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Clinical Trial Results:
A Randomized, 4-Arm, Placebo-Controlled Phase 2 Trial of AMG 386 in Combination with Bevacizumab and Paclitaxel or AMG386 plus Paclitaxel as First-Line Therapy in Subjects with Her2-Negative, Metastatic or Locally Recurrent Breast Cancer

Summary
EudraCT number	2007-003384-51
Trial protocol	FR GB AT BE DK FI NL ES HU
Global end of trial date	19 May 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

Top of page

Sponsor protocol code

20060341

ISRCTN number

-

US NCT number

NCT00511459

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)

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

19 May 2014

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

19 May 2014

Was the trial ended prematurely?

No

Main objective of the trial

To estimate the treatment effect as measured by progression free survival (PFS) of subjects receiving trebananib (at two doses) in combination with paclitaxel and bevacizumab relative to paclitaxel plus bevacizumab and placebo.

Protection of trial subjects

This study was conducted in accordance with United States Food and Drug Administration (FDA) regulations/guidelines set forth in 21 Code of Federal Regulations Parts 11, 50, 54, 56, and 312 and 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

27 Jun 2007

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

48 Months

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Poland: 24

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

United Kingdom: 15

Country: Number of subjects enrolled

Austria: 11

Country: Number of subjects enrolled

Belgium: 32

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

Finland: 10

Country: Number of subjects enrolled

France: 53

Country: Number of subjects enrolled

Hungary: 1

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

India: 14

Country: Number of subjects enrolled

United States: 45

Worldwide total number of subjects

228

EEA total number of subjects

162

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

185

From 65 to 84 years

43

85 years and over

0

Subject disposition

Top of page

Recruitment details

-

Screening details

A total of 263 subjects were screened; 7 of these were rescreened, for a total of 270 screening assessments. Of these, 42 subjects failed screening and a total of 228 subjects were randomized to 1 of 4 treatment arms.

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

Blinding implementation details

Treatment arms A, B, and C were double-blinded. Treatment arm D (Open-label [OL] Trebananib 10 mg/kg + Paclitaxel) was not blinded.

Are arms mutually exclusive

Yes

Placebo + Paclitaxel + Bevacizumab

Arm description

Subjects received blinded placebo administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Arm type

Active comparator

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Administered as an intravenous infustion (IV) infusion weekly

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 90 mg/m² administered as a ≥ 1-hour IV infusion on Weeks 1, 2, and 3 of every 4-week cycle.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Avastin

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bevacizumab 10 mg/kg administered as a 90-minute IV infusion on Weeks 1 and 3 of each 4-week cycle.

Trebananib 3 mg/kg + Paclitaxel + Bevacizumab

Arm description

Subjects received blinded trebananib 3 mg/kg administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Arm type

Experimental

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

Trebananib administered by IV infusion weekly

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 90 mg/m² administered as a ≥ 1-hour IV infusion on Weeks 1, 2, and 3 of every 4-week cycle.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Avastin

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bevacizumab 10 mg/kg administered as a 90-minute IV infusion on Weeks 1 and 3 of each 4-week cycle.

Trebananib 10 mg/kg + Paclitaxel + Bevacizumab

Arm description

Subjects received blinded trebananib 10 mg/kg administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Arm type

Experimental

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

Trebananib administered by IV infusion weekly

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 90 mg/m² administered as a ≥ 1-hour IV infusion on Weeks 1, 2, and 3 of every 4-week cycle.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Avastin

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Bevacizumab 10 mg/kg administered as a 90-minute IV infusion on Weeks 1 and 3 of each 4-week cycle.

OL Trebananib 10 mg/kg + Paclitaxel

Arm description

Subjects received open-label (OL) trebananib 10 mg/kg administered as an IV infusion weekly and paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Arm type

Experimental

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

Trebananib administered by IV infusion weekly

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 90 mg/m² administered as a ≥ 1-hour IV infusion on Weeks 1, 2, and 3 of every 4-week cycle.

Number of subjects in period 1	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Started	58	57	56	57
Received study drug	58	57	55	56
Completed	58	57	55	56
Not completed	0	0	1	1
Did not receive study drug	-	-	1	1

Baseline characteristics

Top of page

Reporting group title

Placebo + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded placebo administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

Trebananib 3 mg/kg + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded trebananib 3 mg/kg administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

Trebananib 10 mg/kg + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded trebananib 10 mg/kg administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

OL Trebananib 10 mg/kg + Paclitaxel

Reporting group description

Subjects received open-label (OL) trebananib 10 mg/kg administered as an IV infusion weekly and paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel	Total
Number of subjects	58	57	56	57	228
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	51.4 ± 11.1	56.2 ± 10.6	55.1 ± 10.5	52.9 ± 11.8	-
Gender categorical
Units: Subjects
Female	58	57	56	57	228
Male	0	0	0	0	0
Race
Units: Subjects
White or Caucasian	48	55	45	52	200
Black or African American	2	0	1	1	4
Hispanic or Latino	1	0	2	0	3
Asian	6	2	7	4	19
Other	1	0	1	0	2
Extent of Disease
Units: Subjects
≤ 3 metastatic sites	48	47	47	44	186
≥ 3 metastatic sites	10	10	9	13	42
Prior Adjuvant Taxane Exposure
Units: Subjects
Yes	14	15	14	14	57
No	44	42	42	43	171

End points

Top of page

Reporting group title

Placebo + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded placebo administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

Trebananib 3 mg/kg + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded trebananib 3 mg/kg administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

Trebananib 10 mg/kg + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded trebananib 10 mg/kg administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

OL Trebananib 10 mg/kg + Paclitaxel

Reporting group description

Subjects received open-label (OL) trebananib 10 mg/kg administered as an IV infusion weekly and paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Primary: Progression-free Survival

Top of page

End point title

Progression-free Survival

End point description

The time from the randomization date to the date of disease progression per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria assessed by the investigator or death from any cause. Progression-free survival was analyzed using the Kaplan-Meier method. Subjects not meeting the criteria for disease progression by the data cutoff date were censored at the last evaluable disease assessment date.

End point type

Primary

End point timeframe

Radiological assessments were performed every 8 weeks throughout the treatment period. Data are reported as of the cut-off date of 22 March 2013; median time on study was 118 weeks.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	58	57	56	57
Units: months
median (confidence interval 80%)	12.7 (10.8 to 14.6)	9.2 (7.1 to 12.9)	12.8 (10.9 to 14.5)	8.6 (7.5 to 12.8)

Blinded Trebananib Combined Versus Placebo

Statistical analysis description

A Cox regression model stratified by adjuvant taxane exposure (yes or no) and number of metastatic sites (≤ 3 or > 3) was used to estimate the hazard ratio and 2-sided 80% confience intervals (CI) for both blinded trebananib + paclitaxel + bevacizumab dose groups combined versus placebo + paclitaxel + bevacizumab. 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 + Paclitaxel + Bevacizumab v Placebo + Paclitaxel + Bevacizumab v Trebananib 10 mg/kg + Paclitaxel + Bevacizumab

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.532

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.118

Confidence interval

level

80%

sides

2-sided

lower limit

0.889

upper limit

1.407

Secondary: Objective Response Rate

Top of page

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. The analysis of ORR was conducted on the Evaluable for Tumor Response analysis set consist of all subjects in the ITT analysis set with at least 1 unidimensionally measurable lesion at baseline per modified RECIST v 1.0.

End point type

Secondary

End point timeframe

Radiological assessments were performed every 8 weeks throughout the treatment period. Data are reported as of the cut-off date of 22 March 2013; median time on study was 118 weeks.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	42	49	41	46
Units: percentage of subjects
number (confidence interval 80%)	59.5 (48.5 to 69.9)	49 (39 to 59)	70.7 (59.8 to 80.1)	45.7 (35.5 to 56.1)

Trebananib Combined vs Placebo Response Rates

Statistical analysis description

Wilson’s score method with continuity correction was used to calculate 80% confidence intervals for the difference in response rates between both trebananib + paclitaxel + bevacizumab dose groups combined and the placebo + paclitaxel + bevacizumab group.

Comparison groups

Placebo + Paclitaxel + Bevacizumab v Trebananib 3 mg/kg + Paclitaxel + Bevacizumab v Trebananib 10 mg/kg + Paclitaxel + Bevacizumab

Number of subjects included in analysis

132

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in response rates

Point estimate

-0.6

Confidence interval

level

80%

sides

2-sided

lower limit

-13.2

upper limit

12.4

Secondary: Duration of Response

Top of page

End point title

Duration of Response

End point description

Calculated only for those subjects with an objective response as the time from the first objective response (subsequently confirmed within no less than 4 weeks) to first observed disease progression per modified-RECIST criteria or death due to any cause. Subjects not meeting these criteria by the analysis data cutoff date were censored at their last evaluable disease assessment date. Duration of response was analyzed using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

Radiological assessments were performed every 8 weeks throughout the treatment period. Data are reported as of the primary analysis cut-off date of 17 May 2010; median time on study was 66 weeks.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	25	25	29	21
Units: months
median (confidence interval 80%)	9 (7.4 to 9.4)	11 (7.4 to 11.2)	9.6 (7.9 to 11.2)	7.4 (6 to 12.9)

No statistical analyses for this end point

Secondary: Overall Survival

Top of page

End point title

Overall Survival

End point description

Time from the randomization date to the date of death from any cause. Subjects who had not died by the analysis data cutoff date were censored at their last contact date. Overall survival was analyzed using the Kaplan-Meier method.

End point type

Secondary

End point timeframe

Data are reported as of the cut-off date of 22 March 2013; median time on study was 118 weeks.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	58	57	56	57
Units: months
median (confidence interval 80%)	35.1 (25 to 37.3)	27.1 (24.2 to 35.1)	28.5 (24.5 to 32.3)	30.7 (25.1 to 34.9)

Blinded Trebananib Combined Versus Placebo

Statistical analysis description

A Cox regression model stratified by adjuvant taxane exposure (yes or no) and number of metastatic sites (≤ 3 or > 3) was used to estimate the hazard ratio and 2-sided 80% confience intervals (CI) for both blinded trebananib + paclitaxel + bevacizumab dose groups combined versus placebo + paclitaxel + bevacizumab. 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

Placebo + Paclitaxel + Bevacizumab v Trebananib 3 mg/kg + Paclitaxel + Bevacizumab v Trebananib 10 mg/kg + Paclitaxel + Bevacizumab

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.81

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

1.046

Confidence interval

level

80%

sides

2-sided

lower limit

0.823

upper limit

1.33

Secondary: Time to Response

Top of page

End point title

Time to Response

End point description

Time from randomization date to first objective response (subsequently confirmed within no less than 4 weeks); subjects with a best response of Stable Disease (SD) at their last evaluable assessment date were censored at this date and subjects with all other categories of best response while on study were censored at the maximum observed time to a first confirmed response among all responders. Time to reponse was analyzed using the Kaplan-Meier method for subjects with a confirmed objective response.

End point type

Secondary

End point timeframe

Radiological assessments were performed every 8 weeks throughout the treatment period. Data are reported as of the primary analysis cut-off date of 17 May 2010; median time on study was 66 weeks.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	25	25	29	21
Units: weeks
median (inter-quartile range (Q1-Q3))	8.7 (7.6 to 15.9)	8.1 (7.7 to 17)	8 (7.6 to 15.1)	15.3 (7.6 to 16.4)

No statistical analyses for this end point

Secondary: Change in Tumor Burden

Top of page

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 performed every 8 weeks throughout the treatment period. Data are reported as of the primary analysis cut-off date of 17 May 2010; median time on study was 66 weeks.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	40 ^[1]	44 ^[2]	40 ^[3]	41 ^[4]
Units: percent reduction
median (inter-quartile range (Q1-Q3))	-50.3 (-66.3 to -28.2)	-49.1 (-65.5 to -22.3)	-52 (-76.8 to -34.1)	-41.1 (-59.5 to -16.4)

Notes
[1] - Subjects with available data
[2] - Subjects with available data
[3] - Subjects with available data
[4] - Subjects with available data

No statistical analyses for this end point

Secondary: Number of Subjects With Adverse Events

Top of page

End point title

Number of Subjects With Adverse Events

End point description

Related, trebananib-related, paclitaxel-related, and bevacizumab-related adverse events are those events for which the investigator considered there to be a reasonable possibility that the event may have been caused by the study treatment, trebananib, paclitaxel, or bevacizumab respectively. The intensity of each adverse event was 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/placebo treatment was 9.0, 6.0, 9.0 and 8.0 months in each treatment group respectively.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	58 ^[5]	57 ^[6]	55 ^[7]	56 ^[8]
Units: subjects
Any adverse event (AE)	58	57	55	56
Worst grade of 3	37	35	40	30
Worst grade of 4	9	8	4	3
Worst grade of 5	1	3	1	4
Serious adverse event (SAE)	21	24	13	18
Leading to discontinuation from therapy or study	9	12	9	3
Any treatment-related adverse event	57	57	52	51
Treatment-related worst grade of 3	30	29	37	23
Treatment-related worst grade of 4	10	7	3	3
Treatment-related worst grade of 5	0	2	0	0
Serious treatment-related AE	12	13	8	6
Treatment-related leading to discontinuation	5	11	7	0

Notes
[5] - All randomized subjects who received at least 1 dose of trebananib or paclitaxel or bevacizumab.
[6] - All randomized subjects who received at least 1 dose of trebananib or paclitaxel or bevacizumab.
[7] - All randomized subjects who received at least 1 dose of trebananib or paclitaxel or bevacizumab.
[8] - All randomized subjects who received at least 1 dose of trebananib or paclitaxel.

No statistical analyses for this end point

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

Top of page

End point title

Number of Subjects with Grade 3 or Higher Laboratory Toxicities

End point description

Textbook laboratory ranges were utilized to determine National Cancer Institute Common Toxicity Criteria version 3.0 (CTC) grades.

End point type

Secondary

End point timeframe

From first dose of study treatment until the last dose, until the data cut-off date of 22 March 2013.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	58	57	55	56
Units: subjects
Alanine amino transferase increased	3	2	0	1
Albumin decreased	0	0	0	1
Alkaline phosphatase increased	0	2	3	1
Aspartate amino transferase increased	2	3	2	2
Calcium decreased	0	0	3	0
Glucose increased	3	0	4	2
Glucose decreased	1	0	0	0
Magnesium increased	1	1	1	2
Magnesium decreased	1	1	0	0
Phosphorus decreased	3	3	0	2
Potassium increased	1	0	2	1
Potassium decreased	1	0	3	1
Sodium decreased	0	2	1	1
Hemoglobin decreased	0	0	1	2
International normalized ratio increased	1	0	1	0
Lymphocytes decreased	18	12	9	10
Partial thromboplastin time increased	2	5	1	3
Platelets decreased	1	1	1	1
Segmented neutrophils decreased	2	0	0	2
Total neutrophils decreased	13	8	14	11
White blood cells decreased	17	12	9	11

No statistical analyses for this end point

Secondary: Number of Trebananib/Placebo, Paclitaxel and/or Bevacizumab Cycles Administered

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End point title

Number of Trebananib/Placebo, Paclitaxel and/or Bevacizumab Cycles Administered

End point description

Two subjects randomized to open label trebananib arm received at least one dose of bevacizumab due to dosing error.

End point type

Secondary

End point timeframe

Up until the cut-off date date of 22 March 2013.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	58	57	55	56
Units: cycles
median (inter-quartile range (Q1-Q3))
Trebananib / Placebo	9 (5 to 13)	6 (4 to 13)	9 (6 to 16)	8 (5 to 14)
Paclitaxel	6 (5 to 9)	6 (4 to 7)	6 (4 to 9)	6 (5 to 8)
Bevacizumab	8.5 (5 to 14)	6 (4 to 13)	9 (5 to 16)	2.5 (2 to 3)

No statistical analyses for this end point

Secondary: Number of Subjects with Trebananib/Placebo, Paclitaxel and/or Bevacizumab Dose Modifications

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End point title

Number of Subjects with Trebananib/Placebo, Paclitaxel and/or Bevacizumab Dose Modifications

End point description

If a subject developed a ≥ grade 3 (per CTCAE, version 3.0) toxicity considered to be related to trebananib, placebo, paclitaxel or bevacizumab, then trebananib, placebo paclitaxel or bevacizumab was to be held until the toxicity resolved. One permanent dose reduction of paclitaxel to 65 mg/m² was permitted. No dose level reductions for trebananib, placebo or bevacizumab were permitted. Two subjects randomized to open label trebananib arm received at least one dose of bevacizumab due to dosing error.

End point type

Secondary

End point timeframe

Up until the data cut-off date of 22 March 2013

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	58	57	55	56
Units: subjects
Trebananib / placebo dose withholdings	49	39	47	44
Paclitaxel dose withholdings	49	43	44	46
Paclitaxel dose reductions	35	33	30	29
Bevacizumab dose withholdings	46	37	39	2

No statistical analyses for this end point

Secondary: Steady-State Maximum and Minimum Observed Concentration of Trebaninib

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End point title

Steady-State Maximum and Minimum Observed Concentration of Trebaninib ^[9]

End point description

Steady-state serum concentration of trebaninib was measured at the end of infusion (maximum observed serum concentration [Cmax]) at Weeks 5 and 15; and predose (minimum observed serum concentration [Cmin], ie, prior to AMG 386 or placebo, bevacizumab, and paclitaxel infusion) on Weeks 5, 9, and 15. Serum concentration was measured using a validated enzyme-linked immunosorbent (ELISA) assay; The lower limit of quantification (LLOQ) of the serum assay was 20 ng/mL. Only samples collected at the protocol-specified dose regimen were included, and concentrations that were below the LLOQ were set to 0.

End point type

Secondary

End point timeframe

Weeks 5, 9, and 15

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Observed Concentration of Trebaninib was assessed in the Trebaninib treatment groups only.

End point values	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	46	45	40
Units: μg/mL
median (full range (min-max))
Cmax at Week 5 (N=44, 43, 40)	79 (52.2 to 167)	260 (65.2 to 809)	270 (125 to 376)
Cmax at Week 15 (N=23, 20, 17)	90.7 (50.5 to 139)	296 (107 to 387)	294 (122 to 471)
Cmin at Week 5 (N=46, 49, 38)	3.99 (1.5 to 17.7)	14.4 (1.63 to 43)	13.8 (0.808 to 30.1)
Cmin at Week 9 (N=44, 45, 37)	4.04 (1.73 to 19.3)	14.6 (0.613 to 81.8)	14.6 (0.998 to 40.8)
Cmin at Week 15 (N=36, 33, 28)	4.2 (1.38 to 22.6)	15.2 (6.43 to 34.7)	18 (2.18 to 40.3)

No statistical analyses for this end point

Secondary: Steady-State Maximum and Minimum Observed Concentration of Bevacizumab

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End point title

Steady-State Maximum and Minimum Observed Concentration of Bevacizumab ^[10]

End point description

Steady-state bevacizumab concentration was measured at the end of infusion (maximum observed serum concentration [Cmax]) on Weeks 5, and 15; and predose (minimum observed serum concentration [Cmin], ie, prior to AMG 386 or placebo, bevacizumab, and paclitaxel infusion) at Week 15. Serum bevacizumab samples were not measured in subjects receiving open-label trebaninib. Bevacizumab concentration was measured using a validated indirect ELISA; the LLOQ of the serum assay was 19.5 ng/mL.

End point type

Secondary

End point timeframe

Weeks 5, 9 and 15

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Observed Concentration of Bevacizumab was assessed in the Bevacizumab treatment groups only.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab
Number of subjects analysed	25	24	26
Units: µg/mL
median (full range (min-max))
Cmax at Week 15 (N=18, 24, 19)	491 (232 to 727)	545 (327 to 785)	525 (93.6 to 901)
Cmin at Week 15 (N=25, 24, 26)	218 (79.7 to 428)	200 (98.5 to 310)	193 (81.7 to 434)

No statistical analyses for this end point

Secondary: Number of Subjects Who Developed Antibodies to Trebaninib Post-Baseline

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End point title

Number of Subjects Who Developed Antibodies to Trebaninib Post-Baseline

End point description

Samples were first tested in a validated electrochemiluminescent (ECL) immunoassay to detect and confirm the presence of antibodies capable of binding to trebaninib. Samples that were positive in the immunoassay were then further tested in a validated ECL receptor-binding assay to measure 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

Week 1, Week 5, Week 9, Week 23 and every 16 weeks thereafter until the data cut-off date of 22 March 2013.

End point values	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg + Paclitaxel
Number of subjects analysed	56 ^[11]	55 ^[12]	52 ^[13]	49 ^[14]
Units: subjects
Binding antibody positive	1	6	2	5
Neutralizing antibody positive	0	0	0	0

Notes
[11] - Subjects with at least one post-baseline immunoassay result
[12] - Subjects with at least one post-baseline immunoassay result
[13] - Subjects with at least one post-baseline immunoassay result
[14] - Subjects with at least one post-baseline immunoassay 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Placebo + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded placebo administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

Trebananib 3 mg/kg + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded trebananib 3 mg/kg administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

Trebananib 10 mg/kg + Paclitaxel + Bevacizumab

Reporting group description

Subjects received blinded trebananib 10 mg/kg administered as an IV infusion weekly, paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle and bevacizumab 10 mg/kg IV on Weeks 1 and 3 of each 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Reporting group title

OL Trebananib 10 mg/kg QW + Paclitaxel

Reporting group description

Subjects received open-label (OL) trebananib 10 mg/kg administered as an IV infusion weekly and paclitaxel 90 mg/m² IV infusion on Weeks 1, 2, and 3 of every 4-week cycle continuing until disease progression, clinical progression, unacceptable toxicity, withdrawal of subject consent, or death.

Serious adverse events	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg QW + Paclitaxel
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 58 (36.21%)	24 / 57 (42.11%)	13 / 55 (23.64%)	18 / 56 (32.14%)
number of deaths (all causes)	46	40	42	35
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BREAST CANCER
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
BREAST NEOPLASM
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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 / 1	0 / 0
MALIGNANT PLEURAL EFFUSION
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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 EYE
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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 MENINGES
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
Vascular disorders
DEEP VEIN THROMBOSIS
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
JUGULAR VEIN THROMBOSIS
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
VENOUS THROMBOSIS
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
General disorders and administration site conditions
CHEST PAIN
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 56 (1.79%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
CHILLS
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
DEVICE DISLOCATION
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
FATIGUE
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
FEELING OF BODY TEMPERATURE CHANGE
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
IMPAIRED HEALING
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
INFLUENZA LIKE ILLNESS
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
LOCAL SWELLING
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
PAIN
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
PYREXIA
subjects affected / exposed	3 / 58 (5.17%)	0 / 57 (0.00%)	1 / 55 (1.82%)	2 / 56 (3.57%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
HYPERSENSITIVITY
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
DYSPNOEA
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	1 / 55 (1.82%)	1 / 56 (1.79%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
DYSPNOEA EXERTIONAL
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
EPISTAXIS
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
HAEMOPTYSIS
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
LUNG INFILTRATION
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
NASAL SEPTUM PERFORATION
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
PNEUMOTHORAX
subjects affected / exposed	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY DISTRESS
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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 / 1	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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 / 1	0 / 0	0 / 0
Psychiatric disorders
DEPRESSION
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
SUICIDAL IDEATION
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
Injury, poisoning and procedural complications
ANKLE FRACTURE
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
FEMORAL NECK FRACTURE
subjects affected / exposed	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
JOINT DISLOCATION
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
RIB FRACTURE
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
Cardiac disorders
ATRIOVENTRICULAR BLOCK SECOND DEGREE
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
BRADYCARDIA
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
CARDIOMYOPATHY
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
LEFT VENTRICULAR DYSFUNCTION
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
MITRAL VALVE INCOMPETENCE
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
EPILEPSY
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
HEADACHE
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
MENINGEAL DISORDER
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
PARESIS
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
SPEECH DISORDER
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
FEBRILE NEUTROPENIA
subjects affected / exposed	2 / 58 (3.45%)	0 / 57 (0.00%)	1 / 55 (1.82%)	1 / 56 (1.79%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	2 / 58 (3.45%)	2 / 57 (3.51%)	0 / 55 (0.00%)	4 / 56 (7.14%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
ASCITES
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
DIARRHOEA
subjects affected / exposed	1 / 58 (1.72%)	2 / 57 (3.51%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL PERFORATION
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
ILEUS
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
NAUSEA
subjects affected / exposed	1 / 58 (1.72%)	2 / 57 (3.51%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PANCREATITIS
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
RECTAL HAEMORRHAGE
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
VOMITING
subjects affected / exposed	0 / 58 (0.00%)	3 / 57 (5.26%)	2 / 55 (3.64%)	0 / 56 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLECYSTITIS
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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 ACUTE
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
HEPATIC FUNCTION ABNORMAL
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
Skin and subcutaneous tissue disorders
DERMATITIS
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
RASH
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
SUBCUTANEOUS EMPHYSEMA
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
BACK PAIN
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
BONE PAIN
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
MUSCLE SPASMS
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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 CHEST PAIN
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
NECK PAIN
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
OSTEONECROSIS
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
PAIN IN EXTREMITY
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
PATHOLOGICAL FRACTURE
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
Infections and infestations
ASPERGILLUS INFECTION
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
BRONCHOPNEUMONIA
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
CATHETER SITE INFECTION
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
CELLULITIS
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
DEVICE RELATED INFECTION
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
DEVICE RELATED SEPSIS
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
GASTROENTERITIS
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
HERPES ZOSTER
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
INFECTION
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	2 / 56 (3.57%)
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
LOBAR PNEUMONIA
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
NAIL INFECTION
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (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
SEPSIS
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	2 / 56 (3.57%)
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 / 2
SKIN INFECTION
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (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
URINARY TRACT INFECTION
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
DECREASED APPETITE
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
DEHYDRATION
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (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
FLUID RETENTION
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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
HYPOCALCAEMIA
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 56 (1.79%)
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

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

Non-serious adverse events	Placebo + Paclitaxel + Bevacizumab	Trebananib 3 mg/kg + Paclitaxel + Bevacizumab	Trebananib 10 mg/kg + Paclitaxel + Bevacizumab	OL Trebananib 10 mg/kg QW + Paclitaxel
Total subjects affected by non serious adverse events
subjects affected / exposed	56 / 58 (96.55%)	57 / 57 (100.00%)	54 / 55 (98.18%)	54 / 56 (96.43%)
Vascular disorders
DEEP VEIN THROMBOSIS
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	3 / 55 (5.45%)	0 / 56 (0.00%)
occurrences all number	0	0	3	0
FLUSHING
subjects affected / exposed	4 / 58 (6.90%)	3 / 57 (5.26%)	4 / 55 (7.27%)	3 / 56 (5.36%)
occurrences all number	23	8	30	3
HOT FLUSH
subjects affected / exposed	12 / 58 (20.69%)	3 / 57 (5.26%)	5 / 55 (9.09%)	9 / 56 (16.07%)
occurrences all number	20	7	8	14
HYPERTENSION
subjects affected / exposed	22 / 58 (37.93%)	22 / 57 (38.60%)	24 / 55 (43.64%)	8 / 56 (14.29%)
occurrences all number	42	33	42	8
HYPOTENSION
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	0 / 55 (0.00%)	4 / 56 (7.14%)
occurrences all number	1	1	0	4
LYMPHOEDEMA
subjects affected / exposed	4 / 58 (6.90%)	7 / 57 (12.28%)	8 / 55 (14.55%)	9 / 56 (16.07%)
occurrences all number	5	9	10	10
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	19 / 58 (32.76%)	19 / 57 (33.33%)	17 / 55 (30.91%)	23 / 56 (41.07%)
occurrences all number	87	74	76	95
CATHETER SITE PAIN
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	3 / 55 (5.45%)	2 / 56 (3.57%)
occurrences all number	1	0	3	3
CHEST DISCOMFORT
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	4 / 55 (7.27%)	1 / 56 (1.79%)
occurrences all number	1	1	5	1
CHEST PAIN
subjects affected / exposed	5 / 58 (8.62%)	4 / 57 (7.02%)	3 / 55 (5.45%)	12 / 56 (21.43%)
occurrences all number	5	5	6	22
FACE OEDEMA
subjects affected / exposed	0 / 58 (0.00%)	3 / 57 (5.26%)	6 / 55 (10.91%)	7 / 56 (12.50%)
occurrences all number	0	5	6	12
FATIGUE
subjects affected / exposed	22 / 58 (37.93%)	33 / 57 (57.89%)	27 / 55 (49.09%)	15 / 56 (26.79%)
occurrences all number	40	67	44	29
GAIT DISTURBANCE
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	2 / 55 (3.64%)	1 / 56 (1.79%)
occurrences all number	3	1	2	1
GENERALISED OEDEMA
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 55 (1.82%)	4 / 56 (7.14%)
occurrences all number	1	0	2	4
INFLUENZA LIKE ILLNESS
subjects affected / exposed	4 / 58 (6.90%)	1 / 57 (1.75%)	4 / 55 (7.27%)	4 / 56 (7.14%)
occurrences all number	5	1	4	4
MUCOSAL INFLAMMATION
subjects affected / exposed	13 / 58 (22.41%)	11 / 57 (19.30%)	9 / 55 (16.36%)	2 / 56 (3.57%)
occurrences all number	21	20	14	2
OEDEMA PERIPHERAL
subjects affected / exposed	11 / 58 (18.97%)	26 / 57 (45.61%)	18 / 55 (32.73%)	30 / 56 (53.57%)
occurrences all number	26	55	37	72
PAIN
subjects affected / exposed	9 / 58 (15.52%)	6 / 57 (10.53%)	2 / 55 (3.64%)	5 / 56 (8.93%)
occurrences all number	11	6	3	5
PYREXIA
subjects affected / exposed	11 / 58 (18.97%)	9 / 57 (15.79%)	14 / 55 (25.45%)	10 / 56 (17.86%)
occurrences all number	19	12	22	18
Immune system disorders
DRUG HYPERSENSITIVITY
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences all number	3	1	2	0
HYPERSENSITIVITY
subjects affected / exposed	1 / 58 (1.72%)	3 / 57 (5.26%)	4 / 55 (7.27%)	1 / 56 (1.79%)
occurrences all number	2	3	5	1
Reproductive system and breast disorders
VULVOVAGINAL DRYNESS
subjects affected / exposed	0 / 58 (0.00%)	3 / 57 (5.26%)	0 / 55 (0.00%)	1 / 56 (1.79%)
occurrences all number	0	3	0	1
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	20 / 58 (34.48%)	15 / 57 (26.32%)	18 / 55 (32.73%)	18 / 56 (32.14%)
occurrences all number	40	23	36	29
DYSPHONIA
subjects affected / exposed	19 / 58 (32.76%)	8 / 57 (14.04%)	11 / 55 (20.00%)	3 / 56 (5.36%)
occurrences all number	37	10	13	4
DYSPNOEA
subjects affected / exposed	11 / 58 (18.97%)	11 / 57 (19.30%)	12 / 55 (21.82%)	11 / 56 (19.64%)
occurrences all number	20	22	23	20
DYSPNOEA EXERTIONAL
subjects affected / exposed	6 / 58 (10.34%)	3 / 57 (5.26%)	4 / 55 (7.27%)	1 / 56 (1.79%)
occurrences all number	10	5	5	1
EPISTAXIS
subjects affected / exposed	29 / 58 (50.00%)	35 / 57 (61.40%)	25 / 55 (45.45%)	10 / 56 (17.86%)
occurrences all number	55	53	44	16
NASAL DRYNESS
subjects affected / exposed	5 / 58 (8.62%)	4 / 57 (7.02%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences all number	5	5	1	0
OROPHARYNGEAL PAIN
subjects affected / exposed	11 / 58 (18.97%)	11 / 57 (19.30%)	6 / 55 (10.91%)	3 / 56 (5.36%)
occurrences all number	17	14	10	5
PLEURAL EFFUSION
subjects affected / exposed	0 / 58 (0.00%)	4 / 57 (7.02%)	3 / 55 (5.45%)	5 / 56 (8.93%)
occurrences all number	0	4	4	6
PRODUCTIVE COUGH
subjects affected / exposed	2 / 58 (3.45%)	2 / 57 (3.51%)	2 / 55 (3.64%)	3 / 56 (5.36%)
occurrences all number	2	2	2	3
RHINORRHOEA
subjects affected / exposed	6 / 58 (10.34%)	6 / 57 (10.53%)	10 / 55 (18.18%)	4 / 56 (7.14%)
occurrences all number	10	6	13	5
Psychiatric disorders
ANXIETY
subjects affected / exposed	6 / 58 (10.34%)	4 / 57 (7.02%)	6 / 55 (10.91%)	2 / 56 (3.57%)
occurrences all number	7	7	6	2
DEPRESSION
subjects affected / exposed	2 / 58 (3.45%)	4 / 57 (7.02%)	5 / 55 (9.09%)	4 / 56 (7.14%)
occurrences all number	2	5	5	7
INSOMNIA
subjects affected / exposed	10 / 58 (17.24%)	8 / 57 (14.04%)	9 / 55 (16.36%)	12 / 56 (21.43%)
occurrences all number	13	10	10	17
SLEEP DISORDER
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	1 / 55 (1.82%)	3 / 56 (5.36%)
occurrences all number	8	1	1	4
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	2 / 58 (3.45%)	4 / 57 (7.02%)	3 / 55 (5.45%)	1 / 56 (1.79%)
occurrences all number	2	7	4	3
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	3 / 58 (5.17%)	4 / 57 (7.02%)	2 / 55 (3.64%)	1 / 56 (1.79%)
occurrences all number	3	9	2	2
NEUTROPHIL COUNT DECREASED
subjects affected / exposed	0 / 58 (0.00%)	2 / 57 (3.51%)	4 / 55 (7.27%)	1 / 56 (1.79%)
occurrences all number	0	3	9	4
WEIGHT DECREASED
subjects affected / exposed	5 / 58 (8.62%)	6 / 57 (10.53%)	4 / 55 (7.27%)	1 / 56 (1.79%)
occurrences all number	8	12	13	3
WEIGHT INCREASED
subjects affected / exposed	1 / 58 (1.72%)	2 / 57 (3.51%)	3 / 55 (5.45%)	4 / 56 (7.14%)
occurrences all number	2	3	5	5
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	4 / 58 (6.90%)	0 / 57 (0.00%)	2 / 55 (3.64%)	2 / 56 (3.57%)
occurrences all number	8	0	6	5
Cardiac disorders
PALPITATIONS
subjects affected / exposed	3 / 58 (5.17%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences all number	3	0	1	0
TACHYCARDIA
subjects affected / exposed	1 / 58 (1.72%)	3 / 57 (5.26%)	3 / 55 (5.45%)	2 / 56 (3.57%)
occurrences all number	1	3	3	2
Nervous system disorders
DIZZINESS
subjects affected / exposed	5 / 58 (8.62%)	11 / 57 (19.30%)	8 / 55 (14.55%)	6 / 56 (10.71%)
occurrences all number	6	14	11	11
DYSAESTHESIA
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	2 / 55 (3.64%)	3 / 56 (5.36%)
occurrences all number	3	1	4	4
DYSGEUSIA
subjects affected / exposed	18 / 58 (31.03%)	10 / 57 (17.54%)	17 / 55 (30.91%)	10 / 56 (17.86%)
occurrences all number	34	15	23	13
HEADACHE
subjects affected / exposed	27 / 58 (46.55%)	24 / 57 (42.11%)	16 / 55 (29.09%)	17 / 56 (30.36%)
occurrences all number	88	48	43	42
HYPOAESTHESIA
subjects affected / exposed	5 / 58 (8.62%)	4 / 57 (7.02%)	4 / 55 (7.27%)	4 / 56 (7.14%)
occurrences all number	6	5	4	7
MEMORY IMPAIRMENT
subjects affected / exposed	4 / 58 (6.90%)	0 / 57 (0.00%)	2 / 55 (3.64%)	0 / 56 (0.00%)
occurrences all number	4	0	2	0
NEUROPATHY PERIPHERAL
subjects affected / exposed	16 / 58 (27.59%)	23 / 57 (40.35%)	19 / 55 (34.55%)	21 / 56 (37.50%)
occurrences all number	49	61	68	46
PARAESTHESIA
subjects affected / exposed	8 / 58 (13.79%)	10 / 57 (17.54%)	11 / 55 (20.00%)	9 / 56 (16.07%)
occurrences all number	17	19	33	26
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	10 / 58 (17.24%)	12 / 57 (21.05%)	11 / 55 (20.00%)	11 / 56 (19.64%)
occurrences all number	24	36	28	26
POLYNEUROPATHY
subjects affected / exposed	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 55 (0.00%)	3 / 56 (5.36%)
occurrences all number	3	0	0	5
SCIATICA
subjects affected / exposed	4 / 58 (6.90%)	2 / 57 (3.51%)	3 / 55 (5.45%)	1 / 56 (1.79%)
occurrences all number	4	2	5	1
SPEECH DISORDER
subjects affected / exposed	0 / 58 (0.00%)	3 / 57 (5.26%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences all number	0	3	0	0
SYNCOPE
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	1 / 55 (1.82%)	5 / 56 (8.93%)
occurrences all number	0	1	1	5
TREMOR
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	5 / 55 (9.09%)	0 / 56 (0.00%)
occurrences all number	0	1	5	0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	5 / 58 (8.62%)	5 / 57 (8.77%)	4 / 55 (7.27%)	8 / 56 (14.29%)
occurrences all number	22	7	17	8
LEUKOPENIA
subjects affected / exposed	4 / 58 (6.90%)	3 / 57 (5.26%)	4 / 55 (7.27%)	5 / 56 (8.93%)
occurrences all number	35	6	8	9
NEUTROPENIA
subjects affected / exposed	24 / 58 (41.38%)	23 / 57 (40.35%)	19 / 55 (34.55%)	17 / 56 (30.36%)
occurrences all number	135	61	82	31
Ear and labyrinth disorders
EAR PAIN
subjects affected / exposed	3 / 58 (5.17%)	2 / 57 (3.51%)	2 / 55 (3.64%)	1 / 56 (1.79%)
occurrences all number	3	2	3	1
TINNITUS
subjects affected / exposed	3 / 58 (5.17%)	2 / 57 (3.51%)	0 / 55 (0.00%)	1 / 56 (1.79%)
occurrences all number	3	3	0	1
VERTIGO
subjects affected / exposed	3 / 58 (5.17%)	10 / 57 (17.54%)	2 / 55 (3.64%)	3 / 56 (5.36%)
occurrences all number	4	13	2	6
Eye disorders
DRY EYE
subjects affected / exposed	4 / 58 (6.90%)	1 / 57 (1.75%)	2 / 55 (3.64%)	1 / 56 (1.79%)
occurrences all number	4	1	3	1
EYELID OEDEMA
subjects affected / exposed	0 / 58 (0.00%)	2 / 57 (3.51%)	2 / 55 (3.64%)	6 / 56 (10.71%)
occurrences all number	0	2	2	8
LACRIMATION INCREASED
subjects affected / exposed	5 / 58 (8.62%)	5 / 57 (8.77%)	5 / 55 (9.09%)	6 / 56 (10.71%)
occurrences all number	6	7	5	8
VISION BLURRED
subjects affected / exposed	1 / 58 (1.72%)	3 / 57 (5.26%)	4 / 55 (7.27%)	0 / 56 (0.00%)
occurrences all number	1	3	4	0
VISUAL ACUITY REDUCED
subjects affected / exposed	3 / 58 (5.17%)	2 / 57 (3.51%)	1 / 55 (1.82%)	1 / 56 (1.79%)
occurrences all number	3	2	1	1
VISUAL IMPAIRMENT
subjects affected / exposed	2 / 58 (3.45%)	4 / 57 (7.02%)	2 / 55 (3.64%)	0 / 56 (0.00%)
occurrences all number	3	4	7	0
Gastrointestinal disorders
ABDOMINAL DISTENSION
subjects affected / exposed	1 / 58 (1.72%)	7 / 57 (12.28%)	5 / 55 (9.09%)	2 / 56 (3.57%)
occurrences all number	1	9	5	2
ABDOMINAL PAIN
subjects affected / exposed	15 / 58 (25.86%)	13 / 57 (22.81%)	14 / 55 (25.45%)	12 / 56 (21.43%)
occurrences all number	36	17	28	14
ABDOMINAL PAIN UPPER
subjects affected / exposed	13 / 58 (22.41%)	11 / 57 (19.30%)	8 / 55 (14.55%)	6 / 56 (10.71%)
occurrences all number	19	12	17	15
CONSTIPATION
subjects affected / exposed	22 / 58 (37.93%)	24 / 57 (42.11%)	14 / 55 (25.45%)	13 / 56 (23.21%)
occurrences all number	36	31	25	19
DENTAL CARIES
subjects affected / exposed	3 / 58 (5.17%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences all number	4	0	0	0
DIARRHOEA
subjects affected / exposed	35 / 58 (60.34%)	31 / 57 (54.39%)	27 / 55 (49.09%)	18 / 56 (32.14%)
occurrences all number	83	59	57	39
DRY MOUTH
subjects affected / exposed	5 / 58 (8.62%)	4 / 57 (7.02%)	6 / 55 (10.91%)	2 / 56 (3.57%)
occurrences all number	7	4	11	2
DYSPEPSIA
subjects affected / exposed	11 / 58 (18.97%)	8 / 57 (14.04%)	9 / 55 (16.36%)	8 / 56 (14.29%)
occurrences all number	14	25	16	15
DYSPHAGIA
subjects affected / exposed	2 / 58 (3.45%)	1 / 57 (1.75%)	4 / 55 (7.27%)	3 / 56 (5.36%)
occurrences all number	4	1	4	3
FLATULENCE
subjects affected / exposed	2 / 58 (3.45%)	3 / 57 (5.26%)	3 / 55 (5.45%)	2 / 56 (3.57%)
occurrences all number	2	3	3	2
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	5 / 58 (8.62%)	3 / 57 (5.26%)	5 / 55 (9.09%)	1 / 56 (1.79%)
occurrences all number	6	4	5	1
GINGIVAL BLEEDING
subjects affected / exposed	5 / 58 (8.62%)	1 / 57 (1.75%)	2 / 55 (3.64%)	0 / 56 (0.00%)
occurrences all number	6	2	2	0
HAEMORRHOIDS
subjects affected / exposed	3 / 58 (5.17%)	6 / 57 (10.53%)	3 / 55 (5.45%)	4 / 56 (7.14%)
occurrences all number	5	6	3	4
NAUSEA
subjects affected / exposed	26 / 58 (44.83%)	25 / 57 (43.86%)	34 / 55 (61.82%)	26 / 56 (46.43%)
occurrences all number	70	58	90	44
ORAL PAIN
subjects affected / exposed	0 / 58 (0.00%)	3 / 57 (5.26%)	1 / 55 (1.82%)	1 / 56 (1.79%)
occurrences all number	0	5	1	1
STOMATITIS
subjects affected / exposed	13 / 58 (22.41%)	12 / 57 (21.05%)	10 / 55 (18.18%)	3 / 56 (5.36%)
occurrences all number	21	16	13	7
TOOTHACHE
subjects affected / exposed	2 / 58 (3.45%)	3 / 57 (5.26%)	4 / 55 (7.27%)	1 / 56 (1.79%)
occurrences all number	2	4	4	2
VOMITING
subjects affected / exposed	17 / 58 (29.31%)	21 / 57 (36.84%)	19 / 55 (34.55%)	12 / 56 (21.43%)
occurrences all number	45	37	40	15
Hepatobiliary disorders
HEPATIC PAIN
subjects affected / exposed	1 / 58 (1.72%)	2 / 57 (3.51%)	1 / 55 (1.82%)	3 / 56 (5.36%)
occurrences all number	1	3	1	4
Skin and subcutaneous tissue disorders
ACNE
subjects affected / exposed	4 / 58 (6.90%)	5 / 57 (8.77%)	4 / 55 (7.27%)	4 / 56 (7.14%)
occurrences all number	8	5	4	9
ALOPECIA
subjects affected / exposed	36 / 58 (62.07%)	35 / 57 (61.40%)	35 / 55 (63.64%)	31 / 56 (55.36%)
occurrences all number	64	62	53	43
DERMATITIS ACNEIFORM
subjects affected / exposed	5 / 58 (8.62%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences all number	6	0	1	0
DRY SKIN
subjects affected / exposed	6 / 58 (10.34%)	5 / 57 (8.77%)	4 / 55 (7.27%)	5 / 56 (8.93%)
occurrences all number	10	5	5	7
ERYTHEMA
subjects affected / exposed	5 / 58 (8.62%)	6 / 57 (10.53%)	10 / 55 (18.18%)	11 / 56 (19.64%)
occurrences all number	9	13	26	37
NAIL DISCOLOURATION
subjects affected / exposed	2 / 58 (3.45%)	3 / 57 (5.26%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences all number	2	3	2	0
NAIL DISORDER
subjects affected / exposed	14 / 58 (24.14%)	20 / 57 (35.09%)	20 / 55 (36.36%)	5 / 56 (8.93%)
occurrences all number	49	39	47	10
NAIL TOXICITY
subjects affected / exposed	4 / 58 (6.90%)	6 / 57 (10.53%)	2 / 55 (3.64%)	7 / 56 (12.50%)
occurrences all number	8	11	10	20
PAIN OF SKIN
subjects affected / exposed	1 / 58 (1.72%)	3 / 57 (5.26%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences all number	1	3	0	0
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	2 / 55 (3.64%)	4 / 56 (7.14%)
occurrences all number	2	1	3	5
PRURITUS
subjects affected / exposed	6 / 58 (10.34%)	7 / 57 (12.28%)	12 / 55 (21.82%)	9 / 56 (16.07%)
occurrences all number	8	9	12	13
RASH
subjects affected / exposed	17 / 58 (29.31%)	13 / 57 (22.81%)	13 / 55 (23.64%)	12 / 56 (21.43%)
occurrences all number	51	17	20	17
SKIN DISCOLOURATION
subjects affected / exposed	1 / 58 (1.72%)	4 / 57 (7.02%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences all number	1	4	0	0
SKIN FISSURES
subjects affected / exposed	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 55 (0.00%)	3 / 56 (5.36%)
occurrences all number	2	0	0	3
SKIN HYPERPIGMENTATION
subjects affected / exposed	2 / 58 (3.45%)	1 / 57 (1.75%)	4 / 55 (7.27%)	1 / 56 (1.79%)
occurrences all number	3	1	4	1
Renal and urinary disorders
DYSURIA
subjects affected / exposed	6 / 58 (10.34%)	1 / 57 (1.75%)	5 / 55 (9.09%)	4 / 56 (7.14%)
occurrences all number	7	1	7	5
PROTEINURIA
subjects affected / exposed	3 / 58 (5.17%)	2 / 57 (3.51%)	3 / 55 (5.45%)	2 / 56 (3.57%)
occurrences all number	5	3	3	2
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	16 / 58 (27.59%)	22 / 57 (38.60%)	15 / 55 (27.27%)	14 / 56 (25.00%)
occurrences all number	26	36	29	24
BACK PAIN
subjects affected / exposed	13 / 58 (22.41%)	15 / 57 (26.32%)	13 / 55 (23.64%)	12 / 56 (21.43%)
occurrences all number	30	27	17	23
BONE PAIN
subjects affected / exposed	11 / 58 (18.97%)	3 / 57 (5.26%)	6 / 55 (10.91%)	7 / 56 (12.50%)
occurrences all number	15	5	12	8
MUSCLE FATIGUE
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	2 / 55 (3.64%)	3 / 56 (5.36%)
occurrences all number	0	1	5	7
MUSCLE SPASMS
subjects affected / exposed	10 / 58 (17.24%)	2 / 57 (3.51%)	4 / 55 (7.27%)	5 / 56 (8.93%)
occurrences all number	12	3	6	5
MUSCULAR WEAKNESS
subjects affected / exposed	4 / 58 (6.90%)	3 / 57 (5.26%)	2 / 55 (3.64%)	4 / 56 (7.14%)
occurrences all number	9	3	3	4
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	6 / 58 (10.34%)	8 / 57 (14.04%)	4 / 55 (7.27%)	3 / 56 (5.36%)
occurrences all number	7	10	4	4
MUSCULOSKELETAL PAIN
subjects affected / exposed	9 / 58 (15.52%)	6 / 57 (10.53%)	7 / 55 (12.73%)	4 / 56 (7.14%)
occurrences all number	15	8	15	6
MUSCULOSKELETAL STIFFNESS
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences all number	4	2	1	0
MYALGIA
subjects affected / exposed	15 / 58 (25.86%)	16 / 57 (28.07%)	13 / 55 (23.64%)	16 / 56 (28.57%)
occurrences all number	38	32	35	31
NECK PAIN
subjects affected / exposed	3 / 58 (5.17%)	4 / 57 (7.02%)	3 / 55 (5.45%)	1 / 56 (1.79%)
occurrences all number	4	7	3	1
PAIN IN EXTREMITY
subjects affected / exposed	14 / 58 (24.14%)	14 / 57 (24.56%)	9 / 55 (16.36%)	12 / 56 (21.43%)
occurrences all number	25	24	14	21
SPINAL PAIN
subjects affected / exposed	3 / 58 (5.17%)	2 / 57 (3.51%)	2 / 55 (3.64%)	1 / 56 (1.79%)
occurrences all number	4	2	2	1
Infections and infestations
BRONCHITIS
subjects affected / exposed	1 / 58 (1.72%)	4 / 57 (7.02%)	2 / 55 (3.64%)	4 / 56 (7.14%)
occurrences all number	1	4	2	4
CELLULITIS
subjects affected / exposed	0 / 58 (0.00%)	2 / 57 (3.51%)	1 / 55 (1.82%)	6 / 56 (10.71%)
occurrences all number	0	2	2	8
CONJUNCTIVITIS
subjects affected / exposed	5 / 58 (8.62%)	3 / 57 (5.26%)	0 / 55 (0.00%)	4 / 56 (7.14%)
occurrences all number	7	3	0	5
CYSTITIS
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	2 / 55 (3.64%)	3 / 56 (5.36%)
occurrences all number	1	0	2	4
EAR INFECTION
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences all number	4	1	0	0
FOLLICULITIS
subjects affected / exposed	4 / 58 (6.90%)	3 / 57 (5.26%)	2 / 55 (3.64%)	1 / 56 (1.79%)
occurrences all number	8	3	8	1
FUNGAL INFECTION
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	0 / 55 (0.00%)	0 / 56 (0.00%)
occurrences all number	3	1	0	0
GASTROENTERITIS
subjects affected / exposed	4 / 58 (6.90%)	2 / 57 (3.51%)	2 / 55 (3.64%)	1 / 56 (1.79%)
occurrences all number	5	2	3	1
GINGIVITIS
subjects affected / exposed	3 / 58 (5.17%)	2 / 57 (3.51%)	4 / 55 (7.27%)	0 / 56 (0.00%)
occurrences all number	3	7	4	0
HERPES VIRUS INFECTION
subjects affected / exposed	0 / 58 (0.00%)	3 / 57 (5.26%)	1 / 55 (1.82%)	1 / 56 (1.79%)
occurrences all number	0	3	1	1
HORDEOLUM
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	1 / 55 (1.82%)	0 / 56 (0.00%)
occurrences all number	3	1	2	0
INFLUENZA
subjects affected / exposed	3 / 58 (5.17%)	1 / 57 (1.75%)	4 / 55 (7.27%)	1 / 56 (1.79%)
occurrences all number	6	1	5	1
NAIL INFECTION
subjects affected / exposed	3 / 58 (5.17%)	0 / 57 (0.00%)	1 / 55 (1.82%)	1 / 56 (1.79%)
occurrences all number	4	0	1	1
NASOPHARYNGITIS
subjects affected / exposed	8 / 58 (13.79%)	5 / 57 (8.77%)	8 / 55 (14.55%)	7 / 56 (12.50%)
occurrences all number	14	6	8	11
ORAL CANDIDIASIS
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	0 / 55 (0.00%)	3 / 56 (5.36%)
occurrences all number	1	1	0	3
ORAL HERPES
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	2 / 55 (3.64%)	3 / 56 (5.36%)
occurrences all number	1	0	3	5
PHARYNGITIS
subjects affected / exposed	4 / 58 (6.90%)	4 / 57 (7.02%)	2 / 55 (3.64%)	3 / 56 (5.36%)
occurrences all number	4	5	2	3
RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 58 (1.72%)	3 / 57 (5.26%)	1 / 55 (1.82%)	4 / 56 (7.14%)
occurrences all number	1	5	1	5
RHINITIS
subjects affected / exposed	7 / 58 (12.07%)	7 / 57 (12.28%)	6 / 55 (10.91%)	3 / 56 (5.36%)
occurrences all number	11	8	8	3
SINUSITIS
subjects affected / exposed	3 / 58 (5.17%)	2 / 57 (3.51%)	8 / 55 (14.55%)	4 / 56 (7.14%)
occurrences all number	3	2	9	5
TOOTH ABSCESS
subjects affected / exposed	0 / 58 (0.00%)	3 / 57 (5.26%)	1 / 55 (1.82%)	1 / 56 (1.79%)
occurrences all number	0	5	1	1
TOOTH INFECTION
subjects affected / exposed	1 / 58 (1.72%)	4 / 57 (7.02%)	2 / 55 (3.64%)	0 / 56 (0.00%)
occurrences all number	1	5	2	0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	11 / 58 (18.97%)	4 / 57 (7.02%)	8 / 55 (14.55%)	7 / 56 (12.50%)
occurrences all number	23	6	11	8
URINARY TRACT INFECTION
subjects affected / exposed	7 / 58 (12.07%)	6 / 57 (10.53%)	12 / 55 (21.82%)	5 / 56 (8.93%)
occurrences all number	15	9	17	13
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	17 / 58 (29.31%)	16 / 57 (28.07%)	13 / 55 (23.64%)	10 / 56 (17.86%)
occurrences all number	36	27	19	12
DEHYDRATION
subjects affected / exposed	1 / 58 (1.72%)	4 / 57 (7.02%)	2 / 55 (3.64%)	2 / 56 (3.57%)
occurrences all number	1	4	2	2
HYPERGLYCAEMIA
subjects affected / exposed	1 / 58 (1.72%)	3 / 57 (5.26%)	0 / 55 (0.00%)	2 / 56 (3.57%)
occurrences all number	1	3	0	3
HYPOCALCAEMIA
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	3 / 55 (5.45%)	3 / 56 (5.36%)
occurrences all number	0	0	3	10
HYPOKALAEMIA
subjects affected / exposed	3 / 58 (5.17%)	2 / 57 (3.51%)	1 / 55 (1.82%)	1 / 56 (1.79%)
occurrences all number	5	3	1	1

More information

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Were there any global substantial amendments to the protocol? Yes

18 Jun 2007

Amendment 1 included the following changes: • Prior malignancy (other than thyroid cancer, in situ cervical cancer, or basal cell cancer of the skin) was added as an exclusion criterion. • Clinical safety and efficacy experience and paclitaxel background were updated. • Baseline samples for anti-AMG 386 antibody tests (immunogenicity), biomarkers, and pharmacokinetic tests) were to be taken within 14 days prior to randomization or before dosing on day 1. • A MUGA scan or echocardiogram was to be performed on week 1 day 1, week 9, and week 21. • Radiological assessments were to include a CT scan or MRI of the chest, abdomen, and pelvis, and the modality selected was to be the same throughout the study. • The timing for the 12-lead ECG was defined: on day 1 of week 1, week 4, and week 21, 60 minutes after the completion of the infusion of AMG 386 and after the subject had been supine for at least 5 minutes. • Additional blood samples for biomarker development were to be drawn every 4 cycles (16 weeks) after cycle 3 (week 9). • All non-serious adverse events that occurred after the subject has signed the ICF were to be captured. • Additional statistical analyses included Arm A and/or B relative to Arm D; andArm C relative to Arm D.

11 Jul 2008

Amendment 2 included the following changes: • Baseline values and changes from baseline in pharmacogenetic markers were added as an exploratory endpoint. • Complete radiology and tumor measurements were to be performed within 28 days prior to randomization. • The brain CT or MRI inclusion criterion was changed to head or brain CT or MRI and was to be performed within 28 days before randomization. • The echocardiogram or MUGA scan was to be performed within 14 days prior to randomization. • aPTT and INR ≤ 1.0 x ULN per institutional laboratory range was added to the PTT laboratory inclusion criterion. • Renal function inclusion criterion was amended to include urinary protein quantitative value of ≤ 30 mg in urinalysis or ≤ 1+ on dipstick, unless quantitative protein is ≤ 1000 mg in a 24 hour urine sample. • Exceptions were added to the prior malignancy exclusion criterion: malignancy treated with curative intent and with no known active disease present for ≥ 3 years; adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease; adequately treated cervical carcinoma in situ without evidence of disease. • Motesanib was added as an excluded medication, and concurrent or prior anticoagulation therapy, excluding aspirin and anti-platelet agents. • Concurrent therapy with any hormonal agents must have been discontinued 14 days before randomization. • Baseline samples for anti-AMG 386 antibody tests, biomarkers, and PK tests were to taken before dosing on day 1 cycle 1. • Treatment procedures were modified to include weight, CT or MRI of head or brain and bone metastases, and bone scan if a subject developed signs or symptoms suggestive of bony metastasis while on study treatment. • Randomization was to be stratified according to adjuvant taxane exposure and number of metastatic sites. • Addition of India and Australia. • Other clarifications regarding study procedures were added.

25 Feb 2009

The third amendment included the following changes: • The echocardiogram or MUGA scan was to be performed within 28 days prior to randomization (previously 14 days). • The sample size consideration for PFS hazard ratio was expanded and clarified. • Plans for two interim analyses of efficacy were changed to one interim analysis, to take place when 75 PFS events (RECIST v 1.0 with modifications progression or death) among subjects in Arms A, B, and C have occurred. • The status of studies listed in the table of clinical safety experience was updated. • The study accrual period was changed from approximately 12 months to approximately 22 months. • It was clarified that investigators could recalculate AMG 386 dose based on subject weight changes per institutional guidelines. • The paclitaxel and bevacizumab dose modification section was updated to include guidelines for dose withholding. • The venous thrombosis toxicity management section was modified to differentiate between symptomatic and asymptomatic grade 4 events. • The safety reporting procedures were expanded and clarified. • The time frame for the primary efficacy analysis was clarified. • The treatment effect statistical analyses were modified. • A description of the use of a peristaltic pump with an in-line filter for AMG 386 infusion was added for consistency with instructions in the Pharmacy Binder.

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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