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Clinical Trial Results:
A Randomized, Double Blinded, Multi-Center Phase 2 Study to Estimate the Efficacy and Evaluate the Safety and Tolerability of Sorafenib in Combination With AMG 386 or Placebo in Subjects With Metastatic Clear Cell Carcinoma of the Kidney

Summary
EudraCT number	2007-000147-98
Trial protocol	FR BE AT
Global end of trial date	10 Jun 2014

Results information
Results version number	v1(current)
This version publication date	20 Jun 2016
First version publication date	05 Aug 2015
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

20060159

ISRCTN number

US NCT number

NCT00467025

WHO universal trial number (UTN)

Sponsor organisation name

Amgen, Inc.

Sponsor organisation address

One Amgen Center Drive, Thousand Oaks, CA, United States, 91320

Public contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com

Scientific contact

IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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

10 Jun 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Jun 2014

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to estimate the efficacy as measured by progression-free survival (PFS) of subjects receiving trebananib in combination with sorafenib compared to subjects receiving sorafenib plus placebo.

Protection of trial subjects

This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 May 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

48 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 42

Country: Number of subjects enrolled

Poland: 67

Country: Number of subjects enrolled

Austria: 7

Country: Number of subjects enrolled

Belgium: 10

Country: Number of subjects enrolled

France: 26

Worldwide total number of subjects

152

EEA total number of subjects

110

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)

103

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Eligible subjects were men or women ≥ 18 years of age with histologically confirmed metastatic renal cell carcinoma (RCC) with a clear cell component, of low or intermediate risk according to the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk classification.

Screening details

Two hundred one subjects were screened for enrollment, and 152 subjects were enrolled in the study: 51 in the Trebananib 3-mg/kg arm, 50 in the Trebananib 10-mg/kg arm, and 51 in the placebo arm. Subjects were stratified by risk classification (low vs intermediate) according to the MSKCC prognostic risk classification.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Trebananib 3 mg/kg + Sorafenib

Arm description

Subjects received trebananib 3 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Arm type

Experimental

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Nexavar

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Sorafenib was administered to subjects in all 3 arms of this clinical trial at a starting dose of 400 mg orally BID.

Investigational medicinal product name

Trebananib

Investigational medicinal product code

AMG 386

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered by intravenous infusion once weekly

Trebananib 10 mg/kg + Sorafenib

Arm description

Subjects received trebananib 10 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Arm type

Experimental

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Nexavar

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Sorafenib was administered to subjects in all 3 arms of this clinical trial at a starting dose of 400 mg orally BID.

Investigational medicinal product name

Trebananib

Investigational medicinal product code

AMG 386

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered by intravenous infusion once weekly

Placebo + Sorafenib

Arm description

Subjects received placebo IV infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered by intravenous infusion once weekly

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Nexavar

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Sorafenib was administered to subjects in all 3 arms of this clinical trial at a starting dose of 400 mg orally BID.

Number of subjects in period 1	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Started	51	50	51
Received Treatment	51	50	50
Crossover to open-label trebananib	0 ^[1]	0 ^[2]	32 ^[3]
Completed	51	50	50
Not completed	0	0	1
Did not receive study drug	-	-	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not applicable to Trebananib 3 mg/kg + Sorafenib treatment arm
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Not applicable to Trebananib 10 mg/kg + Sorafenib treatment arm
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: 32 subjects crossed over to open-label trebananib (10 mg/kg IV QW) and sorafenib upon disease progression

Baseline characteristics

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Reporting group title

Trebananib 3 mg/kg + Sorafenib

Reporting group description

Subjects received trebananib 3 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Reporting group title

Trebananib 10 mg/kg + Sorafenib

Reporting group description

Subjects received trebananib 10 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Reporting group title

Placebo + Sorafenib

Reporting group description

Subjects received placebo IV infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Reporting group values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib	Total
Number of subjects	51	50	51	152
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	58.8 ± 10.9	60.7 ± 8.9	59.7 ± 10.1	-
Gender categorical
Units: Subjects
Female	16	9	13	38
Male	35	41	38	114
Race
Units: Subjects
White or Caucasian	47	49	48	144
Black or African American	2	0	2	4
Hispanic or Latino	2	1	1	4
MSKCC Risk Classification
The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk classification based on the following risk factors: - Karnofsky performance status < 80%; - Serum lactate dehydrogenase > 1.5 x upper limit of normal (ULN); - Serum hemoglobin < lower limit of normal (LLN) for their institutions; - Serum Calcium (corrected) > 10 mg/dL; - Time from diagnosis of RCC to first systemic treatment < 1 year. Low risk is defined as 0 risk factors; intermediate risk is defined as 1-2 risk factors.
Units: Subjects
Low	20	21	21	62
Intermediate	31	29	30	90

End points

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Reporting group title

Trebananib 3 mg/kg + Sorafenib

Reporting group description

Subjects received trebananib 3 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Reporting group title

Trebananib 10 mg/kg + Sorafenib

Reporting group description

Subjects received trebananib 10 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Reporting group title

Placebo + Sorafenib

Reporting group description

Subjects received placebo IV infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Primary: Progression-Free Survival

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End point title

Progression-Free Survival

End point description

Progression-free survival is calculated as the time between the randomization of protocol-specified treatment to the earliest date disease progression per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria or death, assessed by the Investigator. Progression-free survival was analyzed using the Kaplan-Meier method. Subjects who had not died and did not have an assessment of disease progression were censored at their last evaluable disease assessment date.

End point type

Primary

End point timeframe

Radiological assessments were performd every 8 weeks for 2 years and then every 4 months thereafter. Data are reported as of the cut-off date of 28 February 2013; median time on study was 113 weeks.

End point values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Number of subjects analysed	51	50	51
Units: months
median (confidence interval 80%)	8.5 (7.2 to 9.1)	9 (5.6 to 11)	9 (7.2 to 9.2)

Trebananib combined versus placebo

Statistical analysis description

A Cox regression model stratified by MSKCC prognostic risk classification was used to estimate the progression-free survival hazard ratio and 2-sided 80% confidence interval for both trebananib + sorafenib dose groups combined versus placebo + sorafenib. A hazard ratio of < 1.0 indicates a lower average event rate and longer time to event for the trebananib treatment group relative to the placebo group.

Comparison groups

Trebananib 3 mg/kg + Sorafenib v Trebananib 10 mg/kg + Sorafenib v Placebo + Sorafenib

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.97 ^[1]

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.993

Confidence interval

level

80%

sides

2-sided

lower limit

0.782

upper limit

1.261

Notes
[1] - No adjustments for multiple testing were used. Stratifed by MSKCC risk category.

Secondary: Objective Response Rate

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End point title

Objective Response Rate

End point description

Objective Response Rate (ORR) defined as either a confirmed complete response (CR) or partial response (PR) per modified RECIST (v 1.0) criteria (responder). A confirmed CR requires 2 assessments of CR at least 28 days apart. A confirmed PR requires 2 assessments at least 28 days apart of PR or CR. All subjects who did not meet the criteria for an objective response by the analysis cutoff date were considered non-responders.

End point type

Secondary

End point timeframe

Radiological assessments were performd every 8 weeks for 2 years and then every 4 months thereafter. Data are reported as of the cut-off date of 28 February 2013; median time on study was 113 weeks.

End point values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Number of subjects analysed	51 ^[2]	50 ^[3]	51 ^[4]
Units: percentage of subjects
number (confidence interval 80%)	37 (28 to 47)	40 (31 to 50)	27 (19 to 37)

Notes
[2] - Subjects with measurable disease at baseline
[3] - Subjects with measurable disease at baseline
[4] - Subjects with measurable disease at baseline

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 was calculated only for those subjects with an objective response and is defined as the time from first confirmed objective response to first observed disease progression or death due to any cause. Subjects not meeting criteria for progression by the analysis data cutoff date or who had not died were censored at their last evaluable disease assessment date. Duration of response was analyzed using the Kaplan-Meier method. "99999" indicates data not estimable.

End point type

Secondary

End point timeframe

Radiological assessments were performd every 8 weeks for 2 years and then every 4 months thereafter. Data are reported as of the primary analysis cut-off date of February 2010; median time on study was 75 weeks.

End point values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Number of subjects analysed	19 ^[5]	19 ^[6]	13 ^[7]
Units: months
median (confidence interval 80%)	7.4 (6.9 to 13)	8.9 (7.4 to 99999)	8.9 (7.4 to 12.9)

Notes
[5] - Subjects with a response
[6] - Subjects with a response
[7] - Subjects with a response

No statistical analyses for this end point

Secondary: Change in Tumor Burden

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End point title

Change in Tumor Burden

End point description

Reduction in tumor burden was measured as the maximum percent reduction from Baseline (or, for subjects without a reduction, the minimum increase from Baseline) in the sum of the longest diameters (SLD) of target lesions. For each subject the maximum percent reduction in SLD from baseline to the post-baseline nadir was identified, and the mean of these values was then calculated.

End point type

Secondary

End point timeframe

Radiological assessments were performd every 8 weeks for 2 years and then every 4 months thereafter. Data are reported as of the primary analysis cut-off date of 22 February 2010; median time on study was 72 weeks.

End point values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Number of subjects analysed	47 ^[8]	46 ^[9]	47 ^[10]
Units: percent reduction
arithmetic mean (confidence interval 80%)	-29.2 (-33.5 to -24.9)	-34.3 (-38.6 to -30)	-23.8 (-28 to -19.7)

Notes
[8] - Subjects with available data
[9] - Subjects with available data
[10] - Subjects with available data

No statistical analyses for this end point

Secondary: Time-adjusted Area Under the Curve (AUC) for Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index – 15 Items (FKSI-15) Scale Score

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End point title

Time-adjusted Area Under the Curve (AUC) for Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index – 15 Items (FKSI-15) Scale Score

End point description

The FKSI-15 is a validated symptom index for kidney cancer patients containing 15 questions, each scored on a 5-point scale (0 = not at all; 4 = very much). The FKSI-15 summary score ranges from 0 to 60, with higher scores indicating less severe symptoms or concerns. The AUC was calculated using the trapezoidal rule and divided by the duration in weeks of the assessment period to obtain the time-adjusted AUC. The patient-reported outcomes (PRO) analysis set includes all subjects with at least one PRO assessment prior to disease progression.

End point type

Secondary

End point timeframe

Baseline to Week 57

End point values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Number of subjects analysed	51 ^[11]	49 ^[12]	50 ^[13]
Units: units on a scale
least squares mean (confidence interval 95%)	-2 (-3.5 to -0.5)	-0.9 (-2.4 to 0.6)	-2.4 (-3.9 to -0.9)

Notes
[11] - PRO analysis set
[12] - PRO analysis set
[13] - PRO analysis set

Difference Between Trebananib 3 mg/kg and 10 mg/kg

Statistical analysis description

Mixed model analysis including fixed effects for treatment, visit, baseline PRO scale score, the interaction of treatment and visit, and a subject-specific random intercept.

Comparison groups

Trebananib 10 mg/kg + Sorafenib v Trebananib 3 mg/kg + Sorafenib

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

3.2

Difference Between Trebananib 10 mg/kg and Placebo

Statistical analysis description

Mixed model analysis including fixed effects for treatment, visit, baseline PRO scale score, the interaction of treatment and visit, and a subject-specific random intercept.

Comparison groups

Trebananib 10 mg/kg + Sorafenib v Placebo + Sorafenib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

3.6

Difference Between Trebananib 3 mg/kg and Placebo

Statistical analysis description

Mixed model analysis including fixed effects for treatment, visit, baseline PRO scale score, the interaction of treatment and visit, and a subject-specific random intercept.

Comparison groups

Placebo + Sorafenib v Trebananib 3 mg/kg + Sorafenib

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

2.5

Secondary: Number of Subjects With Adverse Events (AE)

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End point title

Number of Subjects With Adverse Events (AE)

End point description

Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

End point type

Secondary

End point timeframe

From first dose until 30 days after last dose of any study therapy. Median duration of trebananib treatment was 8.0, 9.5 and 9.5 months in each treatment group respectively.

End point values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Number of subjects analysed	51 ^[14]	50 ^[15]	50 ^[16]
Units: subjects
Any adverse event	50	49	50
Worst grade of 3	29	28	38
Worst grade of 4	7	4	5
Worst grade of 5	1	3	0
Any serious adverse event	26	20	13
Leading to discontinuation from therapy or study	7	8	3
Any treatment-related adverse event	49	48	47
Treatment-related worst grade of 3	27	25	39
Treatment-related worst grade of 4	4	4	2
Treatment-related worst grade of 5	1	0	0
Serious treatment-related AE	16	14	7
Treatment-related leading to discontinuation	6	5	2

Notes
[14] - Safety analysis set
[15] - Safety analysis set
[16] - Safety analysis set

No statistical analyses for this end point

Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

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End point title

Number of Subjects with Grade 3 or Higher Laboratory Toxicities

End point description

End point type

Secondary

End point timeframe

From first dose of study treatment until the last dose.

End point values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Number of subjects analysed	51 ^[17]	50 ^[18]	50 ^[19]
Units: subjects
Alanine amino transferase increased	1	1	2
Albumin decreased	1	0	0
Alkaline phosphatase increased	1	0	1
Amylase increased	3	3	0
Aspartate amino transferase increased	1	1	2
Bicarbonate decreased	0	1	0
Calcium decreased	1	3	2
Creatinine increased	0	1	0
Glucose increased	2	3	1
Lipase increased	3	10	3
Magnesium decreased	1	2	0
Phosphorus decreased	12	9	9
Potassium increased	1	1	3
Potassium decreased	4	4	0
Sodium decreased	2	3	0
Absolute neutrophil count decreased	1	0	1
Hemoglobin decreased	1	0	2
Lymphocytes decreased	5	1	2
Partial thromboplastin time increased	0	0	1
Platelets decreased	0	0	1
Segmented neutrophils decreased	1	0	0
Total neutrophils decreased	0	0	1
White blood cells decreased	0	0	0

Notes
[17] - Safety analysis set
[18] - Safety analysis set
[19] - Safety analysis set

No statistical analyses for this end point

Secondary: Number of Subjects Who Developed Anti-trebananib Antibodies Post-baseline

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End point title

Number of Subjects Who Developed Anti-trebananib Antibodies Post-baseline

End point description

Serum samples were first tested in an electrochemiluminescent immunoassay to detect and confirm the presence of antibodies capable of binding to trebananib. Samples that tested positive in the immunoassay were then subjected to an electrochemiluminescent receptor-binding assay to detect neutralizing or inhibitory effects of the antibodies in vitro. If a sample was positive in both assays, a subject was defined as positive for neutralizing antibodies. Additionally, if a sample was positive in the immunoassay, but negative in the receptor-binding assay, the sample was defined as positive for binding antibodies.

End point type

Secondary

End point timeframe

Pre-dose, Cycle 3 (Week 9), and every 4 cycles (16 weeks) thereafter.

End point values	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Placebo + Sorafenib
Number of subjects analysed	48 ^[20]	48 ^[21]	46 ^[22]
Units: subjects
Binding antibody positive	2	1	3
Neutralizing antibody positive	0	0	0

Notes
[20] - Subjects with a postbaseline result
[21] - Subjects with a postbaseline result
[22] - Subjects with a postbaseline result

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug until 30 days after the last dose of any study therapy or up to the day before first dose of open-label trebananib. For crossover subjects, from start of open-label therapy until 30 days after the last dose of trebananib.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Placebo + Sorafenib

Reporting group description

Subjects received placebo IV infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Reporting group title

Trebananib 3 mg/kg + Sorafenib

Reporting group description

Subjects received trebananib 3 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Reporting group title

Trebananib 10 mg/kg + Sorafenib

Reporting group description

Subjects received trebananib 10 mg/kg by intravenous infusion once a week and sorafenib at a starting dose of 400 mg orally twice a day (BID).

Reporting group title

Open-label Trebananib 10 mg/kg + Sorafenib

Reporting group description

Subjects initially randomized to Placebo + Sorafenib who discontinued treatment due to disease progression crossed over and received trebananib 10 mg/kg by intravenous infusion once a week and the same dose of sorafenib that they were receiving immediately prior to documentation of disease progression.

Serious adverse events	Placebo + Sorafenib	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Open-label Trebananib 10 mg/kg + Sorafenib
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 50 (26.00%)	26 / 51 (50.98%)	20 / 50 (40.00%)	10 / 32 (31.25%)
number of deaths (all causes)	11	31	31	26
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Cancer pain
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Malignant melanoma
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Malignant neoplasm progression
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Metastases to central nervous system
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	3 / 32 (9.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
Metastases to spine
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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 cell carcinoma
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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 / 1
Tumour necrosis
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Tumour pain
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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 neoplasm
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Arterial thrombosis
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Hypertension
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 50 (0.00%)	2 / 51 (3.92%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Death
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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 / 1	0 / 0
Fatigue
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
General physical health deterioration
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medical device complication
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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 peripheral
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Pyrexia
subjects affected / exposed	0 / 50 (0.00%)	2 / 51 (3.92%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	2 / 50 (4.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Lung disorder
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Pleural effusion
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Pulmonary embolism
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Respiratory failure
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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 / 1
Investigations
Amylase increased
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Injury, poisoning and procedural complications
Arterial restenosis
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Angina pectoris
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Angina unstable
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Cardiopulmonary failure
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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 / 1	0 / 0
Coronary artery insufficiency
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Myocardial infarction
subjects affected / exposed	2 / 50 (4.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	1 / 2	1 / 2	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular insufficiency
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Dizziness
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Incoherent
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Neuropathy peripheral
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Spinal cord compression
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Syncope
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 50 (0.00%)	2 / 51 (3.92%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Blindness
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Diplopia
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Retinal artery thrombosis
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Retinal vascular thrombosis
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Visual acuity reduced
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 50 (0.00%)	3 / 51 (5.88%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Anal fissure
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Anal fistula
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Constipation
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Inguinal hernia, obstructive
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Intestinal obstruction
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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 / 1	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Melaena
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Nausea
subjects affected / exposed	0 / 50 (0.00%)	2 / 51 (3.92%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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	0 / 50 (0.00%)	2 / 51 (3.92%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Cholecystitis
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Cholecystitis acute
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Hepatitis toxic
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Jaundice
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 50 (2.00%)	2 / 51 (3.92%)	0 / 50 (0.00%)	0 / 32 (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
Rash
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	1 / 32 (3.13%)
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
Rash generalised
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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 and urinary disorders
Renal failure
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Urinary retention
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Flank pain
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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 in extremity
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal disorder
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Infections and infestations
Anal abscess
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Bacteraemia
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Bronchitis bacterial
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Cellulitis
subjects affected / exposed	1 / 50 (2.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Diverticulitis
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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
Infection
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Localised infection
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Necrotising fasciitis
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	1 / 32 (3.13%)
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 / 1
Osteomyelitis
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	0 / 32 (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
Pneumonia
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	1 / 32 (3.13%)
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
Tuberculosis
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (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
Urinary tract infection
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (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
Hypovolaemia
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
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	Placebo + Sorafenib	Trebananib 3 mg/kg + Sorafenib	Trebananib 10 mg/kg + Sorafenib	Open-label Trebananib 10 mg/kg + Sorafenib
Total subjects affected by non serious adverse events
subjects affected / exposed	50 / 50 (100.00%)	48 / 51 (94.12%)	48 / 50 (96.00%)	28 / 32 (87.50%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
subjects affected / exposed	3 / 50 (6.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences all number	3	0	1	0
Squamous cell carcinoma
subjects affected / exposed	3 / 50 (6.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences all number	3	0	4	0
Vascular disorders
Hypertension
subjects affected / exposed	24 / 50 (48.00%)	25 / 51 (49.02%)	22 / 50 (44.00%)	5 / 32 (15.63%)
occurrences all number	38	50	42	16
Hypotension
subjects affected / exposed	1 / 50 (2.00%)	3 / 51 (5.88%)	2 / 50 (4.00%)	0 / 32 (0.00%)
occurrences all number	1	4	2	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	10 / 50 (20.00%)	11 / 51 (21.57%)	14 / 50 (28.00%)	2 / 32 (6.25%)
occurrences all number	20	24	19	2
Chest discomfort
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	1	0	3	0
Chest pain
subjects affected / exposed	3 / 50 (6.00%)	6 / 51 (11.76%)	4 / 50 (8.00%)	4 / 32 (12.50%)
occurrences all number	4	9	6	5
Chills
subjects affected / exposed	2 / 50 (4.00%)	4 / 51 (7.84%)	4 / 50 (8.00%)	0 / 32 (0.00%)
occurrences all number	2	4	6	0
Face oedema
subjects affected / exposed	0 / 50 (0.00%)	4 / 51 (7.84%)	3 / 50 (6.00%)	1 / 32 (3.13%)
occurrences all number	0	5	7	1
Fatigue
subjects affected / exposed	11 / 50 (22.00%)	12 / 51 (23.53%)	17 / 50 (34.00%)	5 / 32 (15.63%)
occurrences all number	20	24	27	8
General physical health deterioration
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	0	0	3	0
Mucosal inflammation
subjects affected / exposed	4 / 50 (8.00%)	10 / 51 (19.61%)	13 / 50 (26.00%)	0 / 32 (0.00%)
occurrences all number	4	14	25	0
Oedema peripheral
subjects affected / exposed	5 / 50 (10.00%)	11 / 51 (21.57%)	7 / 50 (14.00%)	4 / 32 (12.50%)
occurrences all number	5	16	15	4
Pain
subjects affected / exposed	4 / 50 (8.00%)	1 / 51 (1.96%)	2 / 50 (4.00%)	0 / 32 (0.00%)
occurrences all number	5	1	2	0
Pyrexia
subjects affected / exposed	8 / 50 (16.00%)	5 / 51 (9.80%)	9 / 50 (18.00%)	0 / 32 (0.00%)
occurrences all number	9	9	15	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	5 / 50 (10.00%)	2 / 51 (3.92%)	0 / 50 (0.00%)	1 / 32 (3.13%)
occurrences all number	6	2	0	1
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	2 / 32 (6.25%)
occurrences all number	1	0	1	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 50 (10.00%)	7 / 51 (13.73%)	13 / 50 (26.00%)	2 / 32 (6.25%)
occurrences all number	10	7	21	2
Dysphonia
subjects affected / exposed	2 / 50 (4.00%)	4 / 51 (7.84%)	6 / 50 (12.00%)	2 / 32 (6.25%)
occurrences all number	2	4	8	2
Dyspnoea
subjects affected / exposed	6 / 50 (12.00%)	8 / 51 (15.69%)	10 / 50 (20.00%)	1 / 32 (3.13%)
occurrences all number	12	9	15	1
Dyspnoea exertional
subjects affected / exposed	1 / 50 (2.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	1 / 32 (3.13%)
occurrences all number	1	3	3	1
Epistaxis
subjects affected / exposed	3 / 50 (6.00%)	1 / 51 (1.96%)	2 / 50 (4.00%)	0 / 32 (0.00%)
occurrences all number	5	1	3	0
Oropharyngeal pain
subjects affected / exposed	0 / 50 (0.00%)	3 / 51 (5.88%)	9 / 50 (18.00%)	0 / 32 (0.00%)
occurrences all number	0	3	11	0
Pleural effusion
subjects affected / exposed	0 / 50 (0.00%)	2 / 51 (3.92%)	4 / 50 (8.00%)	0 / 32 (0.00%)
occurrences all number	0	2	6	0
Productive cough
subjects affected / exposed	3 / 50 (6.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	1 / 32 (3.13%)
occurrences all number	3	0	2	1
Rhinorrhoea
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	5 / 50 (10.00%)	1 / 32 (3.13%)
occurrences all number	0	1	7	1
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 50 (6.00%)	1 / 51 (1.96%)	5 / 50 (10.00%)	0 / 32 (0.00%)
occurrences all number	4	1	5	0
Depression
subjects affected / exposed	2 / 50 (4.00%)	3 / 51 (5.88%)	5 / 50 (10.00%)	1 / 32 (3.13%)
occurrences all number	2	3	6	1
Insomnia
subjects affected / exposed	3 / 50 (6.00%)	9 / 51 (17.65%)	12 / 50 (24.00%)	2 / 32 (6.25%)
occurrences all number	7	9	13	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	4 / 50 (8.00%)	2 / 51 (3.92%)	1 / 50 (2.00%)	2 / 32 (6.25%)
occurrences all number	10	6	1	4
Amylase increased
subjects affected / exposed	2 / 50 (4.00%)	3 / 51 (5.88%)	3 / 50 (6.00%)	1 / 32 (3.13%)
occurrences all number	6	5	4	1
Aspartate aminotransferase increased
subjects affected / exposed	4 / 50 (8.00%)	2 / 51 (3.92%)	1 / 50 (2.00%)	1 / 32 (3.13%)
occurrences all number	7	4	1	2
Blood creatinine increased
subjects affected / exposed	4 / 50 (8.00%)	1 / 51 (1.96%)	4 / 50 (8.00%)	0 / 32 (0.00%)
occurrences all number	5	2	4	0
Blood uric acid increased
subjects affected / exposed	2 / 50 (4.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	2	2	4	0
Lipase increased
subjects affected / exposed	4 / 50 (8.00%)	4 / 51 (7.84%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	7	8	4	0
Weight decreased
subjects affected / exposed	8 / 50 (16.00%)	7 / 51 (13.73%)	9 / 50 (18.00%)	0 / 32 (0.00%)
occurrences all number	13	12	13	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	3 / 32 (9.38%)
occurrences all number	0	0	1	3
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 50 (4.00%)	4 / 51 (7.84%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	2	5	4	0
Dysgeusia
subjects affected / exposed	2 / 50 (4.00%)	6 / 51 (11.76%)	2 / 50 (4.00%)	0 / 32 (0.00%)
occurrences all number	2	6	2	0
Headache
subjects affected / exposed	7 / 50 (14.00%)	10 / 51 (19.61%)	5 / 50 (10.00%)	2 / 32 (6.25%)
occurrences all number	15	15	8	2
Hyperaesthesia
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	0	0	6	0
Hypoaesthesia
subjects affected / exposed	5 / 50 (10.00%)	2 / 51 (3.92%)	2 / 50 (4.00%)	1 / 32 (3.13%)
occurrences all number	7	7	2	2
Paraesthesia
subjects affected / exposed	4 / 50 (8.00%)	2 / 51 (3.92%)	2 / 50 (4.00%)	1 / 32 (3.13%)
occurrences all number	7	5	2	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 50 (8.00%)	5 / 51 (9.80%)	3 / 50 (6.00%)	1 / 32 (3.13%)
occurrences all number	9	12	3	2
Thrombocytopenia
subjects affected / exposed	1 / 50 (2.00%)	3 / 51 (5.88%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences all number	7	3	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 50 (0.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	2 / 32 (6.25%)
occurrences all number	0	3	1	3
Eye disorders
Eyelid oedema
subjects affected / exposed	0 / 50 (0.00%)	3 / 51 (5.88%)	4 / 50 (8.00%)	2 / 32 (6.25%)
occurrences all number	0	17	4	2
Vision blurred
subjects affected / exposed	1 / 50 (2.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	2 / 32 (6.25%)
occurrences all number	1	2	3	3
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	5 / 50 (10.00%)	9 / 51 (17.65%)	9 / 50 (18.00%)	4 / 32 (12.50%)
occurrences all number	8	18	12	5
Abdominal pain upper
subjects affected / exposed	2 / 50 (4.00%)	5 / 51 (9.80%)	9 / 50 (18.00%)	1 / 32 (3.13%)
occurrences all number	2	6	11	1
Constipation
subjects affected / exposed	12 / 50 (24.00%)	6 / 51 (11.76%)	13 / 50 (26.00%)	1 / 32 (3.13%)
occurrences all number	20	6	18	1
Diarrhoea
subjects affected / exposed	28 / 50 (56.00%)	35 / 51 (68.63%)	36 / 50 (72.00%)	7 / 32 (21.88%)
occurrences all number	71	110	135	12
Dry mouth
subjects affected / exposed	2 / 50 (4.00%)	2 / 51 (3.92%)	4 / 50 (8.00%)	0 / 32 (0.00%)
occurrences all number	2	2	5	0
Dyspepsia
subjects affected / exposed	5 / 50 (10.00%)	5 / 51 (9.80%)	5 / 50 (10.00%)	2 / 32 (6.25%)
occurrences all number	6	5	18	2
Flatulence
subjects affected / exposed	2 / 50 (4.00%)	1 / 51 (1.96%)	5 / 50 (10.00%)	0 / 32 (0.00%)
occurrences all number	2	4	6	0
Gastrooesophageal reflux disease
subjects affected / exposed	4 / 50 (8.00%)	2 / 51 (3.92%)	2 / 50 (4.00%)	1 / 32 (3.13%)
occurrences all number	4	5	2	1
Haemorrhoids
subjects affected / exposed	4 / 50 (8.00%)	1 / 51 (1.96%)	3 / 50 (6.00%)	1 / 32 (3.13%)
occurrences all number	4	1	3	1
Nausea
subjects affected / exposed	11 / 50 (22.00%)	16 / 51 (31.37%)	15 / 50 (30.00%)	3 / 32 (9.38%)
occurrences all number	15	29	26	5
Stomatitis
subjects affected / exposed	8 / 50 (16.00%)	7 / 51 (13.73%)	10 / 50 (20.00%)	0 / 32 (0.00%)
occurrences all number	12	8	13	0
Vomiting
subjects affected / exposed	9 / 50 (18.00%)	9 / 51 (17.65%)	10 / 50 (20.00%)	2 / 32 (6.25%)
occurrences all number	12	15	32	3
Skin and subcutaneous tissue disorders
Actinic keratosis
subjects affected / exposed	1 / 50 (2.00%)	0 / 51 (0.00%)	0 / 50 (0.00%)	2 / 32 (6.25%)
occurrences all number	2	0	0	3
Alopecia
subjects affected / exposed	25 / 50 (50.00%)	23 / 51 (45.10%)	25 / 50 (50.00%)	3 / 32 (9.38%)
occurrences all number	38	30	29	3
Blister
subjects affected / exposed	3 / 50 (6.00%)	2 / 51 (3.92%)	0 / 50 (0.00%)	1 / 32 (3.13%)
occurrences all number	13	3	0	1
Dry skin
subjects affected / exposed	9 / 50 (18.00%)	12 / 51 (23.53%)	12 / 50 (24.00%)	0 / 32 (0.00%)
occurrences all number	12	14	24	0
Erythema
subjects affected / exposed	6 / 50 (12.00%)	4 / 51 (7.84%)	7 / 50 (14.00%)	1 / 32 (3.13%)
occurrences all number	8	7	11	1
Hair texture abnormal
subjects affected / exposed	1 / 50 (2.00%)	3 / 51 (5.88%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences all number	1	3	1	0
Hyperkeratosis
subjects affected / exposed	2 / 50 (4.00%)	3 / 51 (5.88%)	5 / 50 (10.00%)	1 / 32 (3.13%)
occurrences all number	4	13	6	1
Nail disorder
subjects affected / exposed	0 / 50 (0.00%)	3 / 51 (5.88%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences all number	0	4	1	0
Night sweats
subjects affected / exposed	0 / 50 (0.00%)	0 / 51 (0.00%)	1 / 50 (2.00%)	2 / 32 (6.25%)
occurrences all number	0	0	1	2
Pain of skin
subjects affected / exposed	4 / 50 (8.00%)	7 / 51 (13.73%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	4	7	3	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	26 / 50 (52.00%)	23 / 51 (45.10%)	27 / 50 (54.00%)	4 / 32 (12.50%)
occurrences all number	72	88	78	11
Pruritus
subjects affected / exposed	12 / 50 (24.00%)	13 / 51 (25.49%)	13 / 50 (26.00%)	0 / 32 (0.00%)
occurrences all number	18	19	17	0
Rash
subjects affected / exposed	15 / 50 (30.00%)	16 / 51 (31.37%)	16 / 50 (32.00%)	1 / 32 (3.13%)
occurrences all number	28	30	29	2
Rash erythematous
subjects affected / exposed	4 / 50 (8.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences all number	4	1	0	0
Rash generalised
subjects affected / exposed	0 / 50 (0.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	0	5	3	0
Rash maculo-papular
subjects affected / exposed	3 / 50 (6.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences all number	6	1	1	0
Skin exfoliation
subjects affected / exposed	3 / 50 (6.00%)	3 / 51 (5.88%)	2 / 50 (4.00%)	0 / 32 (0.00%)
occurrences all number	4	4	8	0
Skin lesion
subjects affected / exposed	1 / 50 (2.00%)	4 / 51 (7.84%)	2 / 50 (4.00%)	1 / 32 (3.13%)
occurrences all number	1	8	4	1
Skin toxicity
subjects affected / exposed	6 / 50 (12.00%)	5 / 51 (9.80%)	2 / 50 (4.00%)	0 / 32 (0.00%)
occurrences all number	13	7	3	0
Renal and urinary disorders
Proteinuria
subjects affected / exposed	4 / 50 (8.00%)	7 / 51 (13.73%)	8 / 50 (16.00%)	1 / 32 (3.13%)
occurrences all number	6	16	22	2
Endocrine disorders
Hypothyroidism
subjects affected / exposed	2 / 50 (4.00%)	4 / 51 (7.84%)	5 / 50 (10.00%)	1 / 32 (3.13%)
occurrences all number	2	6	5	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	11 / 50 (22.00%)	5 / 51 (9.80%)	8 / 50 (16.00%)	3 / 32 (9.38%)
occurrences all number	16	6	13	5
Back pain
subjects affected / exposed	6 / 50 (12.00%)	7 / 51 (13.73%)	9 / 50 (18.00%)	3 / 32 (9.38%)
occurrences all number	8	10	12	5
Bone pain
subjects affected / exposed	2 / 50 (4.00%)	1 / 51 (1.96%)	4 / 50 (8.00%)	2 / 32 (6.25%)
occurrences all number	4	1	10	3
Flank pain
subjects affected / exposed	3 / 50 (6.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences all number	4	1	1	0
Muscle spasms
subjects affected / exposed	4 / 50 (8.00%)	4 / 51 (7.84%)	2 / 50 (4.00%)	0 / 32 (0.00%)
occurrences all number	5	7	2	0
Muscular weakness
subjects affected / exposed	0 / 50 (0.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	0	2	8	0
Musculoskeletal chest pain
subjects affected / exposed	5 / 50 (10.00%)	6 / 51 (11.76%)	3 / 50 (6.00%)	3 / 32 (9.38%)
occurrences all number	5	10	3	3
Musculoskeletal pain
subjects affected / exposed	6 / 50 (12.00%)	5 / 51 (9.80%)	8 / 50 (16.00%)	0 / 32 (0.00%)
occurrences all number	7	5	12	0
Myalgia
subjects affected / exposed	6 / 50 (12.00%)	7 / 51 (13.73%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences all number	6	10	2	0
Neck pain
subjects affected / exposed	1 / 50 (2.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	1	2	3	0
Pain in extremity
subjects affected / exposed	9 / 50 (18.00%)	8 / 51 (15.69%)	11 / 50 (22.00%)	3 / 32 (9.38%)
occurrences all number	25	10	25	4
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 50 (2.00%)	2 / 51 (3.92%)	4 / 50 (8.00%)	1 / 32 (3.13%)
occurrences all number	1	2	5	1
Nasopharyngitis
subjects affected / exposed	1 / 50 (2.00%)	4 / 51 (7.84%)	4 / 50 (8.00%)	0 / 32 (0.00%)
occurrences all number	1	10	6	0
Rhinitis
subjects affected / exposed	1 / 50 (2.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	1 / 32 (3.13%)
occurrences all number	1	4	3	1
Upper respiratory tract infection
subjects affected / exposed	3 / 50 (6.00%)	2 / 51 (3.92%)	1 / 50 (2.00%)	1 / 32 (3.13%)
occurrences all number	3	5	3	3
Urinary tract infection
subjects affected / exposed	0 / 50 (0.00%)	3 / 51 (5.88%)	1 / 50 (2.00%)	0 / 32 (0.00%)
occurrences all number	0	5	1	0
Viral upper respiratory tract infection
subjects affected / exposed	3 / 50 (6.00%)	1 / 51 (1.96%)	1 / 50 (2.00%)	1 / 32 (3.13%)
occurrences all number	3	1	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	11 / 50 (22.00%)	13 / 51 (25.49%)	20 / 50 (40.00%)	5 / 32 (15.63%)
occurrences all number	13	17	31	5
Dehydration
subjects affected / exposed	1 / 50 (2.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	1	2	3	0
Hyperglycaemia
subjects affected / exposed	3 / 50 (6.00%)	3 / 51 (5.88%)	4 / 50 (8.00%)	1 / 32 (3.13%)
occurrences all number	4	5	4	1
Hyperkalaemia
subjects affected / exposed	2 / 50 (4.00%)	3 / 51 (5.88%)	2 / 50 (4.00%)	1 / 32 (3.13%)
occurrences all number	2	4	3	3
Hyperuricaemia
subjects affected / exposed	2 / 50 (4.00%)	1 / 51 (1.96%)	4 / 50 (8.00%)	1 / 32 (3.13%)
occurrences all number	3	1	8	5
Hypoalbuminaemia
subjects affected / exposed	3 / 50 (6.00%)	1 / 51 (1.96%)	0 / 50 (0.00%)	0 / 32 (0.00%)
occurrences all number	4	3	0	0
Hypocalcaemia
subjects affected / exposed	1 / 50 (2.00%)	2 / 51 (3.92%)	3 / 50 (6.00%)	0 / 32 (0.00%)
occurrences all number	1	9	3	0
Hypokalaemia
subjects affected / exposed	2 / 50 (4.00%)	6 / 51 (11.76%)	5 / 50 (10.00%)	1 / 32 (3.13%)
occurrences all number	2	10	6	1
Hyponatraemia
subjects affected / exposed	0 / 50 (0.00%)	4 / 51 (7.84%)	2 / 50 (4.00%)	1 / 32 (3.13%)
occurrences all number	0	9	3	1
Hypophosphataemia
subjects affected / exposed	3 / 50 (6.00%)	4 / 51 (7.84%)	1 / 50 (2.00%)	1 / 32 (3.13%)
occurrences all number	4	5	1	2

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Were there any global substantial amendments to the protocol? Yes

19 Feb 2007

• The informed consent template: − In the Safety section: listed in detail the expected adverse events for sorafenib. − In the Alternative Therapy section: listed the alternative therapies available instead of indicating that the subject’s doctor will discuss them. • Clarified the fasting requirements for sorafenib administration. • The wording on the storage conditions for sorafenib in the Pharmacy Guide (Appendix C) was revised to improve the consistency with the approved sorafenib label. • The confidentiality language in the pharmacogenetic consent was updated.

13 Aug 2008

• Updated Informed Consent and Introduction • Clarified unblinding details • Updated and clarified inclusion/exclusion criteria (serum creatinine, hemostatic function, prior malignancies, concurrent anticoagulation therapy, surgical procedures, pancreatitis) • Revised the sorafenib toxicity management instructions to allow for potential re-escalation of the sorafenib dose, at the investigator’s discretion, in subjects who had undergone a dose reduction due to skin toxicity • Added requirement for all non-serious and serious adverse events to be collected from the time subjects signed the informed consent • Revised AMG 386/placebo pharmacokinetic and immunogenicity sample collection time points • Removed requirement that post-dose ECGs be performed in triplicate • Clarified that all ECG reports were to include the heart rate and QRS, QT, QTc, RR and PR intervals • Clarified time frames for screening safety laboratory assessments and radiological imaging • Required that baseline samples for immunogenicity, biomarker, and pharmacokinetic assessments be taken before infusion • Removed PRO Questionnaires from the screening procedures • Clarified the definition of cycles • Clarified how the dose of AMG 386 was to be calculated • Clarified that long-term follow-up radiographic assessment for subjects who discontinued treatment before disease progression would stop if subjects commence new therapy • Revised the hypothesis statement • Clarified on which CRFs deaths were to be reported and how signs and symptoms of disease progression were to be reported • Reduced the analyses performed on data subsets that were not deemed useful or relevant in this subject population • Included pairwise comparisons between treatment arms for data subsets of interest and removed closed testing procedures throughout the statistical analysis section • Added language encouraging sites to repeat confirmatory scans within 28 to 35 days after initial observation of a P

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.

None reported

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Clinical trials

Clinical Trial Results:
A Randomized, Double Blinded, Multi-Center Phase 2 Study to Estimate the Efficacy and Evaluate the Safety and Tolerability of Sorafenib in Combination With AMG 386 or Placebo in Subjects With Metastatic Clear Cell Carcinoma of the Kidney

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival

Primary: Progression-Free Survival

Secondary: Objective Response Rate

Secondary: Objective Response Rate

Secondary: Duration of response

Secondary: Duration of response

Secondary: Change in Tumor Burden

Secondary: Change in Tumor Burden

Secondary: Time-adjusted Area Under the Curve (AUC) for Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index – 15 Items (FKSI-15) Scale Score

Secondary: Time-adjusted Area Under the Curve (AUC) for Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index – 15 Items (FKSI-15) Scale Score

Secondary: Number of Subjects With Adverse Events (AE)

Secondary: Number of Subjects With Adverse Events (AE)

Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

Secondary: Number of Subjects Who Developed Anti-trebananib Antibodies Post-baseline

Secondary: Number of Subjects Who Developed Anti-trebananib Antibodies Post-baseline

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Randomized, Double Blinded, Multi-Center Phase 2 Study to Estimate the Efficacy and Evaluate the Safety and Tolerability of Sorafenib in Combination With AMG 386 or Placebo in Subjects With Metastatic Clear Cell Carcinoma of the Kidney

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival

Primary: Progression-Free Survival

Secondary: Objective Response Rate

Secondary: Objective Response Rate

Secondary: Duration of response

Secondary: Duration of response

Secondary: Change in Tumor Burden

Secondary: Change in Tumor Burden

Secondary: Time-adjusted Area Under the Curve (AUC) for Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index – 15 Items (FKSI-15) Scale Score

Secondary: Time-adjusted Area Under the Curve (AUC) for Change From Baseline in Functional Assessment of Cancer Therapy-Kidney Symptom Index – 15 Items (FKSI-15) Scale Score

Secondary: Number of Subjects With Adverse Events (AE)

Secondary: Number of Subjects With Adverse Events (AE)

Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

Secondary: Number of Subjects with Grade 3 or Higher Laboratory Toxicities

Secondary: Number of Subjects Who Developed Anti-trebananib Antibodies Post-baseline

Secondary: Number of Subjects Who Developed Anti-trebananib Antibodies Post-baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Randomized, Double Blinded, Multi-Center Phase 2 Study to Estimate the Efficacy and Evaluate the Safety and Tolerability of Sorafenib in Combination With AMG 386 or Placebo in Subjects With Metastatic Clear Cell Carcinoma of the Kidney