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Clinical Trial Results:
A Randomized, Double-blind, Placebo-controlled Phase III Study of Regorafenib Plus BSC Versus Placebo Plus BSC in Patients With Metastatic Colorectal Cancer (CRC) Who Have Progressed After Standard Therapy

Summary
EudraCT number	2009-012787-14
Trial protocol	BE DE HU PT ES CZ IT FR NL
Global end of trial date	22 Jan 2014

Results information
Results version number	v2(current)
This version publication date	03 Sep 2016
First version publication date	12 Jun 2015
Other versions	v1
Version creation reason	New data added to full data set Correction of full data set Bayer sponsor contact information to be updated

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

BAY73-4506/14387

ISRCTN number

-

US NCT number

NCT01103323

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

Final

Date of interim/final analysis

22 Jan 2014

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

22 Jan 2014

Was the trial ended prematurely?

No

Main objective of the trial

To evaluate efficacy and safety of regorafenib in subjects with metastatic CRC who have progressed after standard therapies.

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. Each subject had ample opportunity to ask questions and was assured of the right to withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only subjects who voluntarily signed the informed consent form, were able to enter the study.

Background therapy

Best supportive care (BSC) includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Evidence for comparator

-

Actual start date of recruitment

30 Apr 2010

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 9

Country: Number of subjects enrolled

Spain: 83

Country: Number of subjects enrolled

Switzerland: 3

Country: Number of subjects enrolled

United States: 83

Country: Number of subjects enrolled

Czech Republic: 16

Country: Number of subjects enrolled

Hungary: 8

Country: Number of subjects enrolled

China: 4

Country: Number of subjects enrolled

Japan: 100

Country: Number of subjects enrolled

Australia: 21

Country: Number of subjects enrolled

Belgium: 87

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

France: 116

Country: Number of subjects enrolled

Germany: 64

Country: Number of subjects enrolled

Israel: 14

Country: Number of subjects enrolled

Italy: 143

Worldwide total number of subjects

760

EEA total number of subjects

526

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)

475

From 65 to 84 years

284

85 years and over

1

Subject disposition

Top of page

Recruitment details

This multinational study was conducted at 114 centers that enrolled subjects across 16 countries.

Screening details

Of the 1052 subjects who completed screening, 760 subjects were randomized and 292 subjects who signed the informed consent but were never randomized, were considered as screening failures.

Period 1 title

Without/Before Drug Switch

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Blinding implementation details

For subjects without drug switch (subjects on regorafenib or subjects on placebo without cross-over to regorafenib), the period 1 included both double-blinded and open label. Period 1 was not double-blinded only for these subjects. Only for 4 subjects on placebo who were crossed-over to regorafenib, period 1 was before cross-over (placebo period) and period 2 was after cross-over (regorafenib period).

Are arms mutually exclusive

Yes

Regorafenib (Stivarga, BAY73-4506) + BSC

Arm description

Subjects received regorafenib 160 milligram (mg) per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus BSC. BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Stivarga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle.

Placebo + BSC

Arm description

Subjects received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus BSC. BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle.

Number of subjects in period 1	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo + BSC
Started	505	255
Treated	500	253
Completed	429	237
Not completed	76	18
Physician decision	2	-
Consent withdrawn by subject	17	5
Adverse event	50	7
Protocol Violation	2	-
Switch to Regorafenib	-	4
Did not receive study treatment	5	2

Period 2 title

Switched From Placebo to Regorafenib

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Placebo - Regorafenib After Unblinding

Arm description

Subjects in the placebo + BSC group switched to treatment with regorafenib after unblinding. It is for regorafenib treatment period only.

Arm type

Placebo to Regorafenib

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

BAY73-4506

Other name

Stivarga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle.

Number of subjects in period 2 ^[1]	Placebo - Regorafenib After Unblinding
Started	4
Completed	3
Not completed	1
Adverse event	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Period 1 placebo arm was placebo and placebo-regorafenib with placebo period only. Period 2 was placebo-regorafenib with regorafenib period only. Not every subject in placebo arm was crossed-over to regorafenib treatment in Period 2. In reality, 4 subjects in the placebo group switched to regorafenib treatment after unblinding. Only few placebo subjects were on treatment when the positive study outcome became available and cross-over was possible.

Baseline characteristics

Top of page

Reporting group title

Regorafenib (Stivarga, BAY73-4506) + BSC

Reporting group description

Subjects received regorafenib 160 milligram (mg) per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus BSC. BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Reporting group title

Placebo + BSC

Reporting group description

Subjects received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus BSC. BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Reporting group values	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo + BSC	Total
Number of subjects	505	255	760
Age categorical
Units: Subjects
Age continuous
The age of the subject in years at enrolment in the study.
Units: years
arithmetic mean (full range (min-max))	60.7 (22 to 82)	60.1 (25 to 85)	-
Gender categorical
Units: Subjects
Male	311	153	464
Female	194	102	296
Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment
ECOG PS is a scale that measures how cancer affects the daily life of a subject on an ordinal scale from grade 0 (best) to grade 5 (worst). 0=Fully active without restriction; 1= Restricted in physically strenuous activity; 2= Ambulatory, capable of all selfcare; 3= Capable of limited selfcare; 4= Completely disabled; 5= Dead.
Units: Subjects
grade 0	265	146	411
grade 1	240	109	349
KRAS mutation
Kirsten rat sarcoma viral oncogene homolog (protein), member of the RAS family of GTPases (guanosine triphosphate hydrolases).
Units: Subjects
No	205	94	299
Yes	273	157	430
Unknown	27	4	31

End points

Top of page

Reporting group title

Regorafenib (Stivarga, BAY73-4506) + BSC

Reporting group description

Subjects received regorafenib 160 milligram (mg) per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus BSC. BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Reporting group title

Placebo + BSC

Reporting group description

Subjects received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus BSC. BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Reporting group title

Placebo - Regorafenib After Unblinding

Reporting group description

Subjects in the placebo + BSC group switched to treatment with regorafenib after unblinding. It is for regorafenib treatment period only.

Primary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival (OS) was defined as the time (days) from randomization to death due to any cause. Subjects alive at the time of analysis were censored at the last date known to be alive. If a subject was lost to follow-up and there was no contact after randomization, this subject was censored at Day 1. Efficacy data were of double-blind period and up to 21 July 2011.

End point type

Primary

End point timeframe

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

End point values	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo + BSC
Number of subjects analysed	505 ^[1]	255 ^[2]
Units: Days
median (confidence interval 95%)	196 (178 to 222)	151 (134 to 177)

Notes
[1] - Intention-to-treat (ITT) population included all randomized subjects.
[2] - ITT population included all randomized subjects.

Statistical Analysis for Overall Survival

Statistical analysis description

Sample size based on primary efficacy endpoint of OS. The study was designed to have 90% power to detect 33.3% increase in median OS (i.e. hazard ratio of 0.75, regorafenib / placebo). Assuming 1-sided overall alpha of 0.025, randomization ratio of 2:1 for regorafenib and placebo, and 2 formal interim analyses of OS using an O’Brien-Fleming-type error spending function, a total of 582 death events were required for primary completion. Results based on 2nd planned formal IA with 432 total events.

Comparison groups

Regorafenib (Stivarga, BAY73-4506) + BSC v Placebo + BSC

Number of subjects included in analysis

760

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.005178 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.774

Confidence interval

level

95%

sides

2-sided

lower limit

0.636

upper limit

0.942

Notes
[3] - Two treatment groups compared using a stratified log-rank test, randomization was stratified by prior treatment with vascular endothelial growth factor-targeting drugs, time from diagnosis of metastatic disease, and geographical region. Hazard ratio (regorafenib / placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.
[4] - According to protocol specified O'Brien-Fleming type alpha spending function and 432 death events at 2nd IA, the pre-specified alpha (false positive rate) for this analysis was 0.009279 (1-sided).

Secondary: Progression-free Survival (Based on Investigator’s Assessment)

Top of page

End point title

Progression-free Survival (Based on Investigator’s Assessment)

End point description

Progression-free survival was defined as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented. Efficacy data were of double-blind period and up to 21 July 2011.

End point type

Secondary

End point timeframe

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

End point values	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo + BSC
Number of subjects analysed	505 ^[5]	255 ^[6]
Units: Days
median (confidence interval 95%)	59 (57 to 65)	52 (51 to 53)

Notes
[5] - ITT population included all randomized subjects.
[6] - ITT population included all randomized subjects.

Statistical Analysis for Progression-free Survival

Statistical analysis description

Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (regorafenib / placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.

Comparison groups

Regorafenib (Stivarga, BAY73-4506) + BSC v Placebo + BSC

Number of subjects included in analysis

760

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001 ^[7]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.494

Confidence interval

level

95%

sides

2-sided

lower limit

0.419

upper limit

0.582

Notes
[7] - Comparison based on pre-specified alpha level of 0.025 (1-sided).

Secondary: Objective Tumor Response

Top of page

End point title

Objective Tumor Response

End point description

The objective tumor response was defined as the percentage of subjects with complete response (CR, tumor disappears) or partial response (PR, sum of lesion sizes decreased at least 30% from baseline) as best overall response. A best overall response was defined for all subjects, using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. Subjects whose best overall response was not CR or PR, and any subjects with no post-baseline assessments were considered non-responders for the analysis. Efficacy data were of double-blind period and up to 21 July 2011.

End point type

Secondary

End point timeframe

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

End point values	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo + BSC
Number of subjects analysed	505 ^[8]	255 ^[9]
Units: Percentage of subjects
number (not applicable)	1	0.4

Notes
[8] - ITT population included all randomized subjects.
[9] - ITT population included all randomized subjects.

Statistical Analysis for Objective Tumor Response

Statistical analysis description

Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization. The below parameter estimate 'difference' = Placebo - Regorafenib 160 mg.

Comparison groups

Regorafenib (Stivarga, BAY73-4506) + BSC v Placebo + BSC

Number of subjects included in analysis

760

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.188432 ^[10]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.74

upper limit

0.53

Notes
[10] - Comparison based on pre-specified alpha level of 0.025 (1-sided).

Secondary: Disease Control

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End point title

Disease Control

End point description

Disease control was defined as the percentage of subjects whose best response was not PD [sum of lesion sizes increased at least 20% from smallest sum on study or new lesions] (that was, CR [tumor disappeared], PR [sum of lesion sizes decreased at least 30% from baseline] or SD (stable disease)). SD included if at least 6 weeks after randomization. Efficacy data were of double-blind period and up to 21 July 2011.

End point type

Secondary

End point timeframe

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

End point values	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo + BSC
Number of subjects analysed	505 ^[11]	255 ^[12]
Units: Percentage of subjects
number (not applicable)	41	14.9

Notes
[11] - ITT population included all randomized subjects.
[12] - ITT population included all randomized subjects.

Statistical Analysis for Disease Control

Statistical analysis description

Two treatment groups compared using CMH test adjusting for same stratification factors as at randomization. The below parameter estimate 'difference' = Placebo - Regorafenib 160 mg.

Comparison groups

Regorafenib (Stivarga, BAY73-4506) + BSC v Placebo + BSC

Number of subjects included in analysis

760

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.000001 ^[13]

Method

Cochran-Mantel-Haenszel

Parameter type

Difference

Point estimate

-25.94

Confidence interval

level

95%

sides

2-sided

lower limit

-32.06

upper limit

-19.82

Notes
[13] - Comparison based on pre-specified alpha level of 0.025 (1-sided).

Secondary: Tumor Response

Top of page

End point title

Tumor Response

End point description

A tumor response (best overall response) was defined for all subjects, using the RECIST criteria, version 1.1. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased at least 30% from baseline), stable disease (SD, steady state of disease which was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD], no unequivocal progression of existing non target lesions and no appearance of new lesions), PD (sum of lesion sizes increased at least 20% from smallest sum on study or new lesions), non CR/non PD. Clinical PD considered when radiographic imaging not possible. Efficacy data were of double-blind period and up to 21 July 2011.

End point type

Secondary

End point timeframe

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

End point values	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo + BSC
Number of subjects analysed	505 ^[14]	255 ^[15]
Units: Percentage of subjects
number (not applicable)
Complete Response (CR)	0	0
Partial Response (PR)	1	0.4
Stable Disease (SD)	42.8	14.5
Progressive Disease (PD)	49.5	80
Non CR/Non PD	0.8	0.4
Not applicable	0.2	0
Not assessed	5.7	4.7

Notes
[14] - ITT population included all randomized subjects.
[15] - ITT population included all randomized subjects.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events were collected up to 30 days after end of study treatment (per protocol) over a period of approximately 3.7 years (19 May 2010 [first subject randomized] to 22 January 2014 [last subject last visit])

Adverse event reporting additional description

All subjects who were randomized and received at least 1 dose of study drug were included in the safety analyses.

Assessment type

Non-systematic

Dictionary name

NCI-CTCAE

Dictionary version

3.0

Reporting group title

Regorafenib (Stivarga, BAY73-4506) + BSC

Reporting group description

Subjects received regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus BSC. BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.

Reporting group title

Placebo - Regorafenib after unblinding

Reporting group description

Participants in the placebo + BSC group crossed over to treatment with Regorafenib after unblinding. It is for Regorafenib treatment period only

Reporting group title

Placebo + BSC

Reporting group description

Subjects received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus BSC. BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy. This group included subjects on placebo without cross-over to regorafenib and subjects on placebo who were crossed-over to regorafenib with placebo period only.

Serious adverse events	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo - Regorafenib after unblinding	Placebo + BSC
Total subjects affected by serious adverse events
subjects affected / exposed	232 / 500 (46.40%)	2 / 4 (50.00%)	103 / 253 (40.71%)
number of deaths (all causes)	476	2	235
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy (possibly related to cancer treatment)
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hematoma
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hemorrhage pulmonary, Bronchus
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Hemorrhage pulmonary, Mediastinum
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GI, Abdomen NOS
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hemorrhage, GI, Anus
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Hemorrhage, GI, Lower GI NOS
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GI, Rectum
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GI, Stoma
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GI, Upper GI NOS
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GI, Varices (esophageal)
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GI, Varices (rectal)
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemorrhage, GU, Vagina
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Thrombosis/Embolism (vascular access)
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombosis/Thrombus/Embolism
subjects affected / exposed	6 / 500 (1.20%)	0 / 4 (0.00%)	3 / 253 (1.19%)
occurrences causally related to treatment / all	1 / 6	0 / 0	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Vascular - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
General disorders and administration site conditions
Constitutional symptoms - Other
subjects affected / exposed	34 / 500 (6.80%)	0 / 4 (0.00%)	23 / 253 (9.09%)
occurrences causally related to treatment / all	1 / 49	0 / 0	0 / 39
deaths causally related to treatment / all	0 / 23	0 / 0	0 / 18
Death not associated with CTCAE term, Disease progression NOS
subjects affected / exposed	16 / 500 (3.20%)	1 / 4 (25.00%)	6 / 253 (2.37%)
occurrences causally related to treatment / all	0 / 17	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 16	0 / 1	0 / 6
Death not associated with CTCAE term, Multi-Organ Failure
subjects affected / exposed	4 / 500 (0.80%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 4	0 / 0	0 / 1
Death not associated with CTCAE term, Sudden death
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 2
Fatigue
subjects affected / exposed	5 / 500 (1.00%)	0 / 4 (0.00%)	5 / 253 (1.98%)
occurrences causally related to treatment / all	3 / 6	0 / 0	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fever
subjects affected / exposed	17 / 500 (3.40%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	8 / 21	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pain, Abdomen NOS
subjects affected / exposed	13 / 500 (2.60%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	0 / 21	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Back
subjects affected / exposed	4 / 500 (0.80%)	0 / 4 (0.00%)	4 / 253 (1.58%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Buttock
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Cardiac/Heart
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Chest wall
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Chest/Thorax NOS
subjects affected / exposed	4 / 500 (0.80%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Extremity - limb
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Head/Headache
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Joint
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Liver
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Neuralgia/Peripheral nerve
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Pain NOS
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain, Tumor pain
subjects affected / exposed	3 / 500 (0.60%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syndromes - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tumor flare
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Weight loss
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergic reaction
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ARDS
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Cough
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnea (Shortness of breath)
subjects affected / exposed	12 / 500 (2.40%)	0 / 4 (0.00%)	4 / 253 (1.58%)
occurrences causally related to treatment / all	1 / 18	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 6	0 / 0	0 / 2
Pleural effusion
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	4 / 253 (1.58%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Pulmonary - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrhythmia - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac ischemia/infarction
subjects affected / exposed	6 / 500 (1.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	2 / 6	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Hypertension
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Left ventricular systolic dysfunction
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Supraventricular arrhythmia, Atrial fibrillation
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
cTnT
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
CNS ischemia
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Cognitive disturbance
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusion
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Mood Alteration, Anxiety
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neurology - Other
subjects affected / exposed	3 / 500 (0.60%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Neuropathy: Cranial, CN III Pupil, upper eyelid, extra ocular mov
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuropathy: motor
subjects affected / exposed	3 / 500 (0.60%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Speech impairment
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope (Fainting)
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
DIC
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Edema: Limb
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Edema: Trunk/Genital
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Edema: Viscera
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hemoglobin
subjects affected / exposed	4 / 500 (0.80%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	3 / 8	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
INR
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutrophils
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Platelets
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombotic microangiopathy
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ocular - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anorexia
subjects affected / exposed	5 / 500 (1.00%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	7 / 8	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 500 (0.20%)	1 / 4 (25.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	3 / 500 (0.60%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhea
subjects affected / exposed	8 / 500 (1.60%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	8 / 9	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Distension
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fistula, GI, Abdomen NOS
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fistula, GI, Anus
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fistula, GI, Small bowel NOS
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
GI - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Hemorrhoids
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	3 / 253 (1.19%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Mucositis (functional/symptomatic), Small bowel
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Necrosis, GI, Peritoneal cavity
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstruction, GI, Colon
subjects affected / exposed	9 / 500 (1.80%)	0 / 4 (0.00%)	6 / 253 (2.37%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 2
Obstruction, GI, Ileum
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstruction, GI, Small bowel NOS
subjects affected / exposed	4 / 500 (0.80%)	0 / 4 (0.00%)	7 / 253 (2.77%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2
Obstruction, GI, Stomach
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perforation, GI, Colon
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stricture, GI, Biliary tree
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ulcer, GI, Duodenum
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 500 (0.60%)	1 / 4 (25.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary - Other
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver dysfunction
subjects affected / exposed	17 / 500 (3.40%)	0 / 4 (0.00%)	5 / 253 (1.98%)
occurrences causally related to treatment / all	6 / 28	0 / 0	0 / 11
deaths causally related to treatment / all	2 / 11	0 / 0	0 / 5
Skin and subcutaneous tissue disorders
Dermatology - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Erythema multiforme
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hand-foot skin reaction
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash/Desquamation
subjects affected / exposed	4 / 500 (0.80%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	7 / 7	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound complication, non-infectious
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Cystitis
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fistula, GU, Bladder
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstruction, GU, Ureter
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal - Other
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	5 / 500 (1.00%)	0 / 4 (0.00%)	3 / 253 (1.19%)
occurrences causally related to treatment / all	2 / 6	0 / 0	2 / 5
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Urinary retention
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Fracture
subjects affected / exposed	4 / 500 (0.80%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gait/Walking
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle weakness left-sided
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle weakness, Extremity - lower
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle weakness, Whole body/generalized
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Myositis
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection (documented clinically), Abdomen NOS
subjects affected / exposed	4 / 500 (0.80%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Anal/perianal
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Appendix
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Bladder (urinary)
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Blood
subjects affected / exposed	3 / 500 (0.60%)	0 / 4 (0.00%)	2 / 253 (0.79%)
occurrences causally related to treatment / all	3 / 5	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Bronchus
subjects affected / exposed	3 / 500 (0.60%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Catheter-related
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Kidney
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Lung (Pneumonia)
subjects affected / exposed	9 / 500 (1.80%)	0 / 4 (0.00%)	3 / 253 (1.19%)
occurrences causally related to treatment / all	0 / 11	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 2
Infection (documented clinically), Skin (Cellulitis)
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Soft tissue NOS
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Urinary tract NOS
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection (documented clinically), Wound
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection - Other
subjects affected / exposed	5 / 500 (1.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	4 / 6	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Infection with normal ANC, Blood
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with normal ANC, Catheter-related
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with normal ANC, Colon
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with normal ANC, Gallbladder (Cholecystitis)
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with normal ANC, Kidney
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with normal ANC, Lung (Pneumonia)
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with normal ANC, Soft tissue NOS
subjects affected / exposed	2 / 500 (0.40%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with unknown ANC, Kidney
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection with unknown ANC, Lung (Pneumonia)
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
AST
subjects affected / exposed	0 / 500 (0.00%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bilirubin (Hyperbilirubinemia)
subjects affected / exposed	8 / 500 (1.60%)	0 / 4 (0.00%)	3 / 253 (1.19%)
occurrences causally related to treatment / all	2 / 11	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoalbuminemia
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcemia
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatremia
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic/Lab - Other
subjects affected / exposed	1 / 500 (0.20%)	0 / 4 (0.00%)	0 / 253 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Regorafenib (Stivarga, BAY73-4506) + BSC	Placebo - Regorafenib after unblinding	Placebo + BSC
Total subjects affected by non serious adverse events
subjects affected / exposed	489 / 500 (97.80%)	4 / 4 (100.00%)	229 / 253 (90.51%)
Vascular disorders
Hemorrhage pulmonary, Nose
subjects affected / exposed	45 / 500 (9.00%)	0 / 4 (0.00%)	6 / 253 (2.37%)
occurrences all number	55	0	6
Cardiac disorders
Hypertension
subjects affected / exposed	155 / 500 (31.00%)	1 / 4 (25.00%)	21 / 253 (8.30%)
occurrences all number	213	1	23
Nervous system disorders
Neuropathy: sensory
subjects affected / exposed	51 / 500 (10.20%)	0 / 4 (0.00%)	25 / 253 (9.88%)
occurrences all number	68	0	27
Dizziness
subjects affected / exposed	28 / 500 (5.60%)	0 / 4 (0.00%)	13 / 253 (5.14%)
occurrences all number	31	0	13
Blood and lymphatic system disorders
Edema: Limb
subjects affected / exposed	49 / 500 (9.80%)	0 / 4 (0.00%)	16 / 253 (6.32%)
occurrences all number	57	0	19
Hemoglobin
subjects affected / exposed	76 / 500 (15.20%)	0 / 4 (0.00%)	29 / 253 (11.46%)
occurrences all number	142	0	46
Platelets
subjects affected / exposed	79 / 500 (15.80%)	1 / 4 (25.00%)	6 / 253 (2.37%)
occurrences all number	136	2	9
General disorders and administration site conditions
Constitutional symptoms - Other
subjects affected / exposed	30 / 500 (6.00%)	0 / 4 (0.00%)	17 / 253 (6.72%)
occurrences all number	33	0	19
Fatigue
subjects affected / exposed	318 / 500 (63.60%)	0 / 4 (0.00%)	115 / 253 (45.45%)
occurrences all number	612	0	168
Fever
subjects affected / exposed	136 / 500 (27.20%)	2 / 4 (50.00%)	40 / 253 (15.81%)
occurrences all number	189	3	48
Flu-like syndrome
subjects affected / exposed	27 / 500 (5.40%)	1 / 4 (25.00%)	6 / 253 (2.37%)
occurrences all number	30	1	8
Insomnia
subjects affected / exposed	39 / 500 (7.80%)	0 / 4 (0.00%)	14 / 253 (5.53%)
occurrences all number	43	0	15
Pain, Abdomen NOS
subjects affected / exposed	121 / 500 (24.20%)	0 / 4 (0.00%)	47 / 253 (18.58%)
occurrences all number	239	0	53
Pain, Back
subjects affected / exposed	79 / 500 (15.80%)	0 / 4 (0.00%)	25 / 253 (9.88%)
occurrences all number	114	0	27
Pain, Buttock
subjects affected / exposed	4 / 500 (0.80%)	1 / 4 (25.00%)	0 / 253 (0.00%)
occurrences all number	5	1	0
Pain, Chest/Thorax NOS
subjects affected / exposed	26 / 500 (5.20%)	0 / 4 (0.00%)	12 / 253 (4.74%)
occurrences all number	29	0	14
Pain, Extremity - limb
subjects affected / exposed	51 / 500 (10.20%)	0 / 4 (0.00%)	14 / 253 (5.53%)
occurrences all number	83	0	19
Pain, Head/Headache
subjects affected / exposed	50 / 500 (10.00%)	0 / 4 (0.00%)	18 / 253 (7.11%)
occurrences all number	65	0	23
Pain, Joint
subjects affected / exposed	32 / 500 (6.40%)	0 / 4 (0.00%)	13 / 253 (5.14%)
occurrences all number	34	0	14
Pain, Muscle
subjects affected / exposed	50 / 500 (10.00%)	0 / 4 (0.00%)	14 / 253 (5.53%)
occurrences all number	64	0	16
Pain, Throat/Pharynx/Larynx
subjects affected / exposed	9 / 500 (1.80%)	1 / 4 (25.00%)	1 / 253 (0.40%)
occurrences all number	12	1	1
Weight loss
subjects affected / exposed	167 / 500 (33.40%)	2 / 4 (50.00%)	30 / 253 (11.86%)
occurrences all number	240	7	34
Eye disorders
Ocular - Other
subjects affected / exposed	5 / 500 (1.00%)	1 / 4 (25.00%)	0 / 253 (0.00%)
occurrences all number	5	1	0
Gastrointestinal disorders
Anorexia
subjects affected / exposed	239 / 500 (47.80%)	0 / 4 (0.00%)	73 / 253 (28.85%)
occurrences all number	388	0	96
Ascites
subjects affected / exposed	23 / 500 (4.60%)	1 / 4 (25.00%)	6 / 253 (2.37%)
occurrences all number	24	1	8
Constipation
subjects affected / exposed	119 / 500 (23.80%)	0 / 4 (0.00%)	48 / 253 (18.97%)
occurrences all number	147	0	58
Diarrhea
subjects affected / exposed	218 / 500 (43.60%)	2 / 4 (50.00%)	44 / 253 (17.39%)
occurrences all number	514	2	57
Fistula, GI, Colon/Cecum/Appendix
subjects affected / exposed	0 / 500 (0.00%)	1 / 4 (25.00%)	0 / 253 (0.00%)
occurrences all number	0	1	0
Mucositis (functional/symptomatic), Oral cavity
subjects affected / exposed	145 / 500 (29.00%)	0 / 4 (0.00%)	12 / 253 (4.74%)
occurrences all number	267	0	12
Nausea
subjects affected / exposed	115 / 500 (23.00%)	1 / 4 (25.00%)	55 / 253 (21.74%)
occurrences all number	162	1	67
Taste alteration
subjects affected / exposed	39 / 500 (7.80%)	0 / 4 (0.00%)	6 / 253 (2.37%)
occurrences all number	44	0	6
Vomiting
subjects affected / exposed	85 / 500 (17.00%)	1 / 4 (25.00%)	41 / 253 (16.21%)
occurrences all number	144	3	50
Hepatobiliary disorders
Hepatobiliary - Other
subjects affected / exposed	8 / 500 (1.60%)	1 / 4 (25.00%)	4 / 253 (1.58%)
occurrences all number	9	3	4
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	56 / 500 (11.20%)	1 / 4 (25.00%)	28 / 253 (11.07%)
occurrences all number	77	1	32
Dyspnea (Shortness of breath)
subjects affected / exposed	89 / 500 (17.80%)	0 / 4 (0.00%)	34 / 253 (13.44%)
occurrences all number	110	0	46
Voice changes
subjects affected / exposed	160 / 500 (32.00%)	1 / 4 (25.00%)	16 / 253 (6.32%)
occurrences all number	211	1	17
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	39 / 500 (7.80%)	0 / 4 (0.00%)	4 / 253 (1.58%)
occurrences all number	43	0	4
Cheilitis
subjects affected / exposed	4 / 500 (0.80%)	1 / 4 (25.00%)	0 / 253 (0.00%)
occurrences all number	4	3	0
Dermatology - Other
subjects affected / exposed	30 / 500 (6.00%)	0 / 4 (0.00%)	7 / 253 (2.77%)
occurrences all number	45	0	10
Dry skin
subjects affected / exposed	50 / 500 (10.00%)	0 / 4 (0.00%)	10 / 253 (3.95%)
occurrences all number	59	0	11
Hand-foot skin reaction
subjects affected / exposed	235 / 500 (47.00%)	1 / 4 (25.00%)	19 / 253 (7.51%)
occurrences all number	720	3	21
Pruritus
subjects affected / exposed	29 / 500 (5.80%)	0 / 4 (0.00%)	11 / 253 (4.35%)
occurrences all number	39	0	11
Rash/Desquamation
subjects affected / exposed	145 / 500 (29.00%)	1 / 4 (25.00%)	13 / 253 (5.14%)
occurrences all number	211	2	17
Endocrine disorders
Hypothyroidism
subjects affected / exposed	27 / 500 (5.40%)	1 / 4 (25.00%)	1 / 253 (0.40%)
occurrences all number	29	1	1
Metabolism and nutrition disorders
ALT
subjects affected / exposed	28 / 500 (5.60%)	0 / 4 (0.00%)	7 / 253 (2.77%)
occurrences all number	53	0	8
AST
subjects affected / exposed	37 / 500 (7.40%)	0 / 4 (0.00%)	12 / 253 (4.74%)
occurrences all number	72	0	13
Alkaline phosphatase
subjects affected / exposed	35 / 500 (7.00%)	0 / 4 (0.00%)	8 / 253 (3.16%)
occurrences all number	49	0	12
Bilirubin (Hyperbilirubinemia)
subjects affected / exposed	97 / 500 (19.40%)	1 / 4 (25.00%)	22 / 253 (8.70%)
occurrences all number	160	3	37
Creatinine
subjects affected / exposed	15 / 500 (3.00%)	1 / 4 (25.00%)	7 / 253 (2.77%)
occurrences all number	19	2	8
GFR
subjects affected / exposed	4 / 500 (0.80%)	1 / 4 (25.00%)	1 / 253 (0.40%)
occurrences all number	9	1	2
Hypocalcemia
subjects affected / exposed	34 / 500 (6.80%)	0 / 4 (0.00%)	1 / 253 (0.40%)
occurrences all number	57	0	1
Hyperuricemia
subjects affected / exposed	12 / 500 (2.40%)	1 / 4 (25.00%)	1 / 253 (0.40%)
occurrences all number	13	1	1
Hypokalemia
subjects affected / exposed	50 / 500 (10.00%)	0 / 4 (0.00%)	6 / 253 (2.37%)
occurrences all number	84	0	7
Hyponatremia
subjects affected / exposed	32 / 500 (6.40%)	0 / 4 (0.00%)	6 / 253 (2.37%)
occurrences all number	43	0	10
Hypophosphatemia
subjects affected / exposed	32 / 500 (6.40%)	1 / 4 (25.00%)	2 / 253 (0.79%)
occurrences all number	62	2	3
Lipase
subjects affected / exposed	32 / 500 (6.40%)	0 / 4 (0.00%)	3 / 253 (1.19%)
occurrences all number	74	0	4
Metabolic/Lab - Other
subjects affected / exposed	42 / 500 (8.40%)	0 / 4 (0.00%)	8 / 253 (3.16%)
occurrences all number	69	0	15
Proteinuria
subjects affected / exposed	40 / 500 (8.00%)	0 / 4 (0.00%)	6 / 253 (2.37%)
occurrences all number	109	0	11

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

28 Sep 2010

1. Clarifications were provided for: a. Inclusion criteria b. Exclusion criteria c. Re-screening of screen failures d. Guidance on missed or vomited tablets e. Dose modification/delay f. Permitted concomitant medications g. Non-permissible concomitant medications and procedures i. Pharmacokinetic sampling h. Study procedures/assessments 2. Synopsis was updated with changes to the inclusion/exclusion criteria 3. Updates to adverse events of special safety interest 4. Methods of measurement in RECIST (appendix) was updated 5. Examples of substrates of human liver microsomal P450 enzymes and examples of excluded traditional Chinese medicine were added 6. Approved standard therapies in anticipated participating countries was updated with new country information

03 Aug 2011

1. To exclude liver function test abnormalities 2. Dose modifications for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin increases related to study treatment 3. Guidance regarding subjects with diarrhea, mucositis, anorexia or other events predisposing to fluid loss or inadequate fluid intake was added 4. Text was added to Treatment compliance section regarding use of subject drug diary 5. Schedule of Assessments was updated to include weekly checks of ALT, AST and bilirubin during the first two cycles of treatment 6. Adverse events of special safety interest was updated to add clarification regarding reporting of the adverse events of special interest

01 Nov 2011

'Treatments to be administered' section was updated to allow subjects on placebo treatment to receive regorafenib through open label treatment after positive outcome of the study.

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.

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

http://www.ncbi.nlm.nih.gov/pubmed/22421192
http://www.ncbi.nlm.nih.gov/pubmed/23177514

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