg (BAY73-4506)

Reporting group description

Subjects received regorafenib 160 mg (4 *40 mg tablets) orally every day for 3 weeks followed by 1 week off treatment plus BSC.

Serious adverse events	Placebo	Regorafenib 160mg (BAY73-4506)
Total subjects affected by serious adverse events
subjects affected / exposed	90 / 193 (46.63%)	166 / 374 (44.39%)
number of deaths (all causes)	140	229
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected neoplasm
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine benign neoplasm
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Tumour pain
subjects affected / exposed	0 / 193 (0.00%)	4 / 374 (1.07%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Orthostatic hypotension
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 193 (0.00%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 0	2 / 5
deaths causally related to treatment / all	0 / 0	1 / 2
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 193 (0.00%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Fatigue
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	24 / 193 (12.44%)	39 / 374 (10.43%)
occurrences causally related to treatment / all	1 / 30	8 / 59
deaths causally related to treatment / all	0 / 16	1 / 23
Malaise
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pain
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 193 (0.52%)	5 / 374 (1.34%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial obstruction
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Dyspnoea
subjects affected / exposed	2 / 193 (1.04%)	5 / 374 (1.34%)
occurrences causally related to treatment / all	0 / 3	1 / 7
deaths causally related to treatment / all	0 / 1	0 / 2
Haemoptysis
subjects affected / exposed	2 / 193 (1.04%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 193 (0.52%)	4 / 374 (1.07%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	3 / 193 (1.55%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 3	0 / 1
Tracheal disorder
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	2 / 193 (1.04%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood pressure decreased
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
General physical condition abnormal
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Craniocerebral injury
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Femur fracture
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 193 (0.00%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	3 / 193 (1.55%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Epilepsy
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Headache
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	3 / 193 (1.55%)	7 / 374 (1.87%)
occurrences causally related to treatment / all	0 / 6	5 / 11
deaths causally related to treatment / all	0 / 1	1 / 1
Meningorrhagia
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Myasthenia gravis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Quadriparesis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sciatica
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 193 (0.52%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 3	7 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Retinal artery occlusion
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	4 / 193 (2.07%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 4	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	6 / 193 (3.11%)	9 / 374 (2.41%)
occurrences causally related to treatment / all	0 / 7	1 / 12
deaths causally related to treatment / all	0 / 1	0 / 2
Constipation
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 193 (0.00%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1
Dysphagia
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 193 (1.04%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	2 / 193 (1.04%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal haemorrhage
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	1 / 193 (0.52%)	4 / 374 (1.07%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Pancreatitis
subjects affected / exposed	0 / 193 (0.00%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	3 / 193 (1.55%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 5	2 / 3
deaths causally related to treatment / all	0 / 2	0 / 0
Hepatobiliary disorders
Acute hepatic failure
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Bile duct stenosis
subjects affected / exposed	2 / 193 (1.04%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder obstruction
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	9 / 193 (4.66%)	9 / 374 (2.41%)
occurrences causally related to treatment / all	5 / 14	1 / 13
deaths causally related to treatment / all	2 / 5	0 / 3
Hepatic function abnormal
subjects affected / exposed	3 / 193 (1.55%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	1 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic haemorrhage
subjects affected / exposed	2 / 193 (1.04%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 0
Hepatitis acute
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disease
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatorenal syndrome
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Hyperbilirubinaemia
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
subjects affected / exposed	2 / 193 (1.04%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	1 / 193 (0.52%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Portal vein thrombosis
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 193 (1.04%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis noninfective
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 193 (0.52%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 193 (1.04%)	6 / 374 (1.60%)
occurrences causally related to treatment / all	0 / 2	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Candida infection
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	2 / 193 (1.04%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Peritonitis
subjects affected / exposed	1 / 193 (0.52%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Pleural infection bacterial
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 193 (0.52%)	6 / 374 (1.60%)
occurrences causally related to treatment / all	0 / 1	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 1
Sepsis
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
Septic shock
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Streptococcal bacteraemia
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection bacterial
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 193 (1.55%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 3	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 193 (0.00%)	3 / 374 (0.80%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	2 / 193 (1.04%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 193 (0.52%)	0 / 374 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 193 (0.00%)	2 / 374 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 193 (0.00%)	1 / 374 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	Regorafenib 160mg (BAY73-4506)
Total subjects affected by non serious adverse events
subjects affected / exposed	162 / 193 (83.94%)	364 / 374 (97.33%)
Vascular disorders
Hypertension
subjects affected / exposed	12 / 193 (6.22%)	115 / 374 (30.75%)
occurrences all number	24	314
General disorders and administration site conditions
Asthenia
subjects affected / exposed	18 / 193 (9.33%)	54 / 374 (14.44%)
occurrences all number	30	92
Fatigue
subjects affected / exposed	47 / 193 (24.35%)	107 / 374 (28.61%)
occurrences all number	60	190
Malaise
subjects affected / exposed	5 / 193 (2.59%)	21 / 374 (5.61%)
occurrences all number	5	30
Oedema peripheral
subjects affected / exposed	26 / 193 (13.47%)	56 / 374 (14.97%)
occurrences all number	32	68
Pyrexia
subjects affected / exposed	13 / 193 (6.74%)	73 / 374 (19.52%)
occurrences all number	15	94
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	13 / 193 (6.74%)	41 / 374 (10.96%)
occurrences all number	15	44
Dysphonia
subjects affected / exposed	3 / 193 (1.55%)	67 / 374 (17.91%)
occurrences all number	3	83
Dyspnoea
subjects affected / exposed	13 / 193 (6.74%)	25 / 374 (6.68%)
occurrences all number	13	39
Pleural effusion
subjects affected / exposed	10 / 193 (5.18%)	11 / 374 (2.94%)
occurrences all number	12	12
Psychiatric disorders
Insomnia
subjects affected / exposed	8 / 193 (4.15%)	24 / 374 (6.42%)
occurrences all number	8	29
Investigations
Alanine aminotransferase increased
subjects affected / exposed	21 / 193 (10.88%)	54 / 374 (14.44%)
occurrences all number	33	98
Aspartate aminotransferase increased
subjects affected / exposed	38 / 193 (19.69%)	92 / 374 (24.60%)
occurrences all number	84	215
Blood alkaline phosphatase increased
subjects affected / exposed	8 / 193 (4.15%)	22 / 374 (5.88%)
occurrences all number	15	42
Blood bilirubin increased
subjects affected / exposed	29 / 193 (15.03%)	90 / 374 (24.06%)
occurrences all number	57	247
Gamma-glutamyltransferase increased
subjects affected / exposed	12 / 193 (6.22%)	22 / 374 (5.88%)
occurrences all number	20	61
Lipase increased
subjects affected / exposed	6 / 193 (3.11%)	27 / 374 (7.22%)
occurrences all number	10	60
Platelet count decreased
subjects affected / exposed	2 / 193 (1.04%)	34 / 374 (9.09%)
occurrences all number	8	89
Weight decreased
subjects affected / exposed	8 / 193 (4.15%)	50 / 374 (13.37%)
occurrences all number	10	113
Nervous system disorders
Headache
subjects affected / exposed	12 / 193 (6.22%)	24 / 374 (6.42%)
occurrences all number	12	32
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	21 / 193 (10.88%)	50 / 374 (13.37%)
occurrences all number	40	102
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	10 / 193 (5.18%)	18 / 374 (4.81%)
occurrences all number	13	21
Abdominal pain
subjects affected / exposed	28 / 193 (14.51%)	78 / 374 (20.86%)
occurrences all number	41	118
Abdominal pain upper
subjects affected / exposed	17 / 193 (8.81%)	47 / 374 (12.57%)
occurrences all number	21	70
Ascites
subjects affected / exposed	29 / 193 (15.03%)	53 / 374 (14.17%)
occurrences all number	54	80
Constipation
subjects affected / exposed	21 / 193 (10.88%)	64 / 374 (17.11%)
occurrences all number	24	76
Diarrhoea
subjects affected / exposed	29 / 193 (15.03%)	153 / 374 (40.91%)
occurrences all number	34	310
Dry mouth
subjects affected / exposed	9 / 193 (4.66%)	21 / 374 (5.61%)
occurrences all number	11	23
Nausea
subjects affected / exposed	26 / 193 (13.47%)	64 / 374 (17.11%)
occurrences all number	38	98
Stomatitis
subjects affected / exposed	4 / 193 (2.07%)	31 / 374 (8.29%)
occurrences all number	4	44
Vomiting
subjects affected / exposed	13 / 193 (6.74%)	47 / 374 (12.57%)
occurrences all number	17	69
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	5 / 193 (2.59%)	26 / 374 (6.95%)
occurrences all number	5	26
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	13 / 193 (6.74%)	192 / 374 (51.34%)
occurrences all number	17	495
Pruritus
subjects affected / exposed	14 / 193 (7.25%)	19 / 374 (5.08%)
occurrences all number	19	31
Rash
subjects affected / exposed	14 / 193 (7.25%)	20 / 374 (5.35%)
occurrences all number	15	27
Renal and urinary disorders
Proteinuria
subjects affected / exposed	2 / 193 (1.04%)	32 / 374 (8.56%)
occurrences all number	6	89
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 193 (0.00%)	24 / 374 (6.42%)
occurrences all number	0	27
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 193 (5.70%)	14 / 374 (3.74%)
occurrences all number	12	15
Back pain
subjects affected / exposed	15 / 193 (7.77%)	44 / 374 (11.76%)
occurrences all number	17	64
Muscle spasms
subjects affected / exposed	4 / 193 (2.07%)	38 / 374 (10.16%)
occurrences all number	5	46
Musculoskeletal pain
subjects affected / exposed	11 / 193 (5.70%)	17 / 374 (4.55%)
occurrences all number	19	19
Pain in extremity
subjects affected / exposed	5 / 193 (2.59%)	26 / 374 (6.95%)
occurrences all number	5	38
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	26 / 193 (13.47%)	115 / 374 (30.75%)
occurrences all number	33	165
Hypoalbuminaemia
subjects affected / exposed	14 / 193 (7.25%)	52 / 374 (13.90%)
occurrences all number	19	136
Hypokalaemia
subjects affected / exposed	5 / 193 (2.59%)	26 / 374 (6.95%)
occurrences all number	12	44
Hyponatraemia
subjects affected / exposed	6 / 193 (3.11%)	20 / 374 (5.35%)
occurrences all number	14	30
Hypophosphataemia
subjects affected / exposed	4 / 193 (2.07%)	36 / 374 (9.63%)
occurrences all number	8	88

More information

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Were there any global substantial amendments to the protocol? Yes

02 May 2013

-The term study drug treatment was substituted for regorafenib treatment in a sentence describing whether a subject could continue treatment if considered to be achieving a benefit from the treatment according to the investigator. - An inclusion criterion was modified according to the mRECIST and RECIST 1.1 in order to include subjects who demonstrated progression in previously treated lesions. - An exclusion criteria requiring the assessment of esophageal varices by endoscopy within 6 months and 12 months of the start of the study was modified to require that endoscopy be performed as per local standard of care. - In treatment assignment, text was modified stipulating that subjects should start treatment no later than 3 days after randomization. - Antiviral treatment for hepatitis C virus was included under “not permissible concomitant medication,” in order to not include these subjects due to the unfavorable risk benefit assessment. - The measurement of vital signs was included separately from the physical examinations due to differences in the timing of those assessments. - Vital signs examinations were included to be carried out on Day 15 of each cycle consistent with the design of the electronic case report form (eCRF). - The section on Tumor response Criteria (RECIST 1.1 and mRECIST) was divided into subsections for clarity. Slight modifications were made to the introductory text for the RECIST 1.1 and the mRECIST criteria section for clarity.

13 Dec 2013

- Rewording was done for clarity regarding the planning of the formal futility and formal efficacy analyses stating that there would be one of type of analysis and that data reviews were to be performed according to the data monitoring committee (DMC) charter. - The text excluding subjects from the study who permanently discontinued sorafenib treatment due to any cause more than 8 weeks before randomization was changes to 10 weeks. This change was to allow additional time to recruit subjects who were transferred from other sites. - Under the subsection “Emergency unblinding by the investigator”, text was added following ICH guidelines (ICH Topic E 6 [R1] Guideline for Good Clinical Practice) and in accordance with the Site User Manual for unblinding a subject's treatment assignment. - Text was added for clarification specifying exploratory pharmacokinetic (PK) analyses and an explanation of the timing of sample collection and the calculation of PK parameters. In addition a new subsection was added for completeness entitled “Validity of PK samples” describing the conditions under which PK samples were to be considered acceptable for analysis.

11 Nov 2014

- The number of subjects to be recruited into the study was increased from 530 to 560. - A change was introduced allowing the use of a separate non-genetic biomarker consent form in exceptional cases according to site-specific requirements. This change was introduced in order to cover the case where study sites required a separate non-genetic biomarker consent form. - Administrative changes

02 Nov 2015

-Changes regarding the planned interim analysis: The protocol requirement for performing a second interim efficacy analysis of the study results was removed. Due to the unexpectedly slow recruitment of subjects in China, the second interim analysis would have been conducted before full subject accrual into the study had been reached. It was considered important to optimize subject enrollment in China in light of a Health Authority guidance regarding enrollment. -Changes regarding monthly survival assessments: A requirement was added stating that monthly survival assessments were to continue until the approximate date of unblinding for primary completion of the study. If needed, survival assessments (for example via additional phone contacts) were to be allowed to continue past the primary analysis until the end of the study. This modification was included because overall survival data might be required after the primary completion of the study; additional analyses might be required to include the data from the data cut-off date (date at which approximately 370 events are achieved) up to or beyond the date of unblinding.

01 Dec 2015

-Information was added regarding interactions of regorafenib with neomycin, breast cancer resistant protein (BCRP), UGT1A1, UGT1A9, P-glycoprotein substrates, and bile saltsequestering agents. -The recommendation to proactively monitor subjects taking digoxin was removed. This information was added in light of new information that became available as documented in the latest version of the regorafenib IB. -References to Cytochrome P450 1A2 inhibitors and inducers were removed from the header and in the text since all of the substances were Cytochrome P450 3A4 (CYP 3A4) inhibitors. This change was introduced in order to clarify that only CYP 3A4 inhibitors and inducers were listed in appendix. The underlining of the substances listed in the table was removed since there was no need to differentiate between these substances since all are either inhibitors or inducers of CYP34A.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

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