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    Clinical Trial Results:
    A randomized Phase III, double-blind, placebo-controlled multicenter trial of daily everolimus in combination with trastuzumab and vinorelbine, in pretreated women with HER2/neu over-expressing locally advanced or metastatic breast cancer

    Summary
    EudraCT number
    		 2008-008697-31
    Trial protocol
    		 DE   GR   BE   IT   ES   FR   CZ   GB   HU   SK  
    Global end of trial date
    11 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jun 2016
    First version publication date
    27 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001W2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01007942
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    11 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the combination of everolimus, vinorelbine and trastuzumab to the combination of vinorelbine and trastuzumab with respect to progression-free survival, based on local radiological review, in women with HER2/neu overexpressing advanced or metastatic breast cancer who are resistant to trastuzumab and have been pre-treated with a taxane.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 32
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    China: 49
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Greece: 16
    Country: Number of subjects enrolled
    Hungary: 30
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Japan: 57
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Thailand: 7
    Country: Number of subjects enrolled
    Turkey: 24
    Country: Number of subjects enrolled
    United States: 123
    Worldwide total number of subjects
    569
    EEA total number of subjects
    223
    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)
    472
    From 65 to 84 years
    97
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 DCO ( Data cut-off) for patient disposition is 1-Apr-2015. Each Cycle = 21 days. Patients completed = on treatment at time of DCO. Not Completed = ended treatment as per protocol.

    Pre-assignment
    Screening details
    		 284 patients were randomized to the Everolimus + trastuzumab +vinorelbine arm but only 280 took drug. 285 were randomized to the placebo + trastuzumab + vinorelbine arm but only 282 took drug.

    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
    		 Everolimus + vinorelbine + trastuzumab
    Arm description
    		 Oral everolimus (5 mg/day) + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)
    Arm type
    		 Experimental

    Investigational medicinal product name
    everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral everolimus (5 mg/day) packaged in blister packs.

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)

    Investigational medicinal product name
    vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    intravenous vinorelbine (25 mg/m2 weekly)

    Arm title
    		 placebo + vinorelbine + trastuzumab
    Arm description
    		 Oral daily matching placebo + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)
    Arm type
    		 Placebo

    Investigational medicinal product name
    everolimus placebo
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral everolimus placebo (5 mg/day) packaged in blister packs.

    Number of subjects in period 1
    		Everolimus + vinorelbine + trastuzumab placebo + vinorelbine + trastuzumab
    Started
    284
    285
    Completed
    3
    7
    Not completed
    281
    278
         Adverse event, serious fatal
    3
    2
         Consent withdrawn by subject
    19
    14
         Disease progression
    217
    242
         Abnormal test procedure
    -
    1
         Adverse event, non-fatal
    29
    14
         New cancer therapy
    5
    1
         Administrative problems
    2
    -
         Patients Untreated
    4
    3
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus + vinorelbine + trastuzumab
    Reporting group description
    		 Oral everolimus (5 mg/day) + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)

    Reporting group title
    placebo + vinorelbine + trastuzumab
    Reporting group description
    		 Oral daily matching placebo + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)

    Reporting group values
    		 Everolimus + vinorelbine + trastuzumab placebo + vinorelbine + trastuzumab Total
    Number of subjects
    		 284 285 569
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 230 242 472
        From 65-84 years
    		 54 43 97
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.3 ± 10.98 53.4 ± 11 -
    Gender, Male/Female
    Units: Participants
        Female
    		 284 285 569
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Everolimus + vinorelbine + trastuzumab
    Reporting group description
    		 Oral everolimus (5 mg/day) + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)

    Reporting group title
    placebo + vinorelbine + trastuzumab
    Reporting group description
    		 Oral daily matching placebo + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)

    Subject analysis set title
    Everolimus 2.5 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Oral everolimus of 2.5 mg/day

    Subject analysis set title
    Everolimus 5mg/day
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Oral everolimus of 5 mg/day

    Subject analysis set title
    Everolimus (Vinorelbine blood concentration)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Oral everolimus of 5 mg/day

    Subject analysis set title
    Everolimus Placebo (Vinorelbine blood concentration)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Oral placebo everolimus of 5 mg/day

    Subject analysis set title
    Everolimus (trastuzumab serum concentration)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Oral everolimus of 5 mg/day

    Subject analysis set title
    Everolimus Placebo (trastuzumab serum concentration)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Oral placebo everolimus of 5 mg/day

    Primary: Progressive-free survival (PFS) per Investigator assessment

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    End point title
    		 Progressive-free survival (PFS) per Investigator assessment
    End point description
    PFS was defined as the time from the date of randomization to the date of first radiologically documented tumor progression or death from any cause, whichever occurs first. PFS primary analysis performed when 415 events were reached
    End point type
    Primary
    End point timeframe
    Every 6 weeks until disease progression or death which ever occurred first up to 15-Mar-2013
    End point values
    		 Everolimus + vinorelbine + trastuzumab placebo + vinorelbine + trastuzumab
    Number of subjects analysed
    284
    285
    Units: months
        median (confidence interval 95%)
    7 (6.74 to 8.18)
    5.78 (5.49 to 6.9)
    Statistical analysis title
    		 Comparison of the distribution of PFS
    Comparison groups
    Everolimus + vinorelbine + trastuzumab v placebo + vinorelbine + trastuzumab
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0067
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.95

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time from date of randomization to the date of death from any cause. Final OS was conducted when 388 deaths occurred.
    End point type
    Secondary
    End point timeframe
    Every 3 months until death up to 1-Apr-2015
    End point values
    		 Everolimus + vinorelbine + trastuzumab placebo + vinorelbine + trastuzumab
    Number of subjects analysed
    284
    285
    Units: months
        median (confidence interval 95%)
    23.46 (20.01 to 28.81)
    24.08 (21.49 to 27.63)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR)

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    End point title
    		 Overall response rate (ORR)
    End point description
    ORR was defined as the percentage of participants whose best overall response was either complete response (CR) or partial response (PR) according to RECIST version 1.0
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death which ever occurred first up to 15-Mar-2013
    End point values
    		 Everolimus + vinorelbine + trastuzumab placebo + vinorelbine + trastuzumab
    Number of subjects analysed
    284
    285
    Units: Percentage of participants
        number (confidence interval 95%)
    40.8 (35.1 to 46.8)
    37.2 (31.6 to 43.1)
    No statistical analyses for this end point

    Secondary: Clinical benefit rate (CBR)

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    End point title
    		 Clinical benefit rate (CBR)
    End point description
    CBR was defined as the percentage of participants whose best overall response, according to RECIST, was either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks.
    End point type
    Secondary
    End point timeframe
    Every 6 weeks until disease progression or death which ever occurred first up to 15-Mar-2013
    End point values
    		 Everolimus + vinorelbine + trastuzumab placebo + vinorelbine + trastuzumab
    Number of subjects analysed
    284
    285
    Units: Percentage of participants
        number (confidence interval 95%)
    59.2 (53.2 to 64.9)
    53.3 (47.4 to 59.2)
    No statistical analyses for this end point

    Secondary: Time to deterioration of the ECOG performance status score

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    End point title
    		 Time to deterioration of the ECOG performance status score
    End point description
    The Time to deterioration of the ECOG performance status score was summarized at the time of each assessment.
    End point type
    Secondary
    End point timeframe
    baseline, until disease progression or death up to 15-Mar-2013
    End point values
    		 Everolimus + vinorelbine + trastuzumab placebo + vinorelbine + trastuzumab
    Number of subjects analysed
    284
    285
    Units: months
        number (not applicable)
    32.66
    21.55
    No statistical analyses for this end point

    Secondary: PRO: Time to deterioration in global health status/QoL domain score of the European Organization for the Research and Treatment of Cancer (EORTC)–Core Quality of Life Questionnaire (QLQ-C30) (by at least 10%)

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    End point title
    		 PRO: Time to deterioration in global health status/QoL domain score of the European Organization for the Research and Treatment of Cancer (EORTC)–Core Quality of Life Questionnaire (QLQ-C30) (by at least 10%)
    End point description
    PRO = patient reported outcomes; Time to deterioration (≥ 10% worsening from baseline), in the global health status of EORTC QLQ-C30 scale was done in the 3 functional scales (emotional, physical, & social functioning [EF, PF, & SF]). It contains 30 items & is composed of multi-item scales & single-item measures. These include 5 functional scales (physical, role, emotional, social & cognitive functioning), 3 symptom scales (fatigue, pain, nausea, & vomiting), a global health status/QoL scale, and 6 single items (dyspnea, diarrhea, constipation, anorexia, insomnia & financial impact). Each of the multi-item scale includes a different set of items - no item occurs in more than 1 scale. Each item in the EORTC QLQ-C30 has 4 response categories (1=Not at all, 2= A little, 3= Quite a bit, 4= Very much) with the higher number representing a worse outcome. The global health domain score of the QLQ-C30 questionnaire was pre-specified as the primary QoL domain of interest & disclosed here.
    End point type
    Secondary
    End point timeframe
    Baseline, until disease progression or death up to 15-Mar-2013
    End point values
    		 Everolimus + vinorelbine + trastuzumab placebo + vinorelbine + trastuzumab
    Number of subjects analysed
    284
    285
    Units: months
    median (confidence interval 95%)
        Deterioration - global QoL domain by at least 10%
    8.31 (6.93 to 11.53)
    7.29 (5.55 to 10.38)
        Deterioration in the PF domain by at least 10%
    11.96 (8.31 to 14.09)
    12.48 (8.31 to 20.86)
        Deterioration in the EF domain by at least 10%
    15.18 (9.2 to 17.28)
    12.45 (9.69 to 16.36)
        Deterioration in the SF domain by at least 10%
    11.33 (8.18 to 14.52)
    13.11 (8.31 to 19.32)
    No statistical analyses for this end point

    Secondary: Everolimus blood concentrations by leading dose and time point

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    End point title
    		 Everolimus blood concentrations by leading dose and time point
    End point description
    Pre-dose (Cmin) and 2 hours post-dose (C2h) everolimus PK blood samples were collected at Cycle 2 Day 1. Only valid everolimus PK blood samples collected at steady state were used in the analyses.
    End point type
    Secondary
    End point timeframe
    Cycle 2, Day 1
    End point values
    		 Everolimus 2.5 mg Everolimus 5mg/day
    Number of subjects analysed
    10
    43
    Units: ng/ml
    arithmetic mean (standard deviation)
        Pre-dose (Cmin) (n: 7, 32)
    2.928 ± 2.6197
    5.652 ± 4.1006
        2 hours post administration (C2h) (n:10, 43)
    13.035 ± 6.6842
    22.005 ± 13.38
    No statistical analyses for this end point

    Secondary: Vinorelbine blood concentrations by leading dose and time point

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    End point title
    		 Vinorelbine blood concentrations by leading dose and time point
    End point description
    Pre-infusion (Cmin) and end of infusion (C2h) vinorelbine PK blood samples were collected at Cycle 2 Day 1. Only valid vinorelbine PK blood samples collected at steady state were used in the analyses.
    End point type
    Secondary
    End point timeframe
    Cycle 2, Day 1
    End point values
    		 Everolimus (Vinorelbine blood concentration) Everolimus Placebo (Vinorelbine blood concentration)
    Number of subjects analysed
    76
    64
    Units: ng/ml
    arithmetic mean (standard deviation)
        Pre-infusion - dose (Cmin) (n: 76, 64)
    11.085 ± 66.8551
    0.061 ± 0.4888
        End of infusion (Cmax) (n: 58, 49)
    867.147 ± 971.3057
    1068.51 ± 1145.86
    No statistical analyses for this end point

    Secondary: Trastuzumab blood concentrations by leading dose and time point

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    End point title
    		 Trastuzumab blood concentrations by leading dose and time point
    End point description
    Pre-infusion (Cmin) and end of infusion (C2h) trastuzumab PK blood samples were collected at Cycle 3 Day 1. Only valid trastuzumab PK blood samples collected at steady state were used in the analyses.
    End point type
    Secondary
    End point timeframe
    Cycle 3, Day 1
    End point values
    		 Everolimus (trastuzumab serum concentration) Everolimus Placebo (trastuzumab serum concentration)
    Number of subjects analysed
    74
    59
    Units: ng/ml
    arithmetic mean (standard deviation)
        Pre-infusion - dose (Cmin) (n: 73, 57)
    23.351 ± 6.3344
    24.526 ± 7.996
        End of infusion (Cmax) (n: 75, 59)
    64.279 ± 27.8549
    60.576 ± 15.5198
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Everolimus + trastuzumab + vinorelbine
    Reporting group description
    		 Everolimus + trastuzumab + vinorelbine

    Reporting group title
    Placebo + trastuzumab + vinorelbine
    Reporting group description
    		 Placebo + trastuzumab + vinorelbine

    Serious adverse events
    		 Everolimus + trastuzumab + vinorelbine Placebo + trastuzumab + vinorelbine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    122 / 280 (43.57%)
    58 / 282 (20.57%)
         number of deaths (all causes)
    7
    7
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 280 (0.36%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 280 (1.07%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    13 / 280 (4.64%)
    5 / 282 (1.77%)
         occurrences causally related to treatment / all
    5 / 14
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cough
         subjects affected / exposed
    1 / 280 (0.36%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 280 (1.07%)
    3 / 282 (1.06%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 280 (1.07%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 280 (1.07%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 280 (0.36%)
    5 / 282 (1.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 280 (0.71%)
    3 / 282 (1.06%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 280 (1.07%)
    5 / 282 (1.77%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 280 (0.00%)
    3 / 282 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 280 (0.71%)
    3 / 282 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 280 (1.07%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    10 / 280 (3.57%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    22 / 22
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    30 / 280 (10.71%)
    4 / 282 (1.42%)
         occurrences causally related to treatment / all
    28 / 31
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 280 (1.07%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    12 / 280 (4.29%)
    3 / 282 (1.06%)
         occurrences causally related to treatment / all
    13 / 14
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 280 (1.43%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract subcapsular
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 280 (1.79%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 280 (1.07%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    9 / 280 (3.21%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    9 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 280 (1.79%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 280 (0.00%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 280 (1.07%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 280 (1.43%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 280 (1.07%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    2 / 280 (0.71%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 280 (2.86%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Postoperative wound infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 280 (1.07%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 280 (0.36%)
    2 / 282 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 280 (0.36%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 280 (0.00%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 280 (0.71%)
    1 / 282 (0.35%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 282 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus + trastuzumab + vinorelbine Placebo + trastuzumab + vinorelbine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    280 / 280 (100.00%)
    280 / 282 (99.29%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    37 / 280 (13.21%)
    26 / 282 (9.22%)
         occurrences all number
    49
    46
    Aspartate aminotransferase increased
         subjects affected / exposed
    33 / 280 (11.79%)
    22 / 282 (7.80%)
         occurrences all number
    49
    34
    Ejection fraction decreased
         subjects affected / exposed
    17 / 280 (6.07%)
    5 / 282 (1.77%)
         occurrences all number
    22
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    29 / 280 (10.36%)
    23 / 282 (8.16%)
         occurrences all number
    34
    31
    Haemoglobin decreased
         subjects affected / exposed
    22 / 280 (7.86%)
    18 / 282 (6.38%)
         occurrences all number
    63
    47
    Neutrophil count decreased
         subjects affected / exposed
    14 / 280 (5.00%)
    8 / 282 (2.84%)
         occurrences all number
    90
    32
    Weight decreased
         subjects affected / exposed
    83 / 280 (29.64%)
    47 / 282 (16.67%)
         occurrences all number
    99
    62
    White blood cell count decreased
         subjects affected / exposed
    17 / 280 (6.07%)
    23 / 282 (8.16%)
         occurrences all number
    104
    112
    Vascular disorders
    Hot flush
         subjects affected / exposed
    4 / 280 (1.43%)
    16 / 282 (5.67%)
         occurrences all number
    4
    16
    Hypertension
         subjects affected / exposed
    24 / 280 (8.57%)
    10 / 282 (3.55%)
         occurrences all number
    29
    12
    Phlebitis
         subjects affected / exposed
    14 / 280 (5.00%)
    18 / 282 (6.38%)
         occurrences all number
    19
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 280 (11.07%)
    24 / 282 (8.51%)
         occurrences all number
    35
    30
    Dysgeusia
         subjects affected / exposed
    32 / 280 (11.43%)
    17 / 282 (6.03%)
         occurrences all number
    37
    18
    Headache
         subjects affected / exposed
    74 / 280 (26.43%)
    62 / 282 (21.99%)
         occurrences all number
    105
    98
    Hypoaesthesia
         subjects affected / exposed
    15 / 280 (5.36%)
    7 / 282 (2.48%)
         occurrences all number
    17
    9
    Neuropathy peripheral
         subjects affected / exposed
    27 / 280 (9.64%)
    41 / 282 (14.54%)
         occurrences all number
    32
    47
    Paraesthesia
         subjects affected / exposed
    21 / 280 (7.50%)
    21 / 282 (7.45%)
         occurrences all number
    27
    25
    Peripheral sensory neuropathy
         subjects affected / exposed
    25 / 280 (8.93%)
    17 / 282 (6.03%)
         occurrences all number
    32
    19
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    137 / 280 (48.93%)
    85 / 282 (30.14%)
         occurrences all number
    253
    182
    Febrile neutropenia
         subjects affected / exposed
    17 / 280 (6.07%)
    7 / 282 (2.48%)
         occurrences all number
    21
    7
    Leukopenia
         subjects affected / exposed
    126 / 280 (45.00%)
    105 / 282 (37.23%)
         occurrences all number
    509
    567
    Neutropenia
         subjects affected / exposed
    226 / 280 (80.71%)
    196 / 282 (69.50%)
         occurrences all number
    1117
    1127
    Thrombocytopenia
         subjects affected / exposed
    39 / 280 (13.93%)
    6 / 282 (2.13%)
         occurrences all number
    89
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    74 / 280 (26.43%)
    57 / 282 (20.21%)
         occurrences all number
    166
    100
    Chills
         subjects affected / exposed
    18 / 280 (6.43%)
    18 / 282 (6.38%)
         occurrences all number
    22
    22
    Fatigue
         subjects affected / exposed
    124 / 280 (44.29%)
    119 / 282 (42.20%)
         occurrences all number
    252
    217
    Oedema peripheral
         subjects affected / exposed
    39 / 280 (13.93%)
    23 / 282 (8.16%)
         occurrences all number
    56
    25
    Non-cardiac chest pain
         subjects affected / exposed
    11 / 280 (3.93%)
    20 / 282 (7.09%)
         occurrences all number
    13
    25
    Pyrexia
         subjects affected / exposed
    107 / 280 (38.21%)
    65 / 282 (23.05%)
         occurrences all number
    181
    128
    Pain
         subjects affected / exposed
    20 / 280 (7.14%)
    20 / 282 (7.09%)
         occurrences all number
    24
    27
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    45 / 280 (16.07%)
    52 / 282 (18.44%)
         occurrences all number
    63
    69
    Abdominal pain upper
         subjects affected / exposed
    34 / 280 (12.14%)
    40 / 282 (14.18%)
         occurrences all number
    48
    54
    Constipation
         subjects affected / exposed
    84 / 280 (30.00%)
    88 / 282 (31.21%)
         occurrences all number
    99
    121
    Diarrhoea
         subjects affected / exposed
    108 / 280 (38.57%)
    88 / 282 (31.21%)
         occurrences all number
    200
    177
    Dry mouth
         subjects affected / exposed
    14 / 280 (5.00%)
    7 / 282 (2.48%)
         occurrences all number
    16
    10
    Dyspepsia
         subjects affected / exposed
    21 / 280 (7.50%)
    25 / 282 (8.87%)
         occurrences all number
    28
    33
    Mouth ulceration
         subjects affected / exposed
    32 / 280 (11.43%)
    6 / 282 (2.13%)
         occurrences all number
    68
    8
    Nausea
         subjects affected / exposed
    98 / 280 (35.00%)
    105 / 282 (37.23%)
         occurrences all number
    151
    163
    Stomatitis
         subjects affected / exposed
    174 / 280 (62.14%)
    78 / 282 (27.66%)
         occurrences all number
    412
    140
    Vomiting
         subjects affected / exposed
    57 / 280 (20.36%)
    59 / 282 (20.92%)
         occurrences all number
    88
    106
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    84 / 280 (30.00%)
    55 / 282 (19.50%)
         occurrences all number
    102
    70
    Dyspnoea
         subjects affected / exposed
    51 / 280 (18.21%)
    40 / 282 (14.18%)
         occurrences all number
    63
    50
    Epistaxis
         subjects affected / exposed
    64 / 280 (22.86%)
    38 / 282 (13.48%)
         occurrences all number
    90
    51
    Oropharyngeal pain
         subjects affected / exposed
    27 / 280 (9.64%)
    27 / 282 (9.57%)
         occurrences all number
    32
    33
    Pneumonitis
         subjects affected / exposed
    17 / 280 (6.07%)
    9 / 282 (3.19%)
         occurrences all number
    19
    9
    Rhinorrhoea
         subjects affected / exposed
    17 / 280 (6.07%)
    14 / 282 (4.96%)
         occurrences all number
    21
    17
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    71 / 280 (25.36%)
    54 / 282 (19.15%)
         occurrences all number
    105
    81
    Pruritus
         subjects affected / exposed
    16 / 280 (5.71%)
    29 / 282 (10.28%)
         occurrences all number
    30
    38
    Alopecia
         subjects affected / exposed
    22 / 280 (7.86%)
    29 / 282 (10.28%)
         occurrences all number
    24
    29
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    13 / 280 (4.64%)
    18 / 282 (6.38%)
         occurrences all number
    14
    18
    Insomnia
         subjects affected / exposed
    34 / 280 (12.14%)
    27 / 282 (9.57%)
         occurrences all number
    39
    31
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    37 / 280 (13.21%)
    46 / 282 (16.31%)
         occurrences all number
    52
    59
    Arthralgia
         subjects affected / exposed
    48 / 280 (17.14%)
    36 / 282 (12.77%)
         occurrences all number
    64
    44
    Bone pain
         subjects affected / exposed
    28 / 280 (10.00%)
    24 / 282 (8.51%)
         occurrences all number
    33
    32
    Muscle spasms
         subjects affected / exposed
    31 / 280 (11.07%)
    47 / 282 (16.67%)
         occurrences all number
    45
    69
    Musculoskeletal chest pain
         subjects affected / exposed
    16 / 280 (5.71%)
    12 / 282 (4.26%)
         occurrences all number
    18
    13
    Musculoskeletal pain
         subjects affected / exposed
    14 / 280 (5.00%)
    14 / 282 (4.96%)
         occurrences all number
    15
    15
    Myalgia
         subjects affected / exposed
    39 / 280 (13.93%)
    31 / 282 (10.99%)
         occurrences all number
    51
    42
    Pain in extremity
         subjects affected / exposed
    42 / 280 (15.00%)
    44 / 282 (15.60%)
         occurrences all number
    51
    59
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    37 / 280 (13.21%)
    29 / 282 (10.28%)
         occurrences all number
    67
    62
    Upper respiratory tract infection
         subjects affected / exposed
    38 / 280 (13.57%)
    26 / 282 (9.22%)
         occurrences all number
    55
    36
    Urinary tract infection
         subjects affected / exposed
    26 / 280 (9.29%)
    18 / 282 (6.38%)
         occurrences all number
    37
    27
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    94 / 280 (33.57%)
    49 / 282 (17.38%)
         occurrences all number
    131
    60
    Hypercholesterolaemia
         subjects affected / exposed
    26 / 280 (9.29%)
    12 / 282 (4.26%)
         occurrences all number
    30
    36
    Hyperglycaemia
         subjects affected / exposed
    26 / 280 (9.29%)
    15 / 282 (5.32%)
         occurrences all number
    37
    22
    Hypertriglyceridaemia
         subjects affected / exposed
    23 / 280 (8.21%)
    9 / 282 (3.19%)
         occurrences all number
    36
    10
    Hypokalaemia
         subjects affected / exposed
    34 / 280 (12.14%)
    19 / 282 (6.74%)
         occurrences all number
    62
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2010
    Amendment 1 introduced the following non-administrative changes and was issued when 16 patients had been randomized: Guidelines regarding the management of HBV and HCV infections were added. Reactivation of HBV has been observed in cancer patients receiving either chemotherapy or
    25 Jan 2011
    Amendment 2 was issued when 163 patients had been randomized. The primary purpose of this amendment was to revise exclusion criterion number 4, which had originally excluded all patients with a history of CNS metastases. The amended criterion allowed patients with previously treated CNS metastases to enroll in the study provided that the last treatment received for the CNS metastases was at least 8 weeks prior to randomization, including radiotherapy, steroids and anti-epileptic medication. A total of nine patients with CNS metastases were enrolled in this trial and the time to progression results suggested that everolimus can positively affect CNS disease. Accordingly,
    15 May 2013
    The key changes for Amendment 3 included the following: conduct and dissemination of OS analyses results to Novartis personnel and health authorities; inclusion of central review for tumor assessment data. Overall survival (OS) is pre-specified as a key secondary endpoint, as per the original protocol, results of OS analysis were not to be communicated to clinical team or any party

    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.
    cut off date for the Safety data: 1 Apr 2015
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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