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    Clinical Trial Results:
    A Two-Part, Randomized Phase III, Double-Blind, Multicenter Trial Assessing The Efficacy And Safety of Pertuzumab In Combination With Standard Chemotherapy Vs. Placebo Plus Standard Chemotherapy In Women With Recurrent Platinum-Resistant Epithelial Ovarian Cancer And Low HER3 mRNA Expression

    Summary
    EudraCT number
    		 2011-005975-17
    Trial protocol
    		 ES   DE   IT   NL   SE   BE   AT   DK  
    Global end of trial date
    09 Jun 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    26 Apr 2017
    First version publication date
    19 Oct 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MO28113
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01684878
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alias: PENELOPE
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, 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
    09 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1: Safety Run-in Phase -To determine the safety and tolerability of pertuzumab in combination with either topotecan or paclitaxel. Part 2: -To determine if pertuzumab plus chemotherapy is superior to placebo plus chemotherapy as measured by progression-free survival (PFS) assessed by a blinded IRC including malignant bowel obstruction (MBO)
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Oct 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Spain: 72
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 31
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Italy: 33
    Worldwide total number of subjects
    206
    EEA total number of subjects
    206
    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)
    109
    From 65 to 84 years
    97
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 208 subjects were entered into the study, 52 subjects in Part 1, and 156 subjects in Part 2 of the study. Of these, 203 received treatment with pertuzumab or pertuzumab-placebo (50 subjects in Part 1 and 153 subjects in Part 2).

    Period 1
    Period 1 title
    Part 1: Safety Run in Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: Pertuzumab + Topotecan
    Arm description
    		 Subjects received pertuzumab and topotecan in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered topotecan at a dosage of 1.25 milligram per metre square (mg/m^2) as a 30-minute IV infusion daily on Days 1 to 5 every 3 weeks.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered pertuzumab 840 milligrams (mg) intravenous (IV) infusion on Day 1 of the first treatment cycle as a loading dose, followed by 420 mg on Day 1 of each subsequent 3 weekly cycle.

    Arm title
    		 Part 1: Pertuzumab + Paclitaxel
    Arm description
    		 Subjects received pertuzumab and paclitaxel in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered paclitaxel at a dosage of 80 mg/m^2 as 1-hour IV infusion on Days 1, 8 and 15 every 3 weeks.

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered pertuzumab 840 mg IV infusion on Day 1 of the first treatment cycle as a loading dose, followed by 420 mg on Day 1 of each subsequent 3 weekly cycle.

    Number of subjects in period 1 [1]
    		Part 1: Pertuzumab + Topotecan Part 1: Pertuzumab + Paclitaxel
    Started
    22
    28
    Completed
    6
    5
    Not completed
    16
    23
         Death
    15
    20
         Subjects withdrawn consent
    1
    1
         Lost to follow-up
    -
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The baseline period reflects the safety run-in phase of the study.
    Period 2
    Period 2 title
    Part 2: Randomised Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Part 2: Pertuzumab+Chemotherapy
    Arm description
    		 Subjects received pertuzumab and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigator's discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered pertuzumab 840 mg IV infusion on Day 1 of the first treatment cycle as a loading dose, followed by 420 mg on Day 1 of each subsequent 3 weekly cycle.

    Investigational medicinal product name
    Paclitaxel (Chemotherapy)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered paclitaxel at a dosage of 80 mg/m^2 as 1-hour IV infusion on Days 1, 8 and 15 every 3 weeks as per the directions in the summary of product characteristics (SmPC).

    Investigational medicinal product name
    Topotecan (chemotherapy)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered topotecan at a dosage of 1.25 mg/m^2 as a 30-minute IV infusion daily on Days 1 to 5 every 3 weeks as per the directions described in the SmPC.

    Investigational medicinal product name
    Gemcitabine (Chemotherapy)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered gemcitabine at a dosage of 1000 mg/m^2 IV infusion on Days 1 and 8 every 3 weeks as per the directions described in the SmPC.

    Arm title
    		 Part 2: Placebo+Chemotherapy
    Arm description
    		 Subjects received pertuzumab-matching placebo and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigator's discretion.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered pertuzumab matching placebo IV infusion on Day 1 of each 3 weekly cycle.

    Investigational medicinal product name
    Paclitaxel (Chemotherapy)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered paclitaxel at a dosage of 80 mg/m^2 as 1-hour IV infusion on Days 1, 8 and 15 every 3 weeks as per the directions in the summary of product characteristics (SmPC).

    Investigational medicinal product name
    Topotecan (chemotherapy)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered topotecan at a dosage of 1.25 mg/m^2 as a 30-minute IV infusion daily on Days 1 to 5 every 3 weeks as per the directions described in the SmPC.

    Investigational medicinal product name
    Gemcitabine (Chemotherapy)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered gemcitabine at a dosage of 1000 mg/m^2 IV infusion on Days 1 and 8 every 3 weeks as per the directions described in the SmPC.

    Number of subjects in period 2
    		Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Started
    78
    78
    Subject Randomised But Not Treated
    1
    2
    Subject Mis-randomised
    2
    0
    Completed
    0
    0
    Not completed
    78
    78
         Subject noncompliance
    -
    1
         Subject withdrew consent
    1
    2
         Alive at data-cut
    13
    7
         Death
    62
    68
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Pertuzumab + Topotecan
    Reporting group description
    		 Subjects received pertuzumab and topotecan in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Part 1: Pertuzumab + Paclitaxel
    Reporting group description
    		 Subjects received pertuzumab and paclitaxel in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group values
    		 Part 1: Pertuzumab + Topotecan Part 1: Pertuzumab + Paclitaxel Total
    Number of subjects
    		 22 28 50
    Age categorical
    Units: Subjects
        Less than or equal to (≤)65 years
    		 15 17 32
        Greater than (>)65 years
    		 7 11 18
    Gender categorical
    Units: Subjects
        Female
    		 22 28 50
        Male
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Overall Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Part 1: all subjects enrolled and treated in Part 1 of the study (‘as treated’ analysis) and Part 2: intent-to-treat (ITT) population was defined as all randomized subjects in the group to which they were randomly assigned (‘as randomized’ analysis).

    Subject analysis sets values
    		 Overall Subjects
    Number of subjects
    206
    Age categorical
    Units: Subjects
        Less than or equal to (≤)65 years
    116
        Greater than (>)65 years
    90
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    206
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Pertuzumab + Topotecan
    Reporting group description
    		 Subjects received pertuzumab and topotecan in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Part 1: Pertuzumab + Paclitaxel
    Reporting group description
    		 Subjects received pertuzumab and paclitaxel in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death.
    Reporting group title
    Part 2: Pertuzumab+Chemotherapy
    Reporting group description
    		 Subjects received pertuzumab and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigator's discretion.

    Reporting group title
    Part 2: Placebo+Chemotherapy
    Reporting group description
    		 Subjects received pertuzumab-matching placebo and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigator's discretion.

    Subject analysis set title
    Overall Subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Part 1: all subjects enrolled and treated in Part 1 of the study (‘as treated’ analysis) and Part 2: intent-to-treat (ITT) population was defined as all randomized subjects in the group to which they were randomly assigned (‘as randomized’ analysis).

    Primary: Part 1: Percentage of Subjects With Adverse Events (AEs)

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    End point title
    		 Part 1: Percentage of Subjects With Adverse Events (AEs) [1]
    End point description
    An AE can be any unfavorable and unintended sign (including an abnormality laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. All Treated population included all subjects enrolled and treated in Part 1 of the study (‘as treated’ analysis) and who had received at least 1 dose of pertuzumab or chemotherapy.
    End point type
    Primary
    End point timeframe
    Approximately 28 months (assessed at screening, baseline until 28 days after the last dose of study treatment)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analysis only.
    End point values
    		 Part 1: Pertuzumab + Topotecan Part 1: Pertuzumab + Paclitaxel
    Number of subjects analysed
    22
    28
    Units: percentage of subjects
        number (not applicable)
    95.5
    100
    No statistical analyses for this end point

    Primary: Part 2: Progression Free Survival (PFS) as Assessed by a Blinded Independent Review Committee (IRC) Including Malignant Bowel Obstruction (MBO)

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    End point title
    		 Part 2: Progression Free Survival (PFS) as Assessed by a Blinded Independent Review Committee (IRC) Including Malignant Bowel Obstruction (MBO)
    End point description
    PFS (IRC-Assessed) was defined as the time from randomisation into Part 2 of the trial until progressive disease (PD), MBO or death from any cause, whichever occurred first per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. ITT population was defined as all randomised subjects in the group to which they were randomly assigned (‘as randomised’ analysis).
    End point type
    Primary
    End point timeframe
    Approximately 44 months (assessed at screening and every 9 weeks from randomisation until disease progression)
    End point values
    		 Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Number of subjects analysed
    78
    78
    Units: months
        median (confidence interval 95%)
    4.27 (3.65 to 6.11)
    2.74 (2.14 to 4.73)
    Statistical analysis title
    		 PFS assessed by IRC including MBO
    Statistical analysis description
    The stratified time-to-event analysis included the treatment group variable plus the following stratification factors: selected chemotherapy cohort (gemcitabine versus topotecan vs paclitaxel), previous anti-angiogenic therapy (yes versus no), and progression-free interval (PFI) since platinum therapy (< 3 months versus 3-6 months). A hazard ratio < 1 favored the pertuzumab + chemotherapy treatment arm.
    Comparison groups
    Part 2: Pertuzumab+Chemotherapy v Part 2: Placebo+Chemotherapy
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4983
    Method
    		 2 sided log-rank
    Parameter type
    		 Hazard Ratio (stratified)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.27

    Secondary: Part 1- Objective Response Rate (ORR)

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    End point title
    		 Part 1- Objective Response Rate (ORR)
    End point description
    ORR was defined as the number of participants with best overall response (BOR) of complete response (CR) or partial response (PR) recorded from the start of treatment, until the end of treatment. BOR documented as confirmed CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimetre (mm). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. All Treated subjects with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Approximately 28 months (assessed at baseline and every 9 weeks from randomization until disease progression)
    End point values
    		 Part 1: Pertuzumab + Topotecan Part 1: Pertuzumab + Paclitaxel
    Number of subjects analysed
    14
    24
    Units: percentage of subjects
        number (not applicable)
    14.3
    25
    No statistical analyses for this end point

    Secondary: Part 2- Objective Response Rate (ORR)

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    End point title
    		 Part 2- Objective Response Rate (ORR)
    End point description
    ORR was defined as the number of subjects with BOR of CR or PR recorded from the start of treatment, until the end of treatment. BOR documented as confirmed CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimetre (mm). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ITT population with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Approximately 44 months (assessed at baseline and every 9 weeks from randomisation until disease progression)
    End point values
    		 Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Number of subjects analysed
    61
    69
    Units: percentage of subjects
        number (confidence interval 95%)
    14.8 (7 to 26.2)
    8.7 (3.3 to 18)
    Statistical analysis title
    		 Part 2: ORR
    Statistical analysis description
    Approximate 95% CI for difference of 2 rates using Hauck-Anderson method.
    Comparison groups
    Part 2: Pertuzumab+Chemotherapy v Part 2: Placebo+Chemotherapy
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4102
    Method
    		 Fisher exact
    Parameter type
    		 Difference in response rate
    Point estimate
    6.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6
         upper limit
    		 18.3

    Secondary: Part 1: PFS Assessed by the Investigator

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    End point title
    		 Part 1: PFS Assessed by the Investigator
    End point description
    PFS as assessed by Investigator was defined as the time from first dose of pertuzumab or chemotherapy in Part 1 of the trial, until disease progression according to RECIST version 1.1, symptomatic deterioration or death from any cause, whichever occurs first. PD could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Subjects were censored at the last tumor assessment. Subjects who have no tumor assessments after baseline and who were still alive will be censored at 1 day. All Treated population included all subjects enrolled and treated in Part 1 of the study (‘as treated’ analysis) and who had received at least 1 dose of pertuzumab or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Approximately 28 months (assessed at screening and every 9 weeks from randomisation until disease progression)
    End point values
    		 Part 1: Pertuzumab + Topotecan Part 1: Pertuzumab + Paclitaxel
    Number of subjects analysed
    22
    28
    Units: months
        median (confidence interval 95%)
    4.07 (1.94 to 6.08)
    4.24 (3.45 to 6.01)
    No statistical analyses for this end point

    Secondary: Part 2: Progression-free Survival (PFS) Assessed by the Investigator

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    End point title
    		 Part 2: Progression-free Survival (PFS) Assessed by the Investigator
    End point description
    PFS (Investigator-assessed) is defined as the time from randomisation, until disease progression according to RECIST v1.1 including death or MBO, whichever occurs first. Censoring is based on the last tumor assessment. If no tumor assessment post baseline, then censoring is at day 1. PD could base on symptom deterioration or was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. ITT Population included all randomised subjects in the group to which they were randomly assigned (‘as randomised’ analysis).
    End point type
    Secondary
    End point timeframe
    Approximately 44 months (assessed at screening and every 9 weeks from randomisation until disease progression)
    End point values
    		 Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Number of subjects analysed
    78
    78
    Units: months
        median (confidence interval 95%)
    4.22 (3.25 to 5.22)
    3.94 (2.63 to 4.3)
    No statistical analyses for this end point

    Secondary: Part 2: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire (QLQ) of Core 30 (C30) Score

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    End point title
    		 Part 2: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire (QLQ) of Core 30 (C30) Score
    End point description
    EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4-point scale (1 ‘Not at all’ to 4 ‘Very much’; 2 questions used 7-point scale [1 ‘very poor’ to 7 ‘Excellent’]). Scores averaged, transformed to 0-100 scale; for functional scores, a higher score represents a better level of functioning. For symptom scale scores a higher level represents a more severe level of symptoms. ITT population included all randomised subjects in the group to which they were randomly assigned (‘as randomised’ analysis).
    End point type
    Secondary
    End point timeframe
    Baseline (assessed at baseline and every 9 weeks from randomisation until disease progression)
    End point values
    		 Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Number of subjects analysed
    78
    78
    Units: units on a scale
    arithmetic mean (standard deviation)
        Functional Scales: Physical (n=71, 74)
    71.1 ± 22.77
    74.9 ± 20.85
        Functional Scales: Role (n=70, 73)
    68.6 ± 33.16
    69.4 ± 32.4
        Functional Scales: Emotional (n=71, 73)
    59.5 ± 24.03
    65.9 ± 23.42
        Functional Scales: Cognitive (n=71, 73)
    81.2 ± 25.34
    84.9 ± 20.25
        Functional Scales: Social (n=71, 73)
    70.7 ± 30.01
    68.3 ± 29.81
        Symptomatic Scales: Fatigue (n=71, 74)
    41.2 ± 28.75
    38.4 ± 27.77
        Symptomatic Scales: Nausea and vomiting (n=72, 74)
    10.4 ± 15.68
    12.4 ± 20.47
        Symptomatic Scales: Pain (n=72, 74)
    35.2 ± 31.34
    31.1 ± 29.24
        Symptomatic Scales: Dyspnoea (n=68, 73)
    22.5 ± 28.47
    21.5 ± 27.98
        Symptomatic Scales: Insomnia (n=69, 74)
    35.3 ± 31.25
    31.5 ± 31.16
        Symptomatic Scales: Appetite loss (n=71, 73)
    24.9 ± 30.19
    21 ± 26.36
        Symptomatic Scales: Constipation (n=69, 72)
    25.6 ± 32.41
    26.4 ± 32.59
        Symptomatic Scales: Diarrhoea (n=69, 72)
    14.5 ± 26.49
    14.4 ± 22.26
        Symptomatic Scales:Financial difficulties(n=70,72)
    17.6 ± 28.78
    13.4 ± 22.83
        Global health status / QoL scale (n=71, 72)
    54.1 ± 24.99
    61.1 ± 22.29
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects With Adverse Events (AEs)

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    End point title
    		 Part 2: Percentage of Subjects With Adverse Events (AEs)
    End point description
    An AE can be any unfavorable and unintended sign (including an abnormality laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Safety population included all subjects who had received at least 1 dose of pertuzumab, pertuzumab-placebo, or chemotherapy.
    End point type
    Secondary
    End point timeframe
    Approximately 28 months (assessed at screening, baseline until 28 days after the last dose of study treatment)
    End point values
    		 Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Number of subjects analysed
    77
    76
    Units: percentage of subjects
        number (not applicable)
    98.7
    100
    No statistical analyses for this end point

    Secondary: Part 2: Overall Survival

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    End point title
    		 Part 2: Overall Survival
    End point description
    Overall survival was defined as the time from randomization into Part 2 of the trial until death from any cause.
    End point type
    Secondary
    End point timeframe
    Approximately 44 months (assessed at screening and every 9 weeks from randomisation until disease progression)
    End point values
    		 Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Number of subjects analysed
    78
    78
    Units: months
        median (confidence interval 95%)
    10.18 (6.67 to 15.24)
    8.36 (6.14 to 11.99)
    Statistical analysis title
    		 Part 2: Overall Survival
    Statistical analysis description
    The stratified time-to-event analysis included the treatment group variable plus the following stratification factors: selected chemotherapy cohort (gemcitabine versus topotecan versus paclitaxel), previous angiogenic therapy (yes versus no) and PFI since platinum therapy (<3 months versus 3-6 months). A hazard ratio <1 favored the Pertuzumab + Chemotherapy treatment group.
    Comparison groups
    Part 2: Pertuzumab+Chemotherapy v Part 2: Placebo+Chemotherapy
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.596
    Method
    		 2 sided log-rank
    Parameter type
    		 Hazard ratio (stratified)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.32

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 28 months (assessed at screening, baseline until 28 days after the last dose of study treatment)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Part 1: Pertuzumab + Topotecan
    Reporting group description
    		 Subjects received pertuzumab and topotecan in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Part 1: Pertuzumab + Paclitaxel
    Reporting group description
    		 Subjects received pertuzumab and paclitaxel in cycles of 3 weeks until progressive disease as per investigator’s assessment, unacceptable toxicity, withdrawal of consent, or death.

    Reporting group title
    Part 2: Pertuzumab+Chemotherapy
    Reporting group description
    		 Subjects received pertuzumab and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigators discretion.

    Reporting group title
    Part 2: Placebo+Chemotherapy
    Reporting group description
    		 Subjects received pertuzumab matching placebo and chemotherapy (paclitaxel or topotecan or gemcitabine) in cycles of 3 weeks until progressive disease as per investigator's assessment, unacceptable toxicity, withdrawal of consent, or death. Chemotherapy was administered as per investigators discretion.

    Serious adverse events
    		 Part 1: Pertuzumab + Topotecan Part 1: Pertuzumab + Paclitaxel Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 22 (40.91%)
    11 / 28 (39.29%)
    29 / 77 (37.66%)
    33 / 76 (43.42%)
         number of deaths (all causes)
    0
    2
    6
    11
         number of deaths resulting from adverse events
    0
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian Cancer
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    3 / 77 (3.90%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 28 (3.57%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    Performance Status Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    1 / 1
    Asthenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    2 / 77 (2.60%)
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    Not yet coded
    Additional description: This adverse event was not coded at the time of the primary analysis. The preferred term will be reported when available at the final analysis.
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Reproductive system and breast disorders
    Vaginal Fistula
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 28 (3.57%)
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Injury, poisoning and procedural complications
    Contrast Media Reaction
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Humerus Fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Hydrocephalus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Ischaemic Stroke
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    3 / 77 (3.90%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Marrow Failure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Leukopenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Intestinal Obstruction
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    4 / 76 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Abdominal Pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    2 / 77 (2.60%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    3 / 77 (3.90%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    3 / 77 (3.90%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Anal Fissure
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Duodenal Fistula
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 28 (3.57%)
    0 / 77 (0.00%)
    0 / 76 (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
    Eczema Asteatotic
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Urinary Tract Disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Urinary Tract Obstruction
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 28 (3.57%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 28 (3.57%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 28 (3.57%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (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
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 28 (3.57%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         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
    Encephalitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    1 / 1
    Infective Myositis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Kidney Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Meningitis Pneumococcal
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Staphylococcal Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Anal Abscess
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (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
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased Appetite
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (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
    Dehydration
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Pertuzumab + Topotecan Part 1: Pertuzumab + Paclitaxel Part 2: Pertuzumab+Chemotherapy Part 2: Placebo+Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 22 (95.45%)
    27 / 28 (96.43%)
    72 / 77 (93.51%)
    75 / 76 (98.68%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    5
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 22 (63.64%)
    8 / 28 (28.57%)
    32 / 77 (41.56%)
    24 / 76 (31.58%)
         occurrences all number
    22
    10
    48
    32
    Fatigue
         subjects affected / exposed
    5 / 22 (22.73%)
    10 / 28 (35.71%)
    21 / 77 (27.27%)
    24 / 76 (31.58%)
         occurrences all number
    5
    13
    31
    30
    Pyrexia
         subjects affected / exposed
    5 / 22 (22.73%)
    5 / 28 (17.86%)
    9 / 77 (11.69%)
    12 / 76 (15.79%)
         occurrences all number
    7
    5
    14
    13
    Mucosal Inflammation
         subjects affected / exposed
    7 / 22 (31.82%)
    2 / 28 (7.14%)
    11 / 77 (14.29%)
    6 / 76 (7.89%)
         occurrences all number
    10
    5
    14
    7
    Oedema Peripheral
         subjects affected / exposed
    5 / 22 (22.73%)
    2 / 28 (7.14%)
    12 / 77 (15.58%)
    9 / 76 (11.84%)
         occurrences all number
    5
    2
    12
    9
    Influenza Like Illness
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences all number
    3
    0
    5
    1
    Malaise
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Oedema
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    5 / 22 (22.73%)
    7 / 28 (25.00%)
    16 / 77 (20.78%)
    5 / 76 (6.58%)
         occurrences all number
    5
    13
    19
    5
    Cough
         subjects affected / exposed
    5 / 22 (22.73%)
    2 / 28 (7.14%)
    7 / 77 (9.09%)
    5 / 76 (6.58%)
         occurrences all number
    6
    2
    10
    5
    Dyspnoea
         subjects affected / exposed
    3 / 22 (13.64%)
    4 / 28 (14.29%)
    7 / 77 (9.09%)
    12 / 76 (15.79%)
         occurrences all number
    3
    4
    7
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 28 (10.71%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 28 (10.71%)
    5 / 77 (6.49%)
    5 / 76 (6.58%)
         occurrences all number
    0
    5
    6
    5
    Investigations
    Weight Decreased
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 28 (7.14%)
    2 / 77 (2.60%)
    4 / 76 (5.26%)
         occurrences all number
    2
    2
    2
    4
    Ejection Fraction Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Lymphocyte Count Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    1 / 77 (1.30%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    1
    4
    Platelet Count Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    6 / 77 (7.79%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    10
    3
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    3 / 77 (3.90%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    3
    5
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    3 / 77 (3.90%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    4
    5
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    7 / 77 (9.09%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    8
    4
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    3 / 77 (3.90%)
    7 / 76 (9.21%)
         occurrences all number
    0
    0
    3
    8
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    6 / 77 (7.79%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    6
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    5 / 77 (6.49%)
    6 / 76 (7.89%)
         occurrences all number
    0
    0
    6
    6
    Nervous system disorders
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    2 / 22 (9.09%)
    7 / 28 (25.00%)
    10 / 77 (12.99%)
    9 / 76 (11.84%)
         occurrences all number
    2
    7
    10
    10
    Headache
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 28 (3.57%)
    7 / 77 (9.09%)
    5 / 76 (6.58%)
         occurrences all number
    3
    1
    9
    7
    Dizziness
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 28 (3.57%)
    7 / 77 (9.09%)
    4 / 76 (5.26%)
         occurrences all number
    2
    2
    9
    5
    Neuropathy Peripheral
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 28 (7.14%)
    7 / 77 (9.09%)
    9 / 76 (11.84%)
         occurrences all number
    1
    2
    8
    9
    Paraesthesia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 28 (7.14%)
    4 / 77 (5.19%)
    4 / 76 (5.26%)
         occurrences all number
    1
    7
    6
    8
    Ageusia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    9 / 77 (11.69%)
    7 / 76 (9.21%)
         occurrences all number
    0
    2
    10
    7
    Peripheral Motor Neuropathy
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    0
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 22 (68.18%)
    10 / 28 (35.71%)
    28 / 77 (36.36%)
    32 / 76 (42.11%)
         occurrences all number
    27
    13
    43
    48
    Neutropenia
         subjects affected / exposed
    5 / 22 (22.73%)
    3 / 28 (10.71%)
    23 / 77 (29.87%)
    21 / 76 (27.63%)
         occurrences all number
    13
    3
    45
    36
    Thrombocytopenia
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 28 (0.00%)
    3 / 77 (3.90%)
    5 / 76 (6.58%)
         occurrences all number
    4
    0
    5
    5
    Leukopenia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 28 (7.14%)
    4 / 77 (5.19%)
    9 / 76 (11.84%)
         occurrences all number
    1
    3
    6
    20
    Thrombocytosis
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Febrile Neutropenia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 22 (63.64%)
    22 / 28 (78.57%)
    50 / 77 (64.94%)
    23 / 76 (30.26%)
         occurrences all number
    34
    52
    110
    27
    Nausea
         subjects affected / exposed
    11 / 22 (50.00%)
    10 / 28 (35.71%)
    31 / 77 (40.26%)
    34 / 76 (44.74%)
         occurrences all number
    18
    14
    65
    53
    Vomiting
         subjects affected / exposed
    13 / 22 (59.09%)
    5 / 28 (17.86%)
    19 / 77 (24.68%)
    23 / 76 (30.26%)
         occurrences all number
    18
    6
    35
    35
    Abdominal Pain
         subjects affected / exposed
    6 / 22 (27.27%)
    4 / 28 (14.29%)
    16 / 77 (20.78%)
    21 / 76 (27.63%)
         occurrences all number
    6
    4
    26
    23
    Constipation
         subjects affected / exposed
    5 / 22 (22.73%)
    5 / 28 (17.86%)
    12 / 77 (15.58%)
    22 / 76 (28.95%)
         occurrences all number
    7
    9
    18
    24
    Stomatitis
         subjects affected / exposed
    2 / 22 (9.09%)
    5 / 28 (17.86%)
    9 / 77 (11.69%)
    5 / 76 (6.58%)
         occurrences all number
    2
    7
    9
    5
    Abdominal Pain Upper
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 28 (3.57%)
    6 / 77 (7.79%)
    9 / 76 (11.84%)
         occurrences all number
    3
    1
    7
    12
    Dyspepsia
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 28 (10.71%)
    4 / 77 (5.19%)
    3 / 76 (3.95%)
         occurrences all number
    1
    4
    5
    3
    Dry Mouth
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    2 / 77 (2.60%)
    7 / 76 (9.21%)
         occurrences all number
    0
    6
    2
    9
    Rectal Haemorrhage
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Abdominal Distension
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    8
    5
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences all number
    0
    0
    6
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 22 (31.82%)
    10 / 28 (35.71%)
    15 / 77 (19.48%)
    21 / 76 (27.63%)
         occurrences all number
    8
    11
    15
    21
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 28 (10.71%)
    4 / 77 (5.19%)
    0 / 76 (0.00%)
         occurrences all number
    0
    3
    4
    0
    Nail Disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 28 (10.71%)
    5 / 77 (6.49%)
    3 / 76 (3.95%)
         occurrences all number
    0
    3
    6
    3
    Rash
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 28 (7.14%)
    7 / 77 (9.09%)
    2 / 76 (2.63%)
         occurrences all number
    1
    2
    8
    3
    Dry Skin
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 28 (0.00%)
    7 / 77 (9.09%)
    1 / 76 (1.32%)
         occurrences all number
    2
    0
    7
    1
    Erythema
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Pain Of Skin
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Rash Maculo-Papular
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    5 / 77 (6.49%)
    1 / 76 (1.32%)
         occurrences all number
    0
    0
    6
    1
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 22 (4.55%)
    6 / 28 (21.43%)
    8 / 77 (10.39%)
    9 / 76 (11.84%)
         occurrences all number
    1
    7
    10
    11
    Myalgia
         subjects affected / exposed
    1 / 22 (4.55%)
    4 / 28 (14.29%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    1
    5
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 22 (0.00%)
    4 / 28 (14.29%)
    4 / 77 (5.19%)
    5 / 76 (6.58%)
         occurrences all number
    0
    4
    4
    5
    Muscle Spasms
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    6 / 77 (7.79%)
    3 / 76 (3.95%)
         occurrences all number
    0
    0
    9
    3
    Musculoskeletal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    2 / 77 (2.60%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    2
    4
    Pain In Extremity
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    5
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 28 (7.14%)
    10 / 77 (12.99%)
    6 / 76 (7.89%)
         occurrences all number
    2
    4
    11
    7
    Urinary Tract Infection
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 28 (3.57%)
    7 / 77 (9.09%)
    4 / 76 (5.26%)
         occurrences all number
    3
    1
    10
    7
    Nail Infection
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 28 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    5
    2
    Rhinitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences all number
    0
    0
    8
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    8 / 22 (36.36%)
    5 / 28 (17.86%)
    13 / 77 (16.88%)
    17 / 76 (22.37%)
         occurrences all number
    10
    7
    18
    20
    Hypomagnesaemia
         subjects affected / exposed
    3 / 22 (13.64%)
    4 / 28 (14.29%)
    7 / 77 (9.09%)
    7 / 76 (9.21%)
         occurrences all number
    4
    4
    7
    7
    Hypokalaemia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 28 (7.14%)
    9 / 77 (11.69%)
    5 / 76 (6.58%)
         occurrences all number
    5
    2
    13
    8
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 28 (7.14%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 28 (0.00%)
    4 / 77 (5.19%)
    0 / 76 (0.00%)
         occurrences all number
    0
    0
    4
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2013
    1. The Phase of the study from Phase II to Phase III 2. Added that primary endpoint PFS is IRC-Assessed 3. Added PFS (Investigator-Assessed) as a secondary endpoint 4. Added a pharmacokinetic (PK) sub-study for subjects receiving topotecan in Part 2 of the study 5. Added analysis of the effect of anti-therapeutic antibodies (ATA) 6. The definition of the end of study and the length of the follow-up were modified 7. An efficacy interim analysis for OS was introduced for Part 2 of the study 8. Independent Review Committee was implemented

    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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