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    Clinical Trial Results:
    A Randomized, Phase II, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Onartuzumab and/or Bevacizumab in Combination with Paclitaxel in Patients with Metastatic, Triple-Negative Breast Cancer

    Summary
    EudraCT number
    2010-020101-32
    Trial protocol
    ES   FR   BE   DE   GB  
    Global end of trial date
    08 Mar 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    05 Aug 2016
    First version publication date
    06 Jul 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of a few data points following identification of errors.

    Trial information

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    Trial identification
    Sponsor protocol code
    GO01334
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01186991
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    OAM4861g: Alternate sponsor trial identifier
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland,
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 061 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 061 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    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
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the clinical benefit of onartuzumab+ bevacizumab + paclitaxel (Onar+Bev+Pac) and onartuzumab+ placebo + paclitaxel (Onar+Pbo+Pac) relative to placebo + bevacizumab + paclitaxel (Pbo+Bev+Pac), as measured by investigator assessed Progression Free Survival (PFS), in patients with metastatic or locally recurrent, Triple-Negative Breast Cancer (TNBC) who have received no prior systemic therapy or have progressed following first-line therapy for metastatic disease.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice. All subjects signed an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 69
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    France: 54
    Country: Number of subjects enrolled
    Germany: 8
    Worldwide total number of subjects
    185
    EEA total number of subjects
    116
    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)
    153
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled in 51 centers in 6 countries.

    Pre-assignment
    Screening details
    A total of 250 participants were screened for entry into the study; there were 65 screen failures. A total of 185 participants were randomized in a 1:1:1 ratio to three treatment arms.

    Period 1
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Onartuzumab + Placebo + Paclitaxel
    Arm description
    Onartuzumab was administered every 2 weeks, on Day 1 and 15 of each 28 day cycle. Paclitaxel was administered on Day 1, 8 and 15 of each 28 day cycle. Placebo was administered by IV infusion every 2 weeks, on Day 1 and Day 15 of each 28-day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo dosage consisted of 250 cc of 0.9% NSS (saline IV solution, 0.9%). The initial dose of onartuzumab/placebo was delivered over 90 ±15 minutes. If the first infusion was tolerated without infusion-associated AEs (fever and/or chills), the second infusion was delivered over 60 ± 10 minutes. If the 60-minute infusion was well tolerated, all subsequent infusions were delivered over 30 ±10 minutes.

    Investigational medicinal product name
    Onartuzumab
    Investigational medicinal product code
    Other name
    MetMab
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. The dose of onartuzumab was based on the patient’s weight at screening and remained the same throughout the study. The initial dose of onartuzumab/placebo was delivered over 90 ±15 minutes. If the first infusion was tolerated without infusion-associated AEs (fever and/or chills), the second infusion was delivered over 60 ± 10 minutes. If the 60-minute infusion was well tolerated, all subsequent infusions were delivered over 30 ±10 minutes.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at dose of 90 mg/m2 on Day 1, 8, and 15 of each 28 day cycle. Administered over a period of approximately 1 hour. Due to the known potential for allergic reactions to paclitaxel, participants were pre-medicated with dexamethasone, diphenhydramine, and an H2 blocker 30−60 minutes prior to the paclitaxel administration.

    Arm title
    Onartuzumab + Bevacizumab + Paclitaxel
    Arm description
    Onartuzumab, alone or in combination with Bevacizumab, was administered every two weeks, on Day 1 and 15 of each 28-day cycle. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Paclitaxel was administered on Day 1, 8, and 15 of each 28-day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Onartuzumab
    Investigational medicinal product code
    Other name
    MetMab
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. The dose of onartuzumab was based on the patient’s weight at screening and remained the same throughout the study. The initial dose of onartuzumab/placebo was delivered over 90 ±15 minutes. If the first infusion was tolerated without infusion-associated AEs (fever and/or chills), the second infusion was delivered over 60 ± 10 minutes. If the 60-minute infusion was well tolerated, all subsequent infusions were delivered over 30 ±10 minutes.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at dose of 90 mg/m2 on Day 1, 8, and 15 of each 28 day cycle. Administered over a period of approximately 1 hour. Due to the known potential for allergic reactions to paclitaxel, participants were pre-medicated with dexamethasone, diphenhydramine, and an H2 blocker 30−60 minutes prior to the paclitaxel administration.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at a dose of 10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. The dose of bevacizumab was based on the participant's weight at screening and remained the same throughout the study. The initial dose of bevacizumab/placebo was delivered over 90 ±15 minutes. If the first infusion was tolerated without any infusion-associated AEs (fever and/or chills), the second infusion was delivered over 60 ± 10 minutes. If the 60-minute infusion was well tolerated, all subsequent infusions were delivered over 30 ± 10 minutes.

    Arm title
    Placebo + Bevacizumab + Paclitaxel
    Arm description
    Placebo was administered by IV infusion every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Paclitaxel was administered on Day 1, 8, and 15 of each 28-day cycle.
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo dosage consisted of 250 cc of 0.9% NSS (saline IV solution, 0.9%). The initial dose of bevacizumab/placebo was delivered over 90 ±15 minutes. If the first infusion was tolerated without any infusion-associated AEs (fever and/or chills), the second infusion was delivered over 60 ± 10 minutes. If the 60-minute infusion was well tolerated, all subsequent infusions were delivered over 30 ± 10 minutes.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at a dose of 10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. The dose of bevacizumab was based on the participant's weight at screening and remained the same throughout the study. The initial dose of bevacizumab/placebo was delivered over 90 ±15 minutes. If the first infusion was tolerated without any infusion-associated AEs (fever and/or chills), the second infusion was delivered over 60 ± 10 minutes. If the 60-minute infusion was well tolerated, all subsequent infusions were delivered over 30 ± 10 minutes.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at dose of 90 mg/m2 on Day 1, 8, and 15 of each 28 day cycle. Administered over a period of approximately 1 hour. Due to the known potential for allergic reactions to paclitaxel, participants were pre-medicated with dexamethasone, diphenhydramine, and an H2 blocker 30−60 minutes prior to the paclitaxel administration.

    Number of subjects in period 1
    Onartuzumab + Placebo + Paclitaxel Onartuzumab + Bevacizumab + Paclitaxel Placebo + Bevacizumab + Paclitaxel
    Started
    60
    63
    62
    Completed
    0
    0
    0
    Not completed
    60
    63
    62
         Death
    44
    45
    42
         Physician decision
    -
    -
    2
         Withdrawal by subject
    3
    3
    -
         Study terminated by sponsor
    13
    15
    16
         Adverse event, non-fatal
    -
    -
    1
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Onartuzumab + Placebo + Paclitaxel
    Reporting group description
    Onartuzumab was administered every 2 weeks, on Day 1 and 15 of each 28 day cycle. Paclitaxel was administered on Day 1, 8 and 15 of each 28 day cycle. Placebo was administered by IV infusion every 2 weeks, on Day 1 and Day 15 of each 28-day cycle.

    Reporting group title
    Onartuzumab + Bevacizumab + Paclitaxel
    Reporting group description
    Onartuzumab, alone or in combination with Bevacizumab, was administered every two weeks, on Day 1 and 15 of each 28-day cycle. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Paclitaxel was administered on Day 1, 8, and 15 of each 28-day cycle.

    Reporting group title
    Placebo + Bevacizumab + Paclitaxel
    Reporting group description
    Placebo was administered by IV infusion every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Paclitaxel was administered on Day 1, 8, and 15 of each 28-day cycle.

    Reporting group values
    Onartuzumab + Placebo + Paclitaxel Onartuzumab + Bevacizumab + Paclitaxel Placebo + Bevacizumab + Paclitaxel Total
    Number of subjects
    60 63 62 185
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.4 ± 12.5 53.5 ± 11.7 52.8 ± 9.1 -
    Gender categorical
    Units: Subjects
        Female
    60 63 62 185
        Male
    0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Onartuzumab + Placebo + Paclitaxel
    Reporting group description
    Onartuzumab was administered every 2 weeks, on Day 1 and 15 of each 28 day cycle. Paclitaxel was administered on Day 1, 8 and 15 of each 28 day cycle. Placebo was administered by IV infusion every 2 weeks, on Day 1 and Day 15 of each 28-day cycle.

    Reporting group title
    Onartuzumab + Bevacizumab + Paclitaxel
    Reporting group description
    Onartuzumab, alone or in combination with Bevacizumab, was administered every two weeks, on Day 1 and 15 of each 28-day cycle. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Paclitaxel was administered on Day 1, 8, and 15 of each 28-day cycle.

    Reporting group title
    Placebo + Bevacizumab + Paclitaxel
    Reporting group description
    Placebo was administered by IV infusion every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Bevacizumab was administered at a dose of 10 mg/kg every 2 weeks, on Day 1 and Day 15 of each 28-day cycle. Paclitaxel was administered on Day 1, 8, and 15 of each 28-day cycle.

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    Analyzed population was randomized participants.
    End point type
    Primary
    End point timeframe
    Time from randomization to disease progression or relapse (assessed using Response Evaluation Criteria in Solid Tumors [RECIST], Version 1.1) or death from any cause (defined as death within 30 days of last study treatment), whichever occurs first.
    End point values
    Onartuzumab + Placebo + Paclitaxel Onartuzumab + Bevacizumab + Paclitaxel Placebo + Bevacizumab + Paclitaxel
    Number of subjects analysed
    60
    63
    62
    Units: Months
        median (full range (min-max))
    5.4 (0 to 17.3)
    7.3 (0 to 16.6)
    7.2 (1.6 to 23)
    Statistical analysis title
    PFS Met+Pbo+Pac relative to Pbo+Bev+Pac
    Comparison groups
    Onartuzumab + Placebo + Paclitaxel v Placebo + Bevacizumab + Paclitaxel
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0109
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.739
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.13
         upper limit
    2.675
    Statistical analysis title
    PFS Met+Bev+Pac relative to Pbo+Bev+Pac
    Comparison groups
    Onartuzumab + Bevacizumab + Paclitaxel v Placebo + Bevacizumab + Paclitaxel
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.73
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.083
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.689
         upper limit
    1.702

    Secondary: Objective Response (OR)

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    End point title
    Objective Response (OR)
    End point description
    Analyzed population was randomized participants with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Complete or partial response maintained >/= 4 weeks
    End point values
    Onartuzumab + Placebo + Paclitaxel Onartuzumab + Bevacizumab + Paclitaxel Placebo + Bevacizumab + Paclitaxel
    Number of subjects analysed
    14
    19
    29
    Units: Percentage
        number (confidence interval 95%)
    27.5 (15.9 to 40.6)
    42.2 (28.6 to 57.1)
    54.7 (41 to 68.4)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response

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    End point title
    Duration of Objective Response
    End point description
    Analyzed population was randomized participants with measurable disease at baseline
    End point type
    Secondary
    End point timeframe
    Initial complete or partial response to disease progression or death on study from any cause, whichever occurs first.
    End point values
    Onartuzumab + Placebo + Paclitaxel Onartuzumab + Bevacizumab + Paclitaxel Placebo + Bevacizumab + Paclitaxel
    Number of subjects analysed
    14
    19
    29
    Units: Months
        median (confidence interval 95%)
    5.8 (3.71 to 99999)
    9.8 (4.67 to 99999)
    7.5 (5.36 to 11.53)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival is the time from randomization to death from any cause; data reflects randomized population
    End point type
    Secondary
    End point timeframe
    Through the end of the study
    End point values
    Onartuzumab + Placebo + Paclitaxel Onartuzumab + Bevacizumab + Paclitaxel Placebo + Bevacizumab + Paclitaxel
    Number of subjects analysed
    60
    63
    62
    Units: Months
        median (confidence interval 95%)
    13.4 (9.76 to 9999)
    14.7 (10.58 to 9999)
    17.4 (12.55 to 9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The time frame for the safety data was throughout the course of the study until the data cutoff date.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Onartuzumab +Bevacizumab +Paclitaxel
    Reporting group description
    -

    Reporting group title
    Placebo + Bevacizumab +Paclitaxel
    Reporting group description
    -

    Reporting group title
    Onartuzumab + Placebo + Paclitaxel
    Reporting group description
    -

    Serious adverse events
    Onartuzumab +Bevacizumab +Paclitaxel Placebo + Bevacizumab +Paclitaxel Onartuzumab + Placebo + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 62 (35.48%)
    15 / 62 (24.19%)
    13 / 58 (22.41%)
         number of deaths (all causes)
    44
    43
    43
         number of deaths resulting from adverse events
    3
    2
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic thrombosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemorrhagic tumour necrosis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Infusion site extravasation
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcus test positive
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 62 (6.45%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 62 (4.84%)
    0 / 62 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dural arteriovenous fistula
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokinesia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sensory loss
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 62 (3.23%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic infarction
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Onartuzumab +Bevacizumab +Paclitaxel Placebo + Bevacizumab +Paclitaxel Onartuzumab + Placebo + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 62 (98.39%)
    61 / 62 (98.39%)
    57 / 58 (98.28%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 62 (8.06%)
    1 / 58 (1.72%)
         occurrences all number
    3
    5
    1
    Hot flush
         subjects affected / exposed
    4 / 62 (6.45%)
    7 / 62 (11.29%)
    6 / 58 (10.34%)
         occurrences all number
    4
    8
    7
    Phlebitis
         subjects affected / exposed
    5 / 62 (8.06%)
    0 / 62 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    5
    0
    2
    Lymphoedema
         subjects affected / exposed
    7 / 62 (11.29%)
    5 / 62 (8.06%)
    8 / 58 (13.79%)
         occurrences all number
    7
    6
    8
    Hypotension
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 62 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    3
    0
    3
    Hypertension
         subjects affected / exposed
    13 / 62 (20.97%)
    25 / 62 (40.32%)
    3 / 58 (5.17%)
         occurrences all number
    13
    32
    3
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 62 (6.45%)
    7 / 58 (12.07%)
         occurrences all number
    5
    4
    10
    Asthenia
         subjects affected / exposed
    17 / 62 (27.42%)
    19 / 62 (30.65%)
    20 / 58 (34.48%)
         occurrences all number
    56
    49
    45
    Mucosal inflammation
         subjects affected / exposed
    10 / 62 (16.13%)
    11 / 62 (17.74%)
    1 / 58 (1.72%)
         occurrences all number
    17
    14
    1
    Generalised oedema
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 62 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    2
    0
    6
    Chills
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 62 (1.61%)
    3 / 58 (5.17%)
         occurrences all number
    2
    5
    3
    Face oedema
         subjects affected / exposed
    6 / 62 (9.68%)
    0 / 62 (0.00%)
    8 / 58 (13.79%)
         occurrences all number
    11
    0
    9
    Fatigue
         subjects affected / exposed
    29 / 62 (46.77%)
    32 / 62 (51.61%)
    24 / 58 (41.38%)
         occurrences all number
    40
    41
    35
    Pyrexia
         subjects affected / exposed
    2 / 62 (3.23%)
    11 / 62 (17.74%)
    8 / 58 (13.79%)
         occurrences all number
    5
    14
    11
    Peripheral swelling
         subjects affected / exposed
    5 / 62 (8.06%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences all number
    11
    2
    0
    Oedema peripheral
         subjects affected / exposed
    33 / 62 (53.23%)
    10 / 62 (16.13%)
    34 / 58 (58.62%)
         occurrences all number
    69
    10
    77
    Pain
         subjects affected / exposed
    3 / 62 (4.84%)
    2 / 62 (3.23%)
    3 / 58 (5.17%)
         occurrences all number
    3
    2
    4
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 62 (6.45%)
    4 / 58 (6.90%)
         occurrences all number
    5
    4
    5
    Anxiety
         subjects affected / exposed
    5 / 62 (8.06%)
    5 / 62 (8.06%)
    6 / 58 (10.34%)
         occurrences all number
    5
    5
    9
    Insomnia
         subjects affected / exposed
    13 / 62 (20.97%)
    12 / 62 (19.35%)
    7 / 58 (12.07%)
         occurrences all number
    14
    13
    7
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 62 (3.23%)
    5 / 58 (8.62%)
         occurrences all number
    4
    2
    5
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 62 (1.61%)
    3 / 58 (5.17%)
         occurrences all number
    1
    1
    6
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    5 / 62 (8.06%)
    1 / 62 (1.61%)
    1 / 58 (1.72%)
         occurrences all number
    13
    5
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 62 (1.61%)
    3 / 58 (5.17%)
         occurrences all number
    3
    1
    4
    Neutrophil count decreased
         subjects affected / exposed
    5 / 62 (8.06%)
    5 / 62 (8.06%)
    3 / 58 (5.17%)
         occurrences all number
    11
    8
    4
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    8 / 62 (12.90%)
    7 / 62 (11.29%)
    2 / 58 (3.45%)
         occurrences all number
    9
    8
    2
    Cough
         subjects affected / exposed
    14 / 62 (22.58%)
    15 / 62 (24.19%)
    9 / 58 (15.52%)
         occurrences all number
    19
    19
    10
    Oropharyngeal pain
         subjects affected / exposed
    6 / 62 (9.68%)
    10 / 62 (16.13%)
    4 / 58 (6.90%)
         occurrences all number
    9
    11
    4
    Dyspnoea
         subjects affected / exposed
    12 / 62 (19.35%)
    11 / 62 (17.74%)
    13 / 58 (22.41%)
         occurrences all number
    15
    13
    17
    Rhinitis allergic
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 62 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    4
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    7 / 62 (11.29%)
    3 / 62 (4.84%)
    2 / 58 (3.45%)
         occurrences all number
    7
    3
    2
    Epistaxis
         subjects affected / exposed
    31 / 62 (50.00%)
    37 / 62 (59.68%)
    9 / 58 (15.52%)
         occurrences all number
    49
    57
    12
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 62 (4.84%)
    0 / 58 (0.00%)
         occurrences all number
    5
    3
    0
    Anaemia
         subjects affected / exposed
    13 / 62 (20.97%)
    10 / 62 (16.13%)
    2 / 58 (3.45%)
         occurrences all number
    22
    13
    2
    Neutropenia
         subjects affected / exposed
    16 / 62 (25.81%)
    11 / 62 (17.74%)
    10 / 58 (17.24%)
         occurrences all number
    41
    21
    19
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 62 (27.42%)
    18 / 62 (29.03%)
    9 / 58 (15.52%)
         occurrences all number
    24
    27
    10
    Dizziness
         subjects affected / exposed
    6 / 62 (9.68%)
    8 / 62 (12.90%)
    5 / 58 (8.62%)
         occurrences all number
    7
    9
    5
    Dysaesthesia
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 62 (6.45%)
    1 / 58 (1.72%)
         occurrences all number
    4
    6
    2
    Dysgeusia
         subjects affected / exposed
    7 / 62 (11.29%)
    9 / 62 (14.52%)
    7 / 58 (12.07%)
         occurrences all number
    9
    9
    7
    Paraesthesia
         subjects affected / exposed
    16 / 62 (25.81%)
    21 / 62 (33.87%)
    8 / 58 (13.79%)
         occurrences all number
    24
    29
    11
    Neuropathy peripheral
         subjects affected / exposed
    18 / 62 (29.03%)
    21 / 62 (33.87%)
    15 / 58 (25.86%)
         occurrences all number
    27
    25
    33
    Hypoaesthesia
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 62 (8.06%)
    4 / 58 (6.90%)
         occurrences all number
    4
    6
    4
    Lethargy
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 62 (6.45%)
    2 / 58 (3.45%)
         occurrences all number
    3
    5
    3
    Neuralgia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
    3 / 58 (5.17%)
         occurrences all number
    0
    1
    4
    Peripheral sensory neuropathy
         subjects affected / exposed
    10 / 62 (16.13%)
    5 / 62 (8.06%)
    10 / 58 (17.24%)
         occurrences all number
    11
    7
    12
    Sciatica
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
    0 / 58 (0.00%)
         occurrences all number
    1
    4
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 62 (1.61%)
    5 / 62 (8.06%)
    0 / 58 (0.00%)
         occurrences all number
    3
    5
    0
    Lacrimation increased
         subjects affected / exposed
    7 / 62 (11.29%)
    3 / 62 (4.84%)
    1 / 58 (1.72%)
         occurrences all number
    9
    3
    1
    Vision blurred
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
    2 / 58 (3.45%)
         occurrences all number
    1
    4
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 62 (4.84%)
    3 / 58 (5.17%)
         occurrences all number
    1
    7
    6
    Tinnitus
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 62 (1.61%)
    3 / 58 (5.17%)
         occurrences all number
    1
    1
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    21 / 62 (33.87%)
    23 / 62 (37.10%)
    16 / 58 (27.59%)
         occurrences all number
    26
    30
    18
    Abdominal pain upper
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 62 (4.84%)
    5 / 58 (8.62%)
         occurrences all number
    5
    3
    6
    Abdominal pain
         subjects affected / exposed
    10 / 62 (16.13%)
    8 / 62 (12.90%)
    13 / 58 (22.41%)
         occurrences all number
    13
    12
    17
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 62 (1.61%)
    5 / 62 (8.06%)
    4 / 58 (6.90%)
         occurrences all number
    2
    9
    8
    Diarrhoea
         subjects affected / exposed
    33 / 62 (53.23%)
    32 / 62 (51.61%)
    14 / 58 (24.14%)
         occurrences all number
    54
    55
    27
    Dry mouth
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 62 (1.61%)
    4 / 58 (6.90%)
         occurrences all number
    4
    1
    6
    Dyspepsia
         subjects affected / exposed
    9 / 62 (14.52%)
    5 / 62 (8.06%)
    4 / 58 (6.90%)
         occurrences all number
    11
    5
    5
    Rectal haemorrhage
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 62 (3.23%)
    0 / 58 (0.00%)
         occurrences all number
    4
    3
    0
    Haemorrhoids
         subjects affected / exposed
    7 / 62 (11.29%)
    9 / 62 (14.52%)
    4 / 58 (6.90%)
         occurrences all number
    8
    15
    5
    Nausea
         subjects affected / exposed
    24 / 62 (38.71%)
    26 / 62 (41.94%)
    22 / 58 (37.93%)
         occurrences all number
    34
    40
    32
    Oral pain
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 62 (1.61%)
    0 / 58 (0.00%)
         occurrences all number
    5
    1
    0
    Stomatitis
         subjects affected / exposed
    15 / 62 (24.19%)
    13 / 62 (20.97%)
    3 / 58 (5.17%)
         occurrences all number
    22
    17
    3
    Toothache
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 62 (8.06%)
    1 / 58 (1.72%)
         occurrences all number
    2
    5
    1
    Vomiting
         subjects affected / exposed
    10 / 62 (16.13%)
    13 / 62 (20.97%)
    12 / 58 (20.69%)
         occurrences all number
    16
    21
    21
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 62 (3.23%)
    8 / 62 (12.90%)
    2 / 58 (3.45%)
         occurrences all number
    3
    11
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    5 / 62 (8.06%)
    6 / 62 (9.68%)
    5 / 58 (8.62%)
         occurrences all number
    6
    6
    8
    Dry skin
         subjects affected / exposed
    9 / 62 (14.52%)
    8 / 62 (12.90%)
    7 / 58 (12.07%)
         occurrences all number
    9
    8
    9
    Dermatitis acneiform
         subjects affected / exposed
    5 / 62 (8.06%)
    5 / 62 (8.06%)
    8 / 58 (13.79%)
         occurrences all number
    6
    8
    14
    Alopecia
         subjects affected / exposed
    30 / 62 (48.39%)
    38 / 62 (61.29%)
    30 / 58 (51.72%)
         occurrences all number
    38
    44
    33
    Acne
         subjects affected / exposed
    5 / 62 (8.06%)
    1 / 62 (1.61%)
    3 / 58 (5.17%)
         occurrences all number
    8
    1
    4
    Nail discolouration
         subjects affected / exposed
    5 / 62 (8.06%)
    9 / 62 (14.52%)
    2 / 58 (3.45%)
         occurrences all number
    5
    9
    2
    Nail disorder
         subjects affected / exposed
    11 / 62 (17.74%)
    10 / 62 (16.13%)
    4 / 58 (6.90%)
         occurrences all number
    21
    11
    6
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 62 (8.06%)
    1 / 62 (1.61%)
    1 / 58 (1.72%)
         occurrences all number
    7
    1
    1
    Nail toxicity
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 62 (6.45%)
    4 / 58 (6.90%)
         occurrences all number
    8
    6
    6
    Rash erythematous
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
    1 / 58 (1.72%)
         occurrences all number
    1
    5
    1
    Rash
         subjects affected / exposed
    12 / 62 (19.35%)
    13 / 62 (20.97%)
    6 / 58 (10.34%)
         occurrences all number
    17
    14
    8
    Pruritus
         subjects affected / exposed
    7 / 62 (11.29%)
    4 / 62 (6.45%)
    2 / 58 (3.45%)
         occurrences all number
    7
    5
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 62 (25.81%)
    13 / 62 (20.97%)
    7 / 58 (12.07%)
         occurrences all number
    22
    18
    14
    Back pain
         subjects affected / exposed
    9 / 62 (14.52%)
    9 / 62 (14.52%)
    10 / 58 (17.24%)
         occurrences all number
    12
    11
    10
    Bone pain
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
    6 / 58 (10.34%)
         occurrences all number
    1
    4
    6
    Neck pain
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
    1 / 58 (1.72%)
         occurrences all number
    1
    4
    1
    Myalgia
         subjects affected / exposed
    17 / 62 (27.42%)
    11 / 62 (17.74%)
    11 / 58 (18.97%)
         occurrences all number
    23
    20
    13
    Muscle spasms
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 62 (3.23%)
    5 / 58 (8.62%)
         occurrences all number
    3
    2
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    6 / 62 (9.68%)
    4 / 62 (6.45%)
    3 / 58 (5.17%)
         occurrences all number
    6
    4
    4
    Musculoskeletal pain
         subjects affected / exposed
    8 / 62 (12.90%)
    10 / 62 (16.13%)
    5 / 58 (8.62%)
         occurrences all number
    11
    10
    7
    Pain in extremity
         subjects affected / exposed
    10 / 62 (16.13%)
    12 / 62 (19.35%)
    10 / 58 (17.24%)
         occurrences all number
    14
    16
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 62 (19.35%)
    13 / 62 (20.97%)
    9 / 58 (15.52%)
         occurrences all number
    15
    17
    14
    Hypokalaemia
         subjects affected / exposed
    6 / 62 (9.68%)
    2 / 62 (3.23%)
    3 / 58 (5.17%)
         occurrences all number
    7
    2
    3
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 62 (8.06%)
    1 / 62 (1.61%)
    3 / 58 (5.17%)
         occurrences all number
    7
    1
    3
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    3 / 62 (4.84%)
    2 / 62 (3.23%)
    3 / 58 (5.17%)
         occurrences all number
    3
    2
    3
    Paronychia
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 62 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    6
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
    5 / 58 (8.62%)
         occurrences all number
    1
    5
    5
    Gastroenteritis
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 62 (6.45%)
    2 / 58 (3.45%)
         occurrences all number
    0
    4
    2
    Gingivitis
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 62 (8.06%)
    1 / 58 (1.72%)
         occurrences all number
    4
    7
    1
    Nasopharyngitis
         subjects affected / exposed
    7 / 62 (11.29%)
    10 / 62 (16.13%)
    8 / 58 (13.79%)
         occurrences all number
    9
    18
    10
    Urinary tract infection
         subjects affected / exposed
    12 / 62 (19.35%)
    5 / 62 (8.06%)
    10 / 58 (17.24%)
         occurrences all number
    15
    8
    12
    Rhinitis
         subjects affected / exposed
    3 / 62 (4.84%)
    6 / 62 (9.68%)
    7 / 58 (12.07%)
         occurrences all number
    3
    6
    8
    Sinusitis
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 62 (6.45%)
    1 / 58 (1.72%)
         occurrences all number
    2
    9
    1
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 62 (14.52%)
    8 / 62 (12.90%)
    2 / 58 (3.45%)
         occurrences all number
    10
    9
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2010
    1) Addition of a third treatment arm (Onar+Pbo+Pac) to help estimate the benefit of onartuzumab+paclitaxel independent of bevacizumab.
    21 Aug 2012
    1) Addition of an observation period of 30–60 minutes after completion of each onartuzumab infusion to monitor for infusion-associated symptoms. 2) Clarification that in order to prevent hypersensitivity reactions, all patients should be pre-medicated prior to paclitaxel administration

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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