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Clinical Trial Results:
A Randomized, Double-Blind Study of Ruxolitinib or Placebo in Combination With Regorafenib in Subjects With Relapsed or Refractory Metastatic Colorectal Cancer

Summary
EudraCT number	2013-004714-18
Trial protocol	IT GB AT ES
Global end of trial date	18 Nov 2016

Results information
Results version number	v1(current)
This version publication date	08 Dec 2017
First version publication date	08 Dec 2017
Other versions

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

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Trial information

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Sponsor protocol code

INCB 18424-267

ISRCTN number

US NCT number

NCT02119676

WHO universal trial number (UTN)

Sponsor organisation name

Incyte Corporation

Sponsor organisation address

1801 Augustine Cut-Off, Wilmington, DE, United States, 19803

Public contact

Incyte Corporation Call Centre, Incyte Corporation, +44 (0)330 100 3677, globalmedinfo@incyte.com

Scientific contact

Incyte Corporation Call Centre, Incyte Corporation, +44 (0)330 100 3677, globalmedinfo@incyte.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

29 Mar 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Nov 2016

Was the trial ended prematurely?

Yes

Main objective of the trial

The purpose of this study was to determine if ruxolitinib, in combination with regorafenib, is safe and effective in the treatment of metastatic colorectal cancer. The study consisted of an open-label, Part 1 safety run-in (consisting of 1 to 3 cohorts of 9 subjects each), to confirm the safety of the regorafenib/ruxolitinib combination in subjects with relapsed or refractory metastatic colorectal cancer (CRC). If determined to be tolerable, Part 2 was to proceed as a randomized, double-blind study evaluating ruxolitinib or placebo in combination with regorafenib in subjects with relapsed or refractory metastatic CRC previously treated with fluoropyrimidine, oxaliplatin, and/or irinotecan based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy and if Kirsten rat sarcoma (KRAS) wild type an anti-epidermal growth factor receptor (EGFR) therapy.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 302

Country: Number of subjects enrolled

Israel: 16

Country: Number of subjects enrolled

Korea, Republic of: 13

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

United Kingdom: 16

Country: Number of subjects enrolled

France: 34

Country: Number of subjects enrolled

Germany: 4

Worldwide total number of subjects

396

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

261

From 65 to 84 years

135

85 years and over

Subject disposition

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Recruitment details

In Substudy 1, the first subject was enrolled on 29 OCT 2014, and the last subject was enrolled on 23 JUL 2015. In Substudy 2, the first subject was enrolled on 05 NOV 2014, and the last subject was enrolled on 02 OCT 2015.

Screening details

Substudy 1; 4 participants were assigned a randomization number but were not given study drug because of clinical deterioration or withdrawal of consent. Substudy 2; 9 participants were assigned a randomization number, but weren't given study drug due to clinical deterioration, withdrawal of consent or not meeting all of the eligibility criteria.

Period 1 title

Overall Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Substudy 1: Ruxolitinib + Regorafenib

Arm description

Subjects with modified Glasgow Prognostic Score (mGPS) of 1 or 2 who were randomly assigned to receive ruxolitinib 15 mg twice daily (BID) continuous with regorafenib 160 mg once daily (QD) for the first 21 days of each 28-day cycle.

Arm type

Experimental

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

Other name

Jakafi ®, Jakavi ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib 15 mg (5 mg tablets) twice daily (BID).

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

Other name

Stivarga ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Regorafenib 160mg (40 mg tablets) once daily for the first 21 days of each 28-day cycle. (NOTE: Dose interruptions and modifications for regorafenib are expected when toxicities occur in which dose interruptions or modifications are appropriate.)

Substudy 1: Placebo + Regorafenib

Arm description

Subjects with modified Glasgow Prognostic Score (mGPS) of 1 or 2 who were randomly assigned to receive Placebo twice daily (BID) continuous with regorafenib 160 mg once daily (QD) for the first 21 days of each 28-day cycle.

Arm type

Active comparator

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

Other name

Stivarga ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Regorafenib 160mg once daily for the first 21 days of each 28-day cycle. (NOTE: Dose interruptions and modifications for regorafenib are expected when toxicities occur in which dose interruptions or modifications are appropriate.)

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

5 mg matching placebo tablets to be administered by mouth

Substudy 2: Ruxolitinib + Regorafenib

Arm description

Ruxolitinib 15 mg BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle.

Arm type

Experimental

Investigational medicinal product name

Ruxolitinib

Investigational medicinal product code

Other name

Jakafi ®, Jakavi ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ruxolitinib 20 mg twice a day (BID) (Part 1) (NOTE: The starting dose for the randomized portion of study (Part 2) was 15 mg BID based on results from Part 1.)

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

Other name

Stivarga ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Substudy 2: Placebo + Regorafenib

Arm description

Placebo BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle.

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

5 mg matching placebo tablets to be administered by mouth

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

Other name

Stivarga ®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Substudy 1: Ruxolitinib + Regorafenib	Substudy 1: Placebo + Regorafenib	Substudy 2: Ruxolitinib + Regorafenib	Substudy 2: Placebo + Regorafenib
Started	87	88	110	111
Treated Patients	85	86	106	106
Completed	4	2	13	10
Not completed	83	86	97	101
Physician decision	4	2	3	2
Disease progression	53	55	68	73
Adverse event, non-fatal	9	17	10	10
Patient decision, inc. consent withdrawn	4	5	5	6
Death	9	3	2	1
Other, unspecified	2	1	3	4
Did not receive study med	2	2	4	5
Lost to follow-up	-	-	1	-
Noncompliance	-	1	-	-
Protocol deviation	-	-	1	-

Baseline characteristics

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Reporting group title

Overall Period

Reporting group description

Reporting group values	Overall Period	Total
Number of subjects	396	396
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	261	261
From 65-84 years	135	135
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (full range (min-max))	59.6 (19 to 84)	-
Gender categorical
Units: Subjects
Female	168	168
Male	228	228
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0
Asian	21	21
Native Hawaiian or Other Pacific Islander	1	1
Black or African American	27	27
White	304	304
Other	35	35
Missing	8	8

End points

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Reporting group title

Substudy 1: Ruxolitinib + Regorafenib

Reporting group description

Reporting group title

Substudy 1: Placebo + Regorafenib

Reporting group description

Reporting group title

Substudy 2: Ruxolitinib + Regorafenib

Reporting group description

Ruxolitinib 15 mg BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle.

Reporting group title

Substudy 2: Placebo + Regorafenib

Reporting group description

Placebo BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle.

Primary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall survival is defined as the time from randomization to death due to any cause. Participants without death observed at the time of the analysis will be censored at last date known to be alive. The median overall survival time was estimated using the Kaplan-Meier method. Overall survival was compared between treatment groups using log-rank test.

End point type

Primary

End point timeframe

Baseline until death due to any cause; data cut-off 27 Jan 2016 for Substudy 1 and 11 Feb 2016 for Substudy 2.

End point values	Substudy 1: Ruxolitinib + Regorafenib	Substudy 1: Placebo + Regorafenib	Substudy 2: Ruxolitinib + Regorafenib	Substudy 2: Placebo + Regorafenib
Number of subjects analysed	87 ^[1]	88 ^[2]	110 ^[3]	111 ^[4]
Units: months
median (confidence interval 95%)	4.6 (3.5 to 5.4)	5.3 (4.3 to 6.0)	11.4 (9.0 to 13.2)	10.9 (7.2 to 999.99)

Notes
[1] - Intent-to-treat (ITT) population-all subjects randomized in Substudy 1 & Substudy 2 of the study.
[2] - ITT population-all subjects randomized in Substudy 1 & Substudy 2 of the study.
[3] - ITT population-all subjects randomized in Substudy 1 & Substudy 2 of the study.
[4] - ITT population 999.99= Not estimable due to insufficient number of participants with events.

Overall Survival Substudy 1:

Comparison groups

Substudy 1: Ruxolitinib + Regorafenib v Substudy 1: Placebo + Regorafenib

Number of subjects included in analysis

175

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.588 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

1.49

Notes
[5] - Log-rank test stratified by modified Glasgow Prognostic Score (mGPS) and geographical region.

Overall Survival Substudy 2

Comparison groups

Substudy 2: Ruxolitinib + Regorafenib v Substudy 2: Placebo + Regorafenib

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.136 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

1.23

Notes
[6] - Log rank test stratified by geographical region.

Secondary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS)

End point description

PFS is defined as the number of days from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as at least a 20% increase in the sum of the Longest Diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started, unequivocal progression of non-target lesions, or the appearance of new lesions.

End point type

Secondary

End point timeframe

Baseline through disease progression, data cut-off 27 Jan 2016 for Substudy 1 and 11 Feb 2016 for Substudy 2.

End point values	Substudy 1: Ruxolitinib + Regorafenib	Substudy 1: Placebo + Regorafenib	Substudy 2: Ruxolitinib + Regorafenib	Substudy 2: Placebo + Regorafenib
Number of subjects analysed	87 ^[7]	88 ^[8]	110 ^[9]	111 ^[10]
Units: months
median (confidence interval 95%)	2.2 (1.9 to 3.0)	2.1 (1.8 to 2.7)	3.5 (3.0 to 3.8)	2.0 (1.9 to 3.1)

Notes
[7] - ITT population-all subjects randomized in Substudy 1 & Substudy 2 of the study.
[8] - ITT population-all subjects randomized in Substudy 1 & Substudy 2 of the study.
[9] - ITT population-all subjects randomized in Substudy 1 & Substudy 2 of the study.
[10] - ITT population-all subjects randomized in Substudy 1 & Substudy 2 of the study.

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR)

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End point title

Overall Response Rate (ORR)

End point description

Response defined per Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR)=disappearance of all target and non-target lesions without new lesion; Partial Response (PR)=30% decrease in sum of longest diameter of target lesions, non-target lesion not progressed, and no new lesion; Progressive Disease=20% increase in sum of longest diameter of target lesions, or non-target lesion progression, or identification of new lesion; Stable Disease=small changes that do not meet above criteria. ORR was defined as the proportion of participants who achieved a best response of either CR or PR. ORR=number of participants with CR or PR/number of participants randomized.

End point type

Secondary

End point timeframe

Baseline through end of study; data cut-off 27 Jan 2016 for Substudy 1 and 11 Feb 2016 for Substudy 2.

End point values	Substudy 1: Ruxolitinib + Regorafenib	Substudy 1: Placebo + Regorafenib	Substudy 2: Ruxolitinib + Regorafenib	Substudy 2: Placebo + Regorafenib
Number of subjects analysed	87 ^[11]	88 ^[12]	110 ^[13]	111 ^[14]
Units: percentage of responders
number (confidence interval 95%)	0.0 (0.0 to 4.2)	0.0 (0.0 to 4.1)	2.7 (0.6 to 7.8)	4.5 (1.5 to 10.2)

Notes
[11] - ITT population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
[12] - ITT population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
[13] - ITT population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
[14] - ITT population included all subjects randomized in Substudy 1 and Substudy 2 of the study.

No statistical analyses for this end point

Secondary: Duration of Response

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End point title

Duration of Response

End point description

Duration of response is defined as the time from response (CR/PR) until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause. No data displayed because outcome measure has not been analyzed. Duration of response analyses was not done since there were no responders in Substudy 1 and very few responders in Substudy 2 at data cutoff (27JAN2016 for Substudy 1 and 11Feb2016 for Substudy 2). Duration of response analysis was not done in both substudies.

End point type

Secondary

End point timeframe

Baseline through end of study; data cut-off 27 Jan 2016 for Substudy 1 and 11 Feb 2016 for Substudy 2.

End point values	Substudy 1: Ruxolitinib + Regorafenib	Substudy 1: Placebo + Regorafenib	Substudy 2: Ruxolitinib + Regorafenib	Substudy 2: Placebo + Regorafenib
Number of subjects analysed	0 ^[15]	0 ^[16]	0 ^[17]	0 ^[18]
Units: months
number (not applicable)

Notes
[15] - No data displayed because outcome measure has not been analyzed.
[16] - No data displayed because outcome measure has not been analyzed.
[17] - No data displayed because outcome measure has not been analyzed.
[18] - No data displayed because outcome measure has not been analyzed.

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Disease Control

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End point title

Percentage of Participants Achieving Disease Control

End point description

Disease control as measured by the percentage of participants whose best response was complete response (CR), partial response (PR), or stable disease (SD) per RECIST v.1.1.

End point type

Secondary

End point timeframe

Baseline through end of study; data cut-off 27 Jan 2016 for Substudy 1 and 11 Feb 2016 for Substudy 2.

End point values	Substudy 1: Ruxolitinib + Regorafenib	Substudy 1: Placebo + Regorafenib	Substudy 2: Ruxolitinib + Regorafenib	Substudy 2: Placebo + Regorafenib
Number of subjects analysed	87 ^[19]	88 ^[20]	110 ^[21]	111 ^[22]
Units: Percentage of participants
number (confidence interval 95%)	40.2 (29.9 to 51.3)	34.1 (24.3 to 45.0)	61.8 (52.1 to 70.9)	36.9 (28.0 to 46.6)

Notes
[19] - ITT population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
[20] - ITT population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
[21] - ITT population included all subjects randomized in Substudy 1 and Substudy 2 of the study.
[22] - ITT population included all subjects randomized in Substudy 1 and Substudy 2 of the study.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of study medication up to 16 months or data cut-off 29MAR2016.

Adverse event reporting additional description

The safety evaluable population consisted of all participants exposed to at least 1 dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Substudy 1: Ruxolitinib + Regorafenib

Reporting group description

Ruxolitinib 15 mg BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle.

Reporting group title

Substudy 1: Placebo + Regorafenib

Reporting group description

Placebo BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle.

Reporting group title

Substudy 2: Ruxolitinib + Regorafenib

Reporting group description

Ruxolitinib 15 mg BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle.

Reporting group title

Substudy 2: Placebo + Regorafenib

Reporting group description

Placebo BID continuous with regorafenib 160 mg QD for the first 21 days of each 28-day cycle.

Serious adverse events	Substudy 1: Ruxolitinib + Regorafenib	Substudy 1: Placebo + Regorafenib	Substudy 2: Ruxolitinib + Regorafenib	Substudy 2: Placebo + Regorafenib
Total subjects affected by serious adverse events
subjects affected / exposed	50 / 85 (58.82%)	43 / 86 (50.00%)	40 / 106 (37.74%)	39 / 106 (36.79%)
number of deaths (all causes)	12	6	4	5
number of deaths resulting from adverse events	1	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Embolism
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 85 (0.00%)	2 / 86 (2.33%)	2 / 106 (1.89%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 85 (1.18%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 85 (2.35%)	1 / 86 (1.16%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	4 / 85 (4.71%)	3 / 86 (3.49%)	1 / 106 (0.94%)	2 / 106 (1.89%)
occurrences causally related to treatment / all	1 / 4	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstruction
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ulcer haemorrhage
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hernia obstructive
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 85 (0.00%)	3 / 86 (3.49%)	2 / 106 (1.89%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	4 / 85 (4.71%)	2 / 86 (2.33%)	1 / 106 (0.94%)	3 / 106 (2.83%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 85 (1.18%)	2 / 86 (2.33%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	4 / 106 (3.77%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 85 (1.18%)	1 / 86 (1.16%)	3 / 106 (2.83%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract inflammation
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 85 (1.18%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	5 / 85 (5.88%)	1 / 86 (1.16%)	0 / 106 (0.00%)	3 / 106 (2.83%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme abnormal
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 85 (1.18%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia, obstructive
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seroma
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrospinal fistula
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 85 (1.18%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Grand mal convulsion
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Coagulopathy
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	4 / 106 (3.77%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	9 / 85 (10.59%)	7 / 86 (8.14%)	4 / 106 (3.77%)	5 / 106 (4.72%)
occurrences causally related to treatment / all	0 / 9	0 / 7	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	1 / 85 (1.18%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	3 / 85 (3.53%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bloody peritoneal effluent
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dieulafoy's vascular malformation
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 85 (2.35%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 85 (1.18%)	3 / 86 (3.49%)	1 / 106 (0.94%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	2 / 85 (2.35%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	4 / 85 (4.71%)	2 / 86 (2.33%)	1 / 106 (0.94%)	3 / 106 (2.83%)
occurrences causally related to treatment / all	0 / 5	0 / 2	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal food impaction
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	3 / 85 (3.53%)	1 / 86 (1.16%)	0 / 106 (0.00%)	5 / 106 (4.72%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 85 (2.35%)	4 / 86 (4.65%)	3 / 106 (2.83%)	4 / 106 (3.77%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 3	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	2 / 85 (2.35%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatorenal syndrome
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	2 / 85 (2.35%)	1 / 86 (1.16%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	2 / 106 (1.89%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	2 / 106 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	2 / 106 (1.89%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	3 / 85 (3.53%)	1 / 86 (1.16%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vesical fistula
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal vein thrombosis
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	3 / 85 (3.53%)	1 / 86 (1.16%)	3 / 106 (2.83%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic lupus erythematosus
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Arthritis infective
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic infection bacterial
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	2 / 85 (2.35%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	1 / 85 (1.18%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	5 / 85 (5.88%)	2 / 86 (2.33%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 5	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	6 / 85 (7.06%)	1 / 86 (1.16%)	1 / 106 (0.94%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 6	1 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 85 (2.35%)	1 / 86 (1.16%)	2 / 106 (1.89%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 85 (1.18%)	0 / 86 (0.00%)	1 / 106 (0.94%)	2 / 106 (1.89%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	2 / 106 (1.89%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 85 (0.00%)	1 / 86 (1.16%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	1 / 106 (0.94%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 85 (0.00%)	0 / 86 (0.00%)	0 / 106 (0.00%)	1 / 106 (0.94%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Substudy 1: Ruxolitinib + Regorafenib	Substudy 1: Placebo + Regorafenib	Substudy 2: Ruxolitinib + Regorafenib	Substudy 2: Placebo + Regorafenib
Total subjects affected by non serious adverse events
subjects affected / exposed	81 / 85 (95.29%)	83 / 86 (96.51%)	106 / 106 (100.00%)	104 / 106 (98.11%)
Vascular disorders
Hypertension
subjects affected / exposed	18 / 85 (21.18%)	21 / 86 (24.42%)	43 / 106 (40.57%)	42 / 106 (39.62%)
occurrences all number	22	23	64	53
General disorders and administration site conditions
Asthenia
subjects affected / exposed	20 / 85 (23.53%)	21 / 86 (24.42%)	19 / 106 (17.92%)	23 / 106 (21.70%)
occurrences all number	25	25	29	26
Chills
subjects affected / exposed	2 / 85 (2.35%)	5 / 86 (5.81%)	5 / 106 (4.72%)	4 / 106 (3.77%)
occurrences all number	2	5	5	5
Fatigue
subjects affected / exposed	29 / 85 (34.12%)	31 / 86 (36.05%)	43 / 106 (40.57%)	47 / 106 (44.34%)
occurrences all number	30	35	47	56
Chest pain
subjects affected / exposed	3 / 85 (3.53%)	3 / 86 (3.49%)	7 / 106 (6.60%)	4 / 106 (3.77%)
occurrences all number	3	3	7	4
Oedema peripheral
subjects affected / exposed	8 / 85 (9.41%)	8 / 86 (9.30%)	2 / 106 (1.89%)	8 / 106 (7.55%)
occurrences all number	8	8	3	9
Pain
subjects affected / exposed	5 / 85 (5.88%)	1 / 86 (1.16%)	2 / 106 (1.89%)	5 / 106 (4.72%)
occurrences all number	7	1	2	5
Pyrexia
subjects affected / exposed	14 / 85 (16.47%)	13 / 86 (15.12%)	19 / 106 (17.92%)	13 / 106 (12.26%)
occurrences all number	19	18	22	17
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	9 / 85 (10.59%)	8 / 86 (9.30%)	10 / 106 (9.43%)	7 / 106 (6.60%)
occurrences all number	13	8	10	7
Dysphonia
subjects affected / exposed	11 / 85 (12.94%)	14 / 86 (16.28%)	22 / 106 (20.75%)	27 / 106 (25.47%)
occurrences all number	12	16	25	29
Dyspnoea
subjects affected / exposed	10 / 85 (11.76%)	13 / 86 (15.12%)	12 / 106 (11.32%)	17 / 106 (16.04%)
occurrences all number	11	17	13	17
Epistaxis
subjects affected / exposed	6 / 85 (7.06%)	4 / 86 (4.65%)	4 / 106 (3.77%)	10 / 106 (9.43%)
occurrences all number	7	4	5	10
Oropharyngeal pain
subjects affected / exposed	5 / 85 (5.88%)	5 / 86 (5.81%)	7 / 106 (6.60%)	4 / 106 (3.77%)
occurrences all number	7	5	8	4
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 85 (1.18%)	1 / 86 (1.16%)	0 / 106 (0.00%)	5 / 106 (4.72%)
occurrences all number	1	1	0	5
Insomnia
subjects affected / exposed	7 / 85 (8.24%)	5 / 86 (5.81%)	11 / 106 (10.38%)	5 / 106 (4.72%)
occurrences all number	7	5	11	6
Investigations
Alanine aminotransferase increased
subjects affected / exposed	5 / 85 (5.88%)	8 / 86 (9.30%)	8 / 106 (7.55%)	11 / 106 (10.38%)
occurrences all number	5	8	8	11
Aspartate aminotransferase increased
subjects affected / exposed	7 / 85 (8.24%)	14 / 86 (16.28%)	12 / 106 (11.32%)	13 / 106 (12.26%)
occurrences all number	7	18	13	14
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 85 (3.53%)	6 / 86 (6.98%)	4 / 106 (3.77%)	5 / 106 (4.72%)
occurrences all number	3	8	5	5
Blood bilirubin increased
subjects affected / exposed	8 / 85 (9.41%)	11 / 86 (12.79%)	7 / 106 (6.60%)	14 / 106 (13.21%)
occurrences all number	8	13	11	18
Lipase increased
subjects affected / exposed	0 / 85 (0.00%)	5 / 86 (5.81%)	5 / 106 (4.72%)	4 / 106 (3.77%)
occurrences all number	0	5	6	7
Weight decreased
subjects affected / exposed	13 / 85 (15.29%)	15 / 86 (17.44%)	13 / 106 (12.26%)	16 / 106 (15.09%)
occurrences all number	14	15	13	16
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 85 (4.71%)	5 / 86 (5.81%)	11 / 106 (10.38%)	5 / 106 (4.72%)
occurrences all number	4	6	13	5
Dysgeusia
subjects affected / exposed	6 / 85 (7.06%)	6 / 86 (6.98%)	6 / 106 (5.66%)	4 / 106 (3.77%)
occurrences all number	6	9	7	4
Headache
subjects affected / exposed	13 / 85 (15.29%)	16 / 86 (18.60%)	21 / 106 (19.81%)	26 / 106 (24.53%)
occurrences all number	14	18	24	34
Paraesthesia
subjects affected / exposed	0 / 85 (0.00%)	4 / 86 (4.65%)	5 / 106 (4.72%)	3 / 106 (2.83%)
occurrences all number	0	4	5	3
Neuropathy peripheral
subjects affected / exposed	2 / 85 (2.35%)	2 / 86 (2.33%)	9 / 106 (8.49%)	6 / 106 (5.66%)
occurrences all number	2	2	9	6
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	10 / 85 (11.76%)	12 / 86 (13.95%)	24 / 106 (22.64%)	12 / 106 (11.32%)
occurrences all number	14	16	34	13
Thrombocytopenia
subjects affected / exposed	3 / 85 (3.53%)	1 / 86 (1.16%)	4 / 106 (3.77%)	6 / 106 (5.66%)
occurrences all number	3	1	5	6
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	21 / 85 (24.71%)	26 / 86 (30.23%)	25 / 106 (23.58%)	27 / 106 (25.47%)
occurrences all number	22	29	27	31
Abdominal pain upper
subjects affected / exposed	4 / 85 (4.71%)	6 / 86 (6.98%)	6 / 106 (5.66%)	11 / 106 (10.38%)
occurrences all number	4	6	8	12
Abdominal distension
subjects affected / exposed	2 / 85 (2.35%)	4 / 86 (4.65%)	1 / 106 (0.94%)	7 / 106 (6.60%)
occurrences all number	2	6	1	7
Ascites
subjects affected / exposed	4 / 85 (4.71%)	2 / 86 (2.33%)	2 / 106 (1.89%)	7 / 106 (6.60%)
occurrences all number	4	2	4	12
Constipation
subjects affected / exposed	27 / 85 (31.76%)	20 / 86 (23.26%)	23 / 106 (21.70%)	22 / 106 (20.75%)
occurrences all number	31	25	25	26
Diarrhoea
subjects affected / exposed	32 / 85 (37.65%)	27 / 86 (31.40%)	40 / 106 (37.74%)	30 / 106 (28.30%)
occurrences all number	48	35	77	42
Dry mouth
subjects affected / exposed	3 / 85 (3.53%)	6 / 86 (6.98%)	4 / 106 (3.77%)	4 / 106 (3.77%)
occurrences all number	4	6	4	4
Flatulence
subjects affected / exposed	5 / 85 (5.88%)	6 / 86 (6.98%)	5 / 106 (4.72%)	5 / 106 (4.72%)
occurrences all number	5	8	5	6
Nausea
subjects affected / exposed	19 / 85 (22.35%)	20 / 86 (23.26%)	30 / 106 (28.30%)	19 / 106 (17.92%)
occurrences all number	24	26	40	23
Stomatitis
subjects affected / exposed	20 / 85 (23.53%)	18 / 86 (20.93%)	19 / 106 (17.92%)	21 / 106 (19.81%)
occurrences all number	22	19	26	23
Vomiting
subjects affected / exposed	16 / 85 (18.82%)	18 / 86 (20.93%)	23 / 106 (21.70%)	13 / 106 (12.26%)
occurrences all number	18	23	29	15
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 85 (1.18%)	6 / 86 (6.98%)	3 / 106 (2.83%)	3 / 106 (2.83%)
occurrences all number	1	6	3	3
Dry skin
subjects affected / exposed	6 / 85 (7.06%)	6 / 86 (6.98%)	8 / 106 (7.55%)	10 / 106 (9.43%)
occurrences all number	7	6	8	13
Palmar-plantar erythrodysaesthesia
subjects affected / exposed	36 / 85 (42.35%)	38 / 86 (44.19%)	60 / 106 (56.60%)	50 / 106 (47.17%)
occurrences all number	46	51	86	61
Pruritus
subjects affected / exposed	5 / 85 (5.88%)	3 / 86 (3.49%)	3 / 106 (2.83%)	3 / 106 (2.83%)
occurrences all number	6	3	4	3
Rash
subjects affected / exposed	8 / 85 (9.41%)	12 / 86 (13.95%)	15 / 106 (14.15%)	11 / 106 (10.38%)
occurrences all number	9	13	16	12
Rash maculo-papular
subjects affected / exposed	1 / 85 (1.18%)	5 / 86 (5.81%)	2 / 106 (1.89%)	4 / 106 (3.77%)
occurrences all number	1	5	2	5
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	6 / 85 (7.06%)	1 / 86 (1.16%)	2 / 106 (1.89%)	2 / 106 (1.89%)
occurrences all number	7	2	2	2
Endocrine disorders
Hypothyroidism
subjects affected / exposed	4 / 85 (4.71%)	6 / 86 (6.98%)	4 / 106 (3.77%)	3 / 106 (2.83%)
occurrences all number	4	6	4	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 85 (8.24%)	4 / 86 (4.65%)	7 / 106 (6.60%)	8 / 106 (7.55%)
occurrences all number	7	4	7	8
Back pain
subjects affected / exposed	14 / 85 (16.47%)	10 / 86 (11.63%)	12 / 106 (11.32%)	11 / 106 (10.38%)
occurrences all number	15	10	15	12
Muscle spasms
subjects affected / exposed	7 / 85 (8.24%)	2 / 86 (2.33%)	9 / 106 (8.49%)	11 / 106 (10.38%)
occurrences all number	9	2	12	12
Muscular weakness
subjects affected / exposed	5 / 85 (5.88%)	0 / 86 (0.00%)	3 / 106 (2.83%)	1 / 106 (0.94%)
occurrences all number	5	0	3	1
Myalgia
subjects affected / exposed	6 / 85 (7.06%)	5 / 86 (5.81%)	7 / 106 (6.60%)	13 / 106 (12.26%)
occurrences all number	7	5	8	16
Musculoskeletal pain
subjects affected / exposed	3 / 85 (3.53%)	3 / 86 (3.49%)	6 / 106 (5.66%)	5 / 106 (4.72%)
occurrences all number	3	3	6	5
Pain in extremity
subjects affected / exposed	5 / 85 (5.88%)	2 / 86 (2.33%)	10 / 106 (9.43%)	10 / 106 (9.43%)
occurrences all number	6	3	10	14
Infections and infestations
Urinary tract infection
subjects affected / exposed	9 / 85 (10.59%)	6 / 86 (6.98%)	8 / 106 (7.55%)	8 / 106 (7.55%)
occurrences all number	11	7	9	9
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	31 / 85 (36.47%)	31 / 86 (36.05%)	29 / 106 (27.36%)	34 / 106 (32.08%)
occurrences all number	38	37	35	36
Dehydration
subjects affected / exposed	10 / 85 (11.76%)	7 / 86 (8.14%)	7 / 106 (6.60%)	10 / 106 (9.43%)
occurrences all number	11	7	9	11
Hypoalbuminaemia
subjects affected / exposed	3 / 85 (3.53%)	6 / 86 (6.98%)	0 / 106 (0.00%)	0 / 106 (0.00%)
occurrences all number	3	6	0	0
Hypokalaemia
subjects affected / exposed	8 / 85 (9.41%)	6 / 86 (6.98%)	5 / 106 (4.72%)	5 / 106 (4.72%)
occurrences all number	8	9	5	5
Hypophosphataemia
subjects affected / exposed	11 / 85 (12.94%)	5 / 86 (5.81%)	8 / 106 (7.55%)	13 / 106 (12.26%)
occurrences all number	12	5	10	14

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Were there any global substantial amendments to the protocol? Yes

10 Jun 2014

The primary purpose of the amendment was to be able to test alternate decreased dosing of the reference therapy regorafenib in the event that the labeled dose of 160 mg QD was not tolerated. • Revision of inclusion Criterion 4 to specify that subjects who had previous anti-VEGF therapy or anti-EGFR therapy had to have no contraindication; subjects had to have progressed after the last administration of approved therapy; and subjects who discontinued previous treatment due to unacceptable toxicity were also allowed in the study. • The number of subjects in the safety run-in was increased from 27 to 81 due to the number of cohorts increasing. • Subjects were allowed to take the reference therapy regorafenib in the evening with a low-fat meal with approval, except on days of PK sampling. • Platelet requirement for continuing treatment was revised from > 50 × 109/L to > 75 × 109/L. • Modified dose reduction allowance to describe dose modifications when starting doses are lower than 160 mg QD. • An optional dose escalation section for regorafenib to allow the option to increase the dose for subjects who can tolerate an increase. • Text was added that males and females must continue to use contraception for 2 months after stopping regorafenib.

17 Sep 2014

The primary purpose of the amendment was to simplify and reduce the planned cohorts within the study. • Testing of the regorafenib 80 mg QD dosing cohort was removed from Part 1, the safety run-in. The description of dosing cohort sequences was shortened, including removing the reduction of the regorafenib in the statement that defines the MTD with hematologic toxicities. • The number of subjects tested in Part 1 safety run-in was changed from 81 to 54. • Study completion was defined as when the prespecified number of deaths required for analysis of the primary endpoint had occurred in both substudies and no subjects were on study treatment. − SS1 was considered completed when 121 deaths had been observed and no subjects were on study treatment. − SS2 was considered completed when 125 deaths had been observed and no subjects were on study treatment. • Laboratory sampling for TSH, lipase, and amylase was added to be aligned with the regorafenib Summary of Product Characteristics.

09 Oct 2014

The primary purpose of the amendment was to address the FDA's 01 OCT 2014 advice/information request. • Neutropenic fever definition was amended to match CTCAE v4.03 guidelines • To match the prescribing information for regorafenib and to provide clarity, regorafenib dose modification tables were revised and text was revised to: − Temporarily or permanently withhold regorafenib for severe or uncontrolled hypertension. − State there would be no permitted dose escalations for regorafenib. • Clarification of DLT criteria, measured as ≥ 3 of the first 9 evaluable subjects in a given cohort with a DLT in the first cycle. • Optional tumor tissue biopsy sample was added. Exploratory objective and endpoint was added.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
27 Jan 2016	Termination of Substudy 1 occurred on 27 January 2016 followed by the termination of Substudy 2 on 11 February 2016.	-

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

Substudy 1 was terminated for futility at interim analysis and Substudy 2 was terminated per sponsor decision.

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Clinical Trial Results:
A Randomized, Double-Blind Study of Ruxolitinib or Placebo in Combination With Regorafenib in Subjects With Relapsed or Refractory Metastatic Colorectal Cancer

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Primary: Overall Survival (OS)

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind Study of Ruxolitinib or Placebo in Combination With Regorafenib in Subjects With Relapsed or Refractory Metastatic Colorectal Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Survival (OS)

Primary: Overall Survival (OS)

Secondary: Progression Free Survival (PFS)

Secondary: Progression Free Survival (PFS)

Secondary: Overall Response Rate (ORR)

Secondary: Overall Response Rate (ORR)

Secondary: Duration of Response

Secondary: Duration of Response

Secondary: Percentage of Participants Achieving Disease Control

Secondary: Percentage of Participants Achieving Disease Control

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Randomized, Double-Blind Study of Ruxolitinib or Placebo in Combination With Regorafenib in Subjects With Relapsed or Refractory Metastatic Colorectal Cancer