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Clinical Trial Results:
A Randomized, Phase II, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Onartuzumab (MetMab) in Combination with Either Bevacizumab + Platinum + Paclitaxel or Pemetrexed + Platinum as First-Line Treatment in Patients with Stage IIIb or IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Summary
EudraCT number	2011-003719-42
Trial protocol	DE GB ES LV IT
Global end of trial date	03 Nov 2015

Results information
Results version number	v1(current)
This version publication date	29 Jun 2016
First version publication date	29 Jun 2016
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

GO27821

ISRCTN number

US NCT number

NCT01496742

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann La Roche AG, +41 61 6878333, global.trial_information@roche.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

03 Nov 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Nov 2015

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of onartuzumab compared with placebo in participants with non-squamous NSCLC in the first-line settiing, as measured by investigator-assessed progression free survival (PFS) in each of two combination treatment cohorts: Cohort 1: Onartuzumab + bevacizumab + platinum + paclitaxel (Onartuzumab arm) versus (vs.) placebo + bevacizumab + platinum + paclitaxel (Placebo arm) Cohort 2: Onartuzumab + platinum + pemetrexed (Onartuzumab arm) vs. placebo + platinum + pemetrexed (Placebo arm)

Protection of trial subjects

The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Apr 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

France: 13

Country: Number of subjects enrolled

Germany: 24

Country: Number of subjects enrolled

Italy: 35

Country: Number of subjects enrolled

Latvia: 27

Country: Number of subjects enrolled

Argentina: 4

Country: Number of subjects enrolled

Israel: 7

Country: Number of subjects enrolled

Mexico: 4

Country: Number of subjects enrolled

Malaysia: 9

Country: Number of subjects enrolled

Philippines: 11

Country: Number of subjects enrolled

United States: 107

Worldwide total number of subjects

259

EEA total number of subjects

117

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)

147

From 65 to 84 years

110

85 years and over

Subject disposition

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Recruitment details

Screening details

Screening period was up to 28 days.

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

Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent

Arm description

Induction phase: participants received onartuzumab 15 milligrams per kilogram (mg/kg) intravenous (IV) infusion followed by bevacizumab 15 mg/kg IV infusion followed by paclitaxel 200 milligrams per square meter (mg/m^2) IV infusion followed by carboplatin (area under the concentration curve [AUC] 6 IV) infusion or cisplatin (75 mg/m^2 IV) infusion on Day 1 of every cycle of 21 days for up to 4 cycles. Carboplatin or cisplatin platinum therapy was chosen as per investigator's discretion. Participants who experienced disease progression at any time during the induction phase discontinued all study treatment. In the absence of disease progression, after the 4-Cycle induction phase, participants began maintenance phase. Maintenance phase: participants received onartuzumab 15 mg/kg IV infusion and bevacizumab 15 mg/kg IV infusion on Day 1 of every cycle, until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Onartuzumab

Investigational medicinal product code

RO5490258

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received onartuzumab 15 mg/kg IV infusion on Day 1 of every 21-day cycle. First infusion received over 60 minutes and then over 30 minutes from second infusion onward.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received bevacizumab 15 mg/kg IV infusion over 30-90 minutes on Day 1 of every 21-day cycle.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received paclitaxel 200 mg/m^2 IV infusion over 3 hours on Day 1 of every 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received carboplatin AUC 6 IV infusion over 30-60 minutes on Day 1 of every 21-day cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received cisplatin 75 mg/m^2 IV infusion over 1-2 hours on Day 1 of every 21-day cycle.

Placebo+Bevacizumab+Paclitaxel+Platinum Agent

Arm description

Induction phase: participants received placebo IV infusion followed by bevacizumab 15 mg/kg IV infusion followed by paclitaxel 200 mg/m^2 IV infusion followed by carboplatin (AUC 6 IV) or cisplatin (75 mg/m^2 IV) infusion on Day 1 of every cycle of 21 days for up to 4 cycles. Carboplatin or cisplatin platinum therapy was chosen as per investigator's discretion. Participants who experienced disease progression at any time during the induction phase discontinued all study treatment. In the absence of disease progression, after the 4-Cycle induction phase, participants began maintenance phase. Maintenance phase: participants received placebo infusion and bevacizumab 15 mg/kg IV infusion on Day 1 of every cycle, until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received placebo matched to onartuzumab infusion on Day 1 of every 21-day cycle.

Investigational medicinal product name

Bevacizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received bevacizumab 15 mg/kg IV infusion over 30-90 minutes on Day 1 of every 21-day cycle.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received paclitaxel 200 mg/m^2 IV infusion over 3 hours on Day 1 of every 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received carboplatin AUC 6 IV infusion over 30-60 minutes on Day 1 of every 21-day cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received cisplatin 75 mg/m^2 IV infusion over 1-2 hours on Day 1 of every 21-day cycle.

Onartuzumab+Pemetrexed+Platinum Agent

Arm description

Induction phase: participants received onartuzumab 15 mg/kg IV infusion followed by pemetrexed 500 mg/m^2 IV infusion followed by carboplatin (AUC 6 IV) infusion or cisplatin (75 mg/m^2 IV) infusion on Day 1 of every cycle of 21 days for up to 4 cycles. Carboplatin or cisplatin platinum therapy was chosen as per investigator's discretion. Participants who experienced disease progression at any time during the induction phase discontinued all study treatment. In the absence of disease progression, after the 4-Cycle induction phase, participants began maintenance phase. Maintenance phase: participants received onartuzumab 15 mg/kg IV infusion and pemetrexed 500 mg/m^2 IV infusion on Day 1 of every cycle, until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

Arm type

Experimental

Investigational medicinal product name

Onartuzumab

Investigational medicinal product code

RO5490258

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received onartuzumab 15 mg/kg IV infusion on Day 1 of every 21-day cycle. First infusion received over 60 minutes and then over 30 minutes from second infusion onward.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received pemetrexed 500 mg/m^2 IV infusion over 10 minutes on Day 1 of every 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received carboplatin AUC 6 IV over 30-60 minutes on Day 1 of every 21-day cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received cisplatin 75 mg/m^2 IV over 1-2 hours on Day 1 of every 21-day cycle.

Placebo+Pemetrexed+Platinum Agent

Arm description

Induction phase: participants received placebo infusion followed by pemetrexed 500 mg/m^2 IV infusion followed by carboplatin (AUC 6 IV) infusion or cisplatin (75 mg/m^2 IV) infusion on Day 1 of every cycle of 21 days for up to 4 cycles. Carboplatin or cisplatin platinum therapy was chosen as per investigator's discretion. Participants who experienced disease progression at any time during the induction phase discontinued all study treatment. In the absence of disease progression, after the 4-Cycle induction phase, participants began maintenance phase. Maintenance phase: participants received placebo infusion and pemetrexed 500 mg/m^2 IV infusion on Day 1 of every cycle, until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received placebo matched to onartuzumab infusion on Day 1 of every 21-day cycle.

Investigational medicinal product name

Pemetrexed

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received pemetrexed 500 mg/m^2 IV infusion over 10 minutes on Day 1 of every 21-day cycle.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received carboplatin AUC 6 IV over 30-60 minutes on Day 1 of every 21-day cycle.

Investigational medicinal product name

Cisplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Participants received cisplatin 75 mg/m^2 IV over 1-2 hours on Day 1 of every 21-day cycle.

Number of subjects in period 1	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Started	69	70	59	61
Completed	0	0	0	0
Not completed	69	70	59	61
Consent withdrawn by subject	5	5	6	2
Death	32	29	37	36
Sponsor decision	29	33	15	20
Progressive disease	3	2	1	1
Lost to follow-up	-	1	-	1
Protocol deviation	-	-	-	1

Baseline characteristics

Top of page

Reporting group title

Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent

Reporting group description

Reporting group title

Placebo+Bevacizumab+Paclitaxel+Platinum Agent

Reporting group description

Reporting group title

Onartuzumab+Pemetrexed+Platinum Agent

Reporting group description

Reporting group title

Placebo+Pemetrexed+Platinum Agent

Reporting group description

Reporting group values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent	Total
Number of subjects	69	70	59	61	259
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	60.8 ± 10.6	59.6 ± 11	64.5 ± 7.9	62.5 ± 8.9	-
Gender categorical
Units: Subjects
Female	22	36	26	35	119
Male	47	34	33	26	140

End points

Top of page

Reporting group title

Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent

Reporting group description

Reporting group title

Placebo+Bevacizumab+Paclitaxel+Platinum Agent

Reporting group description

Reporting group title

Onartuzumab+Pemetrexed+Platinum Agent

Reporting group description

Reporting group title

Placebo+Pemetrexed+Platinum Agent

Reporting group description

Subject analysis set title

Onartuzumab participants

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who received onartuzumab were included in this group.

Primary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS)

End point description

PFS was defined as the time between the date of randomization and the date of the first documented disease progression or death, whichever occurred first. Progressive disease (PD): At least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. All randomized participants were included in analysis of this end point.

End point type

Primary

End point timeframe

Screening, every 6 weeks during the first 4 cycles of treatment, and every 9 weeks thereafter until disease progression or death (up to approximately 20 months)

End point values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Number of subjects analysed	69	70	59	61
Units: months
median (confidence interval 95%)	5 (4.7 to 6.9)	6.8 (4.9 to 8.8)	4.9 (4.4 to 5.9)	5.1 (4.6 to 7)

Statistical analysis I

Statistical analysis description

Stratified analysis is reported. The stratification factor is MET IHC status (positive versus negative). Hazard ratios were estimated by Cox regression.

Comparison groups

Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent v Placebo+Bevacizumab+Paclitaxel+Platinum Agent

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3327

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

1.95

Statistical analysis II

Statistical analysis description

Stratified analysis is reported. The stratification factor is MET IHC status (positive versus negative). Hazard ratios were estimated by Cox regression.

Comparison groups

Placebo+Pemetrexed+Platinum Agent v Onartuzumab+Pemetrexed+Platinum Agent

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3286

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.23

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.86

Primary: PFS in Subgroup of Participants with MET Diagnostic Positive Tumors

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End point title

PFS in Subgroup of Participants with MET Diagnostic Positive Tumors

End point description

PFS was defined as the time between the date of randomization and the date of the first documented disease progression or death, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. MET diagnostic-positive population included all randomized participants with MET immunohistochemistry (IHC) score of 2+ or 3+.

End point type

Primary

End point timeframe

Screening, every 6 weeks during the first 4 cycles of treatment, and every 9 weeks thereafter until disease progression or death (up to approximately 20 months)

End point values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Number of subjects analysed	45	44	36	37
Units: months
median (confidence interval 95%)	4.8 (3.7 to 6.2)	6.9 (4.9 to 10.9)	5 (4.5 to 6)	5 (3.7 to 7.2)

Statistical analysis I

Comparison groups

Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent v Placebo+Bevacizumab+Paclitaxel+Platinum Agent

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0576

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

3.02

Statistical analysis II

Comparison groups

Onartuzumab+Pemetrexed+Platinum Agent v Placebo+Pemetrexed+Platinum Agent

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4271

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.25

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

2.15

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS is defined as the time from date of randomization until death from any cause. All randomized participants were included in analysis of this end point. Median OS time was not estimated for "Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent" treatment arm and was reported as 99999. The upper confidence interval was reported as "99999" wherever it was not estimable.

End point type

Secondary

End point timeframe

Screening, every 6 weeks during the first 4 cycles of treatment, and every 9 weeks thereafter until death (up to approximately 20 months)

End point values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Number of subjects analysed	69	70	59	61
Units: months
median (confidence interval 95%)	99999 (8.1 to 99999)	16.5 (8.8 to 16.5)	8.5 (6.8 to 13.2)	13.7 (6.6 to 99999)

Statistical analysis I

Statistical analysis description

Stratified analysis is reported. The stratification factor is MET IHC status (positive versus negative). Hazard ratios were estimated by Cox regression.

Comparison groups

Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent v Placebo+Bevacizumab+Paclitaxel+Platinum Agent

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3523

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

2.48

Statistical analysis II

Statistical analysis description

Stratified analysis is reported. The stratification factor is MET IHC status (positive versus negative). Hazard ratios were estimated by Cox regression.

Comparison groups

Onartuzumab+Pemetrexed+Platinum Agent v Placebo+Pemetrexed+Platinum Agent

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5906

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

1.96

Secondary: Percentage of Participants with an Objective Response Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1

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End point title

Percentage of Participants with an Objective Response Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1

End point description

Objective response is defined as a complete response (CR) or partial response (PR). Participants without a post-baseline tumor assessment will be considered as nonresponders. CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Randomized participants with measurable disease at baseline were considered for analysis of this end point.

End point type

Secondary

End point timeframe

Screening, every 6 weeks during the first 4 cycles of treatment, and every 9 weeks thereafter until disease progression or death (up to approximately 20 months)

End point values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Number of subjects analysed	66	67	56	61
Units: percentage of participants
number (confidence interval 95%)	51.5 (38.88 to 64.01)	44.8 (32.6 to 57.42)	28.6 (17.3 to 42.21)	36.1 (24.16 to 49.37)

Statistical analysis I

Comparison groups

Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent v Placebo+Bevacizumab+Paclitaxel+Platinum Agent

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4385

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

6.74

Confidence interval

level

95%

sides

2-sided

lower limit

-10.21

upper limit

23.68

Statistical analysis II

Comparison groups

Onartuzumab+Pemetrexed+Platinum Agent v Placebo+Pemetrexed+Platinum Agent

Number of subjects included in analysis

117

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3892

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rates

Point estimate

-7.49

Confidence interval

level

95%

sides

2-sided

lower limit

-24.38

upper limit

9.39

Secondary: Duration of Response (DoR)

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End point title

Duration of Response (DoR)

End point description

DoR is defined as the time from the first occurrence of a documented objective response to disease progression. CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

End point type

Secondary

End point timeframe

Screening, every 6 weeks during the first 4 cycles of treatment, and every 9 weeks thereafter until disease progression or death (up to approximately 20 months)

End point values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Number of subjects analysed	0 ^[1]	0 ^[2]	0 ^[3]	0 ^[4]
Units: months
median (full range (min-max))	( to )	( to )	( to )	( to )

Notes
[1] - Due to lack of efficacy, it was decided not to evaluate DoR.
[2] - Due to lack of efficacy, it was decided not to evaluate DoR.
[3] - Due to lack of efficacy, it was decided not to evaluate DoR.
[4] - Due to lack of efficacy, it was decided not to evaluate DoR.

No statistical analyses for this end point

Secondary: Disease Control Rate

Top of page

End point title

Disease Control Rate

End point description

Disease control rate includes tumor responses of CR, PR and SD. CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum on study.

End point type

Secondary

End point timeframe

Screening, every 6 weeks during the first 4 cycles of treatment, and every 9 weeks thereafter until disease progression or death (up to approximately 20 months)

End point values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Number of subjects analysed	0 ^[5]	0 ^[6]	0 ^[7]	0 ^[8]
Units: percentage of participants
number (confidence interval 95%)	( to )	( to )	( to )	( to )

Notes
[5] - Due to general lack of efficacy, disease control rate was not analysed.
[6] - Due to general lack of efficacy, disease control rate was not analysed.
[7] - Due to general lack of efficacy, disease control rate was not analysed.
[8] - Due to general lack of efficacy, disease control rate was not analysed.

No statistical analyses for this end point

Secondary: Pre-dose Serum Onartuzumab Concentration (Cmin) on Day 1 of Cycles 1 and 4

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End point title

Pre-dose Serum Onartuzumab Concentration (Cmin) on Day 1 of Cycles 1 and 4 ^[9]

End point description

All randomized participants with measurable pharmacokinetic (PK) data were considered for analysis of this end point.

End point type

Secondary

End point timeframe

Pre-dose (within 1 hour) on Day 1 of Cycles 1 and Cycle 4

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: PK end point is reported for only onartuzumab arms and not for placebo arms.

End point values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent
Number of subjects analysed	69	58
Units: micrograms per milliliter (mcg/mL)
arithmetic mean (standard deviation)
Cycle 1	28.8 ± 11.9	44.5 ± 62.9
Cycle 4	60 ± 70.6	61.1 ± 37.4

No statistical analyses for this end point

Secondary: Post-dose Serum Onartuzumab Concentration (Cmax) on Day 1 of Cycles 1 and 4

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End point title

Post-dose Serum Onartuzumab Concentration (Cmax) on Day 1 of Cycles 1 and 4 ^[10]

End point description

All randomized participants with measurable PK data were considered for analysis of this end point.

End point type

Secondary

End point timeframe

30 minutes post-dose on Day 1 of Cycles 1 and 4

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: PK end point is reported for only onartuzumab arms and not for placebo arms.

End point values	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent
Number of subjects analysed	69	58
Units: mcg/mL
arithmetic mean (standard deviation)
Cycle 1	348 ± 361	330 ± 112
Cycle 4	403 ± 139	370 ± 141

No statistical analyses for this end point

Secondary: Number of Participants with Anti-therapeutic Antibodies (ATA) Against Onartuzumab

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End point title

Number of Participants with Anti-therapeutic Antibodies (ATA) Against Onartuzumab

End point description

Included all participants who received study treatment and had at least 1 postdose sample available for ATA analysis.

End point type

Secondary

End point timeframe

Pre-dose (within 1 hour) on Day 1 of Cycles 1 and 4 and at study drug discontinuation visit (up to approximately 20 months)

End point values	Onartuzumab participants
Number of subjects analysed	109
Units: participants	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 20 months

Adverse event reporting additional description

Adverse events data were reported for safety population which included all participants who were randomized and received at least one dose of study treatment, with participants allocated to the treatment arm associated with the regimen actually received.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent

Reporting group description

Induction phase: participants received onartuzumab 15 mg/kg IV infusion followed by bevacizumab 15 mg/kg IV followed by paclitaxel 200 mg/m^2 IV followed by carboplatin (AUC 6 IV) or cisplatin (75 mg/m^2 IV) on Day 1 of every cycle of 21 days for up to 4 cycles. Carboplatin or cisplatin platinum therapy was chosen as per investigator's discretion. Participants who experienced disease progression at any time during the induction phase discontinued all study treatment. In the absence of disease progression, after the 4-Cycle induction phase, participants began maintenance phase. Maintenance phase: participants received onartuzumab 15 mg/kg IV infusion and bevacizumab 15 mg/kg IV on Day 1 of every cycle, until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

Reporting group title

Placebo+Bevacizumab+Paclitaxel+Platinum Agent

Reporting group description

Induction phase: participants received placebo IV infusion followed by bevacizumab 15 mg/kg IV followed by paclitaxel 200 mg/m^2 IV followed by carboplatin (AUC 6 IV) or cisplatin (75 mg/m^2 IV) on Day 1 of every cycle of 21 days for up to 4 cycles. Carboplatin or cisplatin platinum therapy was chosen as per investigator's discretion. Participants who experienced disease progression at any time during the induction phase discontinued all study treatment. In the absence of disease progression, after the 4-Cycle induction phase, participants began maintenance phase. Maintenance phase: participants received placebo infusion and bevacizumab 15 mg/kg IV on Day 1 of every cycle, until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

Reporting group title

Onartuzumab+Pemetrexed+Platinum Agent

Reporting group description

Induction phase: participants received onartuzumab 15 mg/kg IV infusion followed by pemetrexed 500 mg/m^2 IV followed by carboplatin (AUC 6 IV) or cisplatin (75 mg/m^2 IV) on Day 1 of every cycle of 21 days for up to 4 cycles. Carboplatin or cisplatin platinum therapy was chosen as per investigator's discretion. Participants who experienced disease progression at any time during the induction phase discontinued all study treatment. In the absence of disease progression, after the 4-Cycle induction phase, participants began maintenance phase. Maintenance phase: participants received onartuzumab 15 mg/kg IV infusion and pemetrexed 500 mg/m^2 IV on Day 1 of every cycle, until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

Reporting group title

Placebo+Pemetrexed+Platinum Agent

Reporting group description

Induction phase: participants received placebo infusion followed by pemetrexed 500 mg/m^2 IV followed by carboplatin (AUC 6 IV) or cisplatin (75 mg/m^2 IV) on Day 1 of every cycle of 21 days for up to 4 cycles. Carboplatin or cisplatin platinum therapy was chosen as per investigator's discretion. Participants who experienced disease progression at any time during the induction phase discontinued all study treatment. In the absence of disease progression, after the 4-Cycle induction phase, participants began maintenance phase. Maintenance phase: participants received placebo infusion and pemetrexed 500 mg/m^2 IV on Day 1 of every cycle, until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

Serious adverse events	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Total subjects affected by serious adverse events
subjects affected / exposed	24 / 69 (34.78%)	21 / 69 (30.43%)	17 / 58 (29.31%)	22 / 57 (38.60%)
number of deaths (all causes)	3	4	0	3
number of deaths resulting from adverse events
Vascular disorders
Aortic dissection
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Arterial occlusive disease
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Deep vein thrombosis
subjects affected / exposed	3 / 69 (4.35%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Subclavian vein thrombosis
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Venous thrombosis
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 69 (1.45%)	1 / 69 (1.45%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Fatigue
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
General physical health deterioration
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Impaired healing
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Pain
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Pyrexia
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (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
Bronchitis chronic
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (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
Dyspnoea
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	3 / 58 (5.17%)	3 / 57 (5.26%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 6	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 69 (1.45%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	0 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Increased bronchial secretion
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (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	1 / 69 (1.45%)	2 / 69 (2.90%)	2 / 58 (3.45%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pulmonary haemorrhage
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Respiratory failure
subjects affected / exposed	0 / 69 (0.00%)	2 / 69 (2.90%)	3 / 58 (5.17%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Investigations
Weight decreased
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Cardiac arrest
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Cardiac failure congestive
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (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
Cardiopulmonary failure
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Myocardial infarction
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (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
Dizziness
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	1 / 58 (1.72%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (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
Seizure
subjects affected / exposed	0 / 69 (0.00%)	3 / 69 (4.35%)	0 / 58 (0.00%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 69 (1.45%)	1 / 69 (1.45%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 69 (7.25%)	0 / 69 (0.00%)	0 / 58 (0.00%)	2 / 57 (3.51%)
occurrences causally related to treatment / all	5 / 7	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 69 (0.00%)	2 / 69 (2.90%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Neutropenia
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Spontaneous haematoma
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Thrombocytopenia
subjects affected / exposed	1 / 69 (1.45%)	1 / 69 (1.45%)	1 / 58 (1.72%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (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
Abdominal pain upper
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Constipation
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	2 / 57 (3.51%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Dysphagia
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Gastric ulcer
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Gastritis
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	1 / 58 (1.72%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Loose tooth
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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	2 / 69 (2.90%)	0 / 69 (0.00%)	1 / 58 (1.72%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Vomiting
subjects affected / exposed	3 / 69 (4.35%)	1 / 69 (1.45%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences causally related to treatment / all	3 / 4	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Endocrine disorders
Hypercalcaemia of malignancy
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Bone pain
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Groin pain
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Intervertebral disc protrusion
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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 pain
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Bacterial sepsis
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Device related infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Lower respiratory tract infection
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	2 / 58 (3.45%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Peritonitis
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	0 / 58 (0.00%)	1 / 57 (1.75%)
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
Pneumonia
subjects affected / exposed	4 / 69 (5.80%)	2 / 69 (2.90%)	2 / 58 (3.45%)	3 / 57 (5.26%)
occurrences causally related to treatment / all	1 / 4	1 / 2	1 / 2	1 / 3
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
Pseudomonal bacteraemia
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Pyelonephritis acute
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Sepsis
subjects affected / exposed	1 / 69 (1.45%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Urinary tract infection
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (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
Urosepsis
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Wound infection
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Dehydration
subjects affected / exposed	2 / 69 (2.90%)	2 / 69 (2.90%)	1 / 58 (1.72%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	2 / 2	3 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 69 (0.00%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (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
Hyponatraemia
subjects affected / exposed	2 / 69 (2.90%)	1 / 69 (1.45%)	0 / 58 (0.00%)	0 / 57 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 1	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	Onartuzumab+Bevacizumab+Paclitaxel+Platinum Agent	Placebo+Bevacizumab+Paclitaxel+Platinum Agent	Onartuzumab+Pemetrexed+Platinum Agent	Placebo+Pemetrexed+Platinum Agent
Total subjects affected by non serious adverse events
subjects affected / exposed	65 / 69 (94.20%)	66 / 69 (95.65%)	57 / 58 (98.28%)	57 / 57 (100.00%)
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	3 / 69 (4.35%)	0 / 69 (0.00%)	4 / 58 (6.90%)	4 / 57 (7.02%)
occurrences all number	3	0	5	4
Hypertension
subjects affected / exposed	16 / 69 (23.19%)	20 / 69 (28.99%)	4 / 58 (6.90%)	5 / 57 (8.77%)
occurrences all number	19	29	4	5
Hypotension
subjects affected / exposed	5 / 69 (7.25%)	4 / 69 (5.80%)	5 / 58 (8.62%)	0 / 57 (0.00%)
occurrences all number	5	4	6	0
Thrombosis
subjects affected / exposed	4 / 69 (5.80%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)
occurrences all number	4	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	11 / 69 (15.94%)	8 / 69 (11.59%)	13 / 58 (22.41%)	15 / 57 (26.32%)
occurrences all number	12	9	18	16
Chest pain
subjects affected / exposed	2 / 69 (2.90%)	7 / 69 (10.14%)	4 / 58 (6.90%)	4 / 57 (7.02%)
occurrences all number	2	7	4	5
Fatigue
subjects affected / exposed	34 / 69 (49.28%)	25 / 69 (36.23%)	21 / 58 (36.21%)	23 / 57 (40.35%)
occurrences all number	40	34	36	27
Mucosal inflammation
subjects affected / exposed	2 / 69 (2.90%)	7 / 69 (10.14%)	4 / 58 (6.90%)	2 / 57 (3.51%)
occurrences all number	3	8	4	2
Oedema peripheral
subjects affected / exposed	23 / 69 (33.33%)	2 / 69 (2.90%)	30 / 58 (51.72%)	9 / 57 (15.79%)
occurrences all number	32	2	40	9
Pain
subjects affected / exposed	5 / 69 (7.25%)	5 / 69 (7.25%)	6 / 58 (10.34%)	3 / 57 (5.26%)
occurrences all number	6	6	8	3
Pyrexia
subjects affected / exposed	4 / 69 (5.80%)	3 / 69 (4.35%)	1 / 58 (1.72%)	12 / 57 (21.05%)
occurrences all number	7	3	1	14
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	19 / 69 (27.54%)	12 / 69 (17.39%)	8 / 58 (13.79%)	12 / 57 (21.05%)
occurrences all number	24	15	9	13
Dysphonia
subjects affected / exposed	6 / 69 (8.70%)	3 / 69 (4.35%)	1 / 58 (1.72%)	1 / 57 (1.75%)
occurrences all number	6	3	1	2
Dyspnoea
subjects affected / exposed	18 / 69 (26.09%)	16 / 69 (23.19%)	13 / 58 (22.41%)	11 / 57 (19.30%)
occurrences all number	18	18	13	14
Epistaxis
subjects affected / exposed	13 / 69 (18.84%)	8 / 69 (11.59%)	1 / 58 (1.72%)	2 / 57 (3.51%)
occurrences all number	13	10	1	3
Oropharyngeal pain
subjects affected / exposed	5 / 69 (7.25%)	2 / 69 (2.90%)	3 / 58 (5.17%)	1 / 57 (1.75%)
occurrences all number	5	2	5	1
Pulmonary embolism
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	1 / 58 (1.72%)	4 / 57 (7.02%)
occurrences all number	1	0	1	4
Rhinorrhoea
subjects affected / exposed	2 / 69 (2.90%)	2 / 69 (2.90%)	4 / 58 (6.90%)	0 / 57 (0.00%)
occurrences all number	2	2	5	0
Psychiatric disorders
Anxiety
subjects affected / exposed	4 / 69 (5.80%)	2 / 69 (2.90%)	6 / 58 (10.34%)	10 / 57 (17.54%)
occurrences all number	4	2	6	10
Depression
subjects affected / exposed	6 / 69 (8.70%)	1 / 69 (1.45%)	4 / 58 (6.90%)	6 / 57 (10.53%)
occurrences all number	6	1	4	6
Insomnia
subjects affected / exposed	5 / 69 (7.25%)	10 / 69 (14.49%)	14 / 58 (24.14%)	6 / 57 (10.53%)
occurrences all number	5	15	15	6
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 69 (2.90%)	2 / 69 (2.90%)	3 / 58 (5.17%)	0 / 57 (0.00%)
occurrences all number	2	4	3	0
Blood creatinine increased
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	3 / 58 (5.17%)	1 / 57 (1.75%)
occurrences all number	1	0	3	1
Neutrophil count decreased
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	3 / 58 (5.17%)	0 / 57 (0.00%)
occurrences all number	1	0	4	0
Weight decreased
subjects affected / exposed	4 / 69 (5.80%)	4 / 69 (5.80%)	4 / 58 (6.90%)	5 / 57 (8.77%)
occurrences all number	4	4	5	6
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	0 / 69 (0.00%)	4 / 69 (5.80%)	0 / 58 (0.00%)	0 / 57 (0.00%)
occurrences all number	0	4	0	0
Procedural pain
subjects affected / exposed	2 / 69 (2.90%)	0 / 69 (0.00%)	3 / 58 (5.17%)	1 / 57 (1.75%)
occurrences all number	2	0	3	1
Cardiac disorders
Tachycardia
subjects affected / exposed	4 / 69 (5.80%)	2 / 69 (2.90%)	3 / 58 (5.17%)	1 / 57 (1.75%)
occurrences all number	4	2	3	1
Nervous system disorders
Dizziness
subjects affected / exposed	5 / 69 (7.25%)	6 / 69 (8.70%)	5 / 58 (8.62%)	4 / 57 (7.02%)
occurrences all number	5	6	5	4
Dysgeusia
subjects affected / exposed	3 / 69 (4.35%)	5 / 69 (7.25%)	6 / 58 (10.34%)	6 / 57 (10.53%)
occurrences all number	3	5	8	6
Headache
subjects affected / exposed	10 / 69 (14.49%)	6 / 69 (8.70%)	7 / 58 (12.07%)	6 / 57 (10.53%)
occurrences all number	11	6	7	9
Neuropathy peripheral
subjects affected / exposed	22 / 69 (31.88%)	15 / 69 (21.74%)	2 / 58 (3.45%)	1 / 57 (1.75%)
occurrences all number	25	21	2	1
Paraesthesia
subjects affected / exposed	7 / 69 (10.14%)	3 / 69 (4.35%)	1 / 58 (1.72%)	3 / 57 (5.26%)
occurrences all number	8	3	2	4
Peripheral sensory neuropathy
subjects affected / exposed	6 / 69 (8.70%)	7 / 69 (10.14%)	1 / 58 (1.72%)	1 / 57 (1.75%)
occurrences all number	6	9	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	15 / 69 (21.74%)	19 / 69 (27.54%)	24 / 58 (41.38%)	25 / 57 (43.86%)
occurrences all number	21	23	32	39
Leukopenia
subjects affected / exposed	1 / 69 (1.45%)	4 / 69 (5.80%)	2 / 58 (3.45%)	0 / 57 (0.00%)
occurrences all number	1	4	2	0
Neutropenia
subjects affected / exposed	19 / 69 (27.54%)	12 / 69 (17.39%)	11 / 58 (18.97%)	15 / 57 (26.32%)
occurrences all number	31	18	16	33
Thrombocytopenia
subjects affected / exposed	13 / 69 (18.84%)	11 / 69 (15.94%)	12 / 58 (20.69%)	8 / 57 (14.04%)
occurrences all number	22	15	16	14
Ear and labyrinth disorders
Deafness
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	2 / 58 (3.45%)	4 / 57 (7.02%)
occurrences all number	1	0	2	4
Tinnitus
subjects affected / exposed	0 / 69 (0.00%)	2 / 69 (2.90%)	1 / 58 (1.72%)	3 / 57 (5.26%)
occurrences all number	0	2	1	3
Eye disorders
Dry eye
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	3 / 58 (5.17%)	3 / 57 (5.26%)
occurrences all number	1	0	3	3
Lacrimation increased
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	3 / 58 (5.17%)	6 / 57 (10.53%)
occurrences all number	1	0	3	6
Periorbital oedema
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	4 / 58 (6.90%)	1 / 57 (1.75%)
occurrences all number	0	0	4	1
Vision blurred
subjects affected / exposed	4 / 69 (5.80%)	1 / 69 (1.45%)	2 / 58 (3.45%)	3 / 57 (5.26%)
occurrences all number	4	1	2	3
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 69 (4.35%)	3 / 69 (4.35%)	4 / 58 (6.90%)	5 / 57 (8.77%)
occurrences all number	3	3	5	6
Abdominal pain upper
subjects affected / exposed	2 / 69 (2.90%)	2 / 69 (2.90%)	2 / 58 (3.45%)	4 / 57 (7.02%)
occurrences all number	3	3	2	5
Constipation
subjects affected / exposed	24 / 69 (34.78%)	15 / 69 (21.74%)	23 / 58 (39.66%)	24 / 57 (42.11%)
occurrences all number	28	18	26	29
Diarrhoea
subjects affected / exposed	13 / 69 (18.84%)	19 / 69 (27.54%)	16 / 58 (27.59%)	13 / 57 (22.81%)
occurrences all number	18	25	19	15
Dyspepsia
subjects affected / exposed	7 / 69 (10.14%)	4 / 69 (5.80%)	4 / 58 (6.90%)	3 / 57 (5.26%)
occurrences all number	7	5	4	3
Nausea
subjects affected / exposed	28 / 69 (40.58%)	24 / 69 (34.78%)	28 / 58 (48.28%)	30 / 57 (52.63%)
occurrences all number	40	33	52	55
Stomatitis
subjects affected / exposed	3 / 69 (4.35%)	5 / 69 (7.25%)	6 / 58 (10.34%)	6 / 57 (10.53%)
occurrences all number	3	5	6	9
Vomiting
subjects affected / exposed	13 / 69 (18.84%)	16 / 69 (23.19%)	16 / 58 (27.59%)	17 / 57 (29.82%)
occurrences all number	19	18	19	22
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	36 / 69 (52.17%)	32 / 69 (46.38%)	4 / 58 (6.90%)	4 / 57 (7.02%)
occurrences all number	36	32	4	4
Dry skin
subjects affected / exposed	2 / 69 (2.90%)	4 / 69 (5.80%)	4 / 58 (6.90%)	2 / 57 (3.51%)
occurrences all number	2	7	4	2
Pruritus
subjects affected / exposed	2 / 69 (2.90%)	3 / 69 (4.35%)	3 / 58 (5.17%)	3 / 57 (5.26%)
occurrences all number	3	5	3	4
Rash
subjects affected / exposed	4 / 69 (5.80%)	5 / 69 (7.25%)	5 / 58 (8.62%)	11 / 57 (19.30%)
occurrences all number	4	5	5	14
Renal and urinary disorders
Haematuria
subjects affected / exposed	4 / 69 (5.80%)	2 / 69 (2.90%)	1 / 58 (1.72%)	0 / 57 (0.00%)
occurrences all number	4	2	1	0
Proteinuria
subjects affected / exposed	8 / 69 (11.59%)	8 / 69 (11.59%)	0 / 58 (0.00%)	1 / 57 (1.75%)
occurrences all number	9	15	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	10 / 69 (14.49%)	7 / 69 (10.14%)	5 / 58 (8.62%)	5 / 57 (8.77%)
occurrences all number	13	9	6	6
Back pain
subjects affected / exposed	8 / 69 (11.59%)	10 / 69 (14.49%)	11 / 58 (18.97%)	8 / 57 (14.04%)
occurrences all number	9	11	11	8
Bone pain
subjects affected / exposed	2 / 69 (2.90%)	3 / 69 (4.35%)	3 / 58 (5.17%)	7 / 57 (12.28%)
occurrences all number	4	6	3	8
Muscular weakness
subjects affected / exposed	2 / 69 (2.90%)	3 / 69 (4.35%)	0 / 58 (0.00%)	4 / 57 (7.02%)
occurrences all number	2	3	0	4
Musculoskeletal chest pain
subjects affected / exposed	1 / 69 (1.45%)	3 / 69 (4.35%)	3 / 58 (5.17%)	2 / 57 (3.51%)
occurrences all number	1	3	4	2
Musculoskeletal pain
subjects affected / exposed	4 / 69 (5.80%)	6 / 69 (8.70%)	6 / 58 (10.34%)	2 / 57 (3.51%)
occurrences all number	4	6	8	2
Myalgia
subjects affected / exposed	13 / 69 (18.84%)	13 / 69 (18.84%)	1 / 58 (1.72%)	2 / 57 (3.51%)
occurrences all number	25	23	1	2
Pain in extremity
subjects affected / exposed	7 / 69 (10.14%)	6 / 69 (8.70%)	8 / 58 (13.79%)	9 / 57 (15.79%)
occurrences all number	7	9	8	10
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 69 (1.45%)	4 / 69 (5.80%)	2 / 58 (3.45%)	3 / 57 (5.26%)
occurrences all number	1	4	2	3
Conjunctivitis
subjects affected / exposed	0 / 69 (0.00%)	0 / 69 (0.00%)	3 / 58 (5.17%)	3 / 57 (5.26%)
occurrences all number	0	0	3	3
Folliculitis
subjects affected / exposed	4 / 69 (5.80%)	0 / 69 (0.00%)	0 / 58 (0.00%)	0 / 57 (0.00%)
occurrences all number	4	0	0	0
Nasopharyngitis
subjects affected / exposed	2 / 69 (2.90%)	2 / 69 (2.90%)	2 / 58 (3.45%)	4 / 57 (7.02%)
occurrences all number	2	2	2	5
Oral candidiasis
subjects affected / exposed	2 / 69 (2.90%)	2 / 69 (2.90%)	2 / 58 (3.45%)	4 / 57 (7.02%)
occurrences all number	3	2	2	4
Pneumonia
subjects affected / exposed	3 / 69 (4.35%)	4 / 69 (5.80%)	7 / 58 (12.07%)	0 / 57 (0.00%)
occurrences all number	3	4	7	0
Upper respiratory tract infection
subjects affected / exposed	3 / 69 (4.35%)	4 / 69 (5.80%)	2 / 58 (3.45%)	2 / 57 (3.51%)
occurrences all number	3	5	2	3
Urinary tract infection
subjects affected / exposed	3 / 69 (4.35%)	7 / 69 (10.14%)	3 / 58 (5.17%)	5 / 57 (8.77%)
occurrences all number	4	7	3	6
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	19 / 69 (27.54%)	17 / 69 (24.64%)	19 / 58 (32.76%)	10 / 57 (17.54%)
occurrences all number	19	18	23	12
Dehydration
subjects affected / exposed	6 / 69 (8.70%)	5 / 69 (7.25%)	8 / 58 (13.79%)	9 / 57 (15.79%)
occurrences all number	8	7	9	25
Hyperglycaemia
subjects affected / exposed	4 / 69 (5.80%)	3 / 69 (4.35%)	8 / 58 (13.79%)	1 / 57 (1.75%)
occurrences all number	5	3	8	1
Hypoalbuminaemia
subjects affected / exposed	10 / 69 (14.49%)	2 / 69 (2.90%)	12 / 58 (20.69%)	0 / 57 (0.00%)
occurrences all number	11	2	14	0
Hypocalcaemia
subjects affected / exposed	7 / 69 (10.14%)	2 / 69 (2.90%)	6 / 58 (10.34%)	1 / 57 (1.75%)
occurrences all number	8	2	7	1
Hypokalaemia
subjects affected / exposed	5 / 69 (7.25%)	2 / 69 (2.90%)	9 / 58 (15.52%)	9 / 57 (15.79%)
occurrences all number	6	3	11	13
Hypomagnesaemia
subjects affected / exposed	5 / 69 (7.25%)	7 / 69 (10.14%)	9 / 58 (15.52%)	4 / 57 (7.02%)
occurrences all number	7	7	12	5
Hyponatraemia
subjects affected / exposed	6 / 69 (8.70%)	2 / 69 (2.90%)	7 / 58 (12.07%)	1 / 57 (1.75%)
occurrences all number	10	2	9	1
Hypophosphataemia
subjects affected / exposed	1 / 69 (1.45%)	0 / 69 (0.00%)	3 / 58 (5.17%)	2 / 57 (3.51%)
occurrences all number	1	0	4	2

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Were there any global substantial amendments to the protocol? Yes

15 Nov 2011

The infusion time for onartuzumab/placebo and carboplatin was clarified. The subset of participants who consent to additional blood draws for pharmacokinetic (PK) analysis might be subjected to safety issues with a shorter than standard infusion time for the given chemotherapeutic agents, thus, the protocol was amended to indicate that all participants were to be dosed on the same schedule. With regard to carboplatin dose calculation, the correction for the Cockcroft-Gault method for calculation of creatinine clearance in females, which was inadvertently omitted from the original protocol, was provided. For the participants who consent to additional PK sampling, in an effort to shorten their time in the clinic, the final sampling timepoint for plasma paclitaxel pharmacokinetics at Cycle 1 Day 1 and Cycle 4 Day 1 was changed from 8 hours to 6 hours after the end of the paclitaxel infusion for participants in Cohort 1.

13 Apr 2012

The study inclusion criterion regarding participants who undergo prior adjuvant therapy was clarified to include chemoradiotherapy along with chemotherapy. In the study inclusion criteria regarding contraception, for Cohort 1, the required duration of the use of adequate contraception after study treatment was increased in accordance with the current labeling for paclitaxel. The study exclusion criterion regarding participants with endothelial growth factor receptor (EGFR)-activating mutations who were suitable for anti-EGFR therapy was modified to allow for cases where treatment was unavailable to or refused by the participant. The exclusion criterion regarding history of malignancy was modified to allow for in-situ cancer or localized prostate cancer that was treated surgically with curative intent. Clarification was provided regarding the administration of chemotherapy in accordance with local standard of care. Clarification was provided regarding the use of positron emission tomography (PET) - Computed tomography (CT) for tumor and response evaluations. With regard to tumor tissue samples, clarification was provided on the number of tissue slides to be submitted when EGFR status was already known. It was clarified that baseline weight (rather than screening weight) will be used to calculate onartuzumab/placebo dosage. For Cohort 1, the timing for paclitaxel administration was clarified to be after bevacizumab infusion, not after onartuzumab/placebo. For Cohorts 1 and 2, the timing of carboplatin treatment after paclitaxel or pemetrexed infusion has been clarified. The maximum allowed onartuzumab/placebo dose delay was extended from 7 days to one treatment cycle. To more fully comply with updated regulations, serious adverse events (SAEs) and pregnancies were planned to be reported within 24 hours rather than 1 working day.

03 Apr 2013

For the Sponsor’s internal decision-making process, a third data review by the Internal Monitoring Committee (IMC) was added to assess the treatment effect in participants with MET diagnostic-positive tumors at an earlier time point than the planned final analysis. For consistency with other clinical studies with onartuzumab, the observation period following onartuzumab/placebo infusion was reduced to greater than or equal to (≥) 30 minutes after the second and subsequent doses. It has been clarified that if a chemotherapy regimen other than those specified in the protocol was administered, onartuzumab will be discontinued. Clarification was provided regarding what tests were required to be performed as part of an evaluation for proteinuria. The measurement of partial thromboplastin time (PTT), which was inadvertently included in the original protocol, was removed from the exclusion criterion regarding coagulation testing at screening. It was clarified that EGFR testing was not required to be completed prior to randomization.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
31 Oct 2013	A decision was made by the sponsor to discontinue further clinical development of onartuzumab.	-

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

The clinical development of onartuzumab was terminated as per decision made by sponsor primarily due to limited efficacy observed in the conduct of this study and was not based on safety-related issues.

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Primary: Progression Free Survival (PFS)

Primary: Progression Free Survival (PFS)

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Primary: PFS in Subgroup of Participants with MET Diagnostic Positive Tumors

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Percentage of Participants with an Objective Response Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1

Secondary: Percentage of Participants with an Objective Response Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1

Secondary: Duration of Response (DoR)

Secondary: Duration of Response (DoR)

Secondary: Disease Control Rate

Secondary: Disease Control Rate

Secondary: Pre-dose Serum Onartuzumab Concentration (Cmin) on Day 1 of Cycles 1 and 4

Secondary: Pre-dose Serum Onartuzumab Concentration (Cmin) on Day 1 of Cycles 1 and 4

Secondary: Post-dose Serum Onartuzumab Concentration (Cmax) on Day 1 of Cycles 1 and 4

Secondary: Post-dose Serum Onartuzumab Concentration (Cmax) on Day 1 of Cycles 1 and 4

Secondary: Number of Participants with Anti-therapeutic Antibodies (ATA) Against Onartuzumab

Secondary: Number of Participants with Anti-therapeutic Antibodies (ATA) Against Onartuzumab

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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