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    Clinical Trial Results:
    A phase III trial of vinflunine + capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with or resistant to an anthracycline and who are taxane resistant

    Summary
    EudraCT number
    2008-004171-21
    Trial protocol
    ES   FR   CZ   EE   IT   GB   BE   HU   BG  
    Global end of trial date
    18 Feb 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    20 Jun 2019
    First version publication date
    09 Jun 2016
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Update safety data.

    Trial information

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    Trial identification
    Sponsor protocol code
    L00070 IN 3 05 B0
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01095003
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pierre Fabre Medicament
    Sponsor organisation address
    45 Place Abel Gance, Boulogne Billancourt, France, 92654
    Public contact
    Jean Claude VEDOVATO, Centre de Recherche et Developpement Clinique Pierre FABRE 3 avenue Hubert CURIEN 31100 TOULOUSE, jean.claude.vedovato@pierre-fabre.com
    Scientific contact
    Jean Claude VEDOVATO, Centre de Recherche et Developpement Clinique Pierre FABRE 3 avenue Hubert CURIEN 31100 TOULOUSE, jean.claude.vedovato@pierre-fabre.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
    15 Mar 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Dec 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study investigated the comparative efficacy ( progression free survival (primary criteria), response to treatment and disease control parameters (secondary criteria)) of vinflunine plus capecitabine versus capecitabine alone in patients with metastatic breast cancer who were previously treated with or resistant to an anthracycline and who were taxane resistant.
    Protection of trial subjects
    The trial was conducted according to Good Clinical Practice (CPMP/ICH/135/95), the Declaration of Helsinki and its subsequent amendments thereto and local legal regulations. The study protocol and the informed consent form were submitted for approval to Ethics Committees before the study set up according to the national regulations. The patient underwent a health assessment at the start of the study and remained under regular medical control during the whole study.
    Background therapy
    Antiemetic prophylaxis (dexamethasone 8mg or equivalent just before each infusion) and constipation prophylaxis (ditary measures and laxatives from day1 to 5 of each cycle)
    Evidence for comparator
    -
    Actual start date of recruitment
    06 May 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
    Poland: 47
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Estonia: 14
    Country: Number of subjects enrolled
    France: 100
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Belarus: 84
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    India: 101
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Serbia: 7
    Country: Number of subjects enrolled
    South Africa: 21
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Ukraine: 117
    Country: Number of subjects enrolled
    Argentina: 22
    Country: Number of subjects enrolled
    Russian Federation: 103
    Worldwide total number of subjects
    770
    EEA total number of subjects
    274
    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)
    669
    From 65 to 84 years
    101
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    From 6th of May 2009 (First patient enrolled) up to 25th May 2011 (last patient enrolled), 770 patients were enrolled from 129 active centres in 21 countries. Patients were to be treated until disease progression, unacceptable toxicity or patient’s request. After the study treatment discontinuation, patients were to be followed until death.

    Pre-assignment
    Screening details
    -21 years and older female patients, with an histologically/cytologically confirmed breast carcinoma, documented locally recurrent or metastatic disease not amenable to curative surgery or radiotherapy -Having received at least one prior chemotherapy (neo/adjuvant setting) -previously treated with or resistant to anthracycline and taxane

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Capecitabine single agent
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received: Capecitabine at the dose of 1250 mg/m² per os twice per day each morning and each evening for 14 consecutive days beginning on day 1 of each cycle repeated every 3 weeks (self-administered).

    Arm title
    Vinflunine + capecitabine
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received: Capecitabine at the dose of 825mg/m² per os twice per day each morning and each evening for 14 consecutive days beginning on day 1 of each cycle repeated every 3 weeks (self-administered).

    Investigational medicinal product name
    Vinflunine
    Investigational medicinal product code
    L00070 IN
    Other name
    Javlor
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received (in combination with capecitabine) • Vinflunine at the dose of 280 mg/m² and as a 20-minute IV. infusion on day 1 of each cycle repeated every 3 weeks.

    Number of subjects in period 1
    Capecitabine single agent Vinflunine + capecitabine
    Started
    386
    384
    cut-off date: 20 december 2011
    144
    143
    cut-off date: 15 March 2013
    60
    49
    Completed
    60
    49
    Not completed
    326
    335
         death
    319
    324
         Lost to follow-up
    7
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Capecitabine single agent
    Reporting group description
    -

    Reporting group title
    Vinflunine + capecitabine
    Reporting group description
    -

    Reporting group values
    Capecitabine single agent Vinflunine + capecitabine Total
    Number of subjects
    386 384 770
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    340 329 669
        From 65-84 years
    46 55 101
        85 years and over
    0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    54 (26.8 to 77.7) 53.6 (27 to 80.6) -
    Gender categorical
    Units: Subjects
        Female
    386 384 770
        Male
    0 0 0
    Karnofski Performance status
    Karnofsky Performance Scale Index allows patients to be classified as to their functional impairment The lower the Karnofsky score, the worse the survival for most serious illnesses: The Karnofsky score runs from 100 to 0, where 100 is "perfect" health and 0 is death.
    Units: Subjects
        90-100
    247 253 500
        70-80
    138 130 268
        <70
    1 1 2
    Main histopathological type of breast cancer
    Units: Subjects
        ductal
    273 283 556
        lobular
    40 29 69
        carcinoma NOS
    54 43 97
        others
    19 29 48
    Desease measurability
    Units: Subjects
        Yes
    343 339 682
        No
    43 45 88
    Time from diagnosis
    Units: years
        median (full range (min-max))
    2.1 (0.2 to 31.5) 2.4 (0.2 to 21.2) -

    End points

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    End points reporting groups
    Reporting group title
    Capecitabine single agent
    Reporting group description
    -

    Reporting group title
    Vinflunine + capecitabine
    Reporting group description
    -

    Primary: Progression Free survival (PFS)

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    End point title
    Progression Free survival (PFS)
    End point description
    PFS is defined as time from date of randomization to date of the first documentation of objective tumor progression (according to the IRC and based on RECIST version 1.1) or death due to any cause The PFS was primarily analysed in the Intent-to-treat (ITT) population. Patients lost to follow-up, or without a known record of progression or death at time of analysis had the progression-free survival censored at the date of last tumour assessment or the date of last contact of a follow-up showing no progression, whichever occurs last.
    End point type
    Primary
    End point timeframe
    Baseline up to first cut-off date (20 december 2011)
    End point values
    Capecitabine single agent Vinflunine + capecitabine
    Number of subjects analysed
    386 [1]
    384 [2]
    Units: Months
        median (confidence interval 95%)
    4.3 (4.1 to 5.6)
    5.6 (5.3 to 6.3)
    Notes
    [1] - 312 events -74 censored patients
    [2] - 312 events- 70 censored
    Statistical analysis title
    Primary efficacy analysis
    Statistical analysis description
    The final analysis of progression free survival was conducted once the required number of events(615 progressions or deaths) was reached. using the IRC assessment of date of progressions following the blinded radiological and clinical review of data. Kaplan-Meier curves and life tables by treatment arm were provided. A stratified Cox proportional model was used to compare the two treatment arms tak
    Comparison groups
    Vinflunine + capecitabine v Capecitabine single agent
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.0426 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    0.99
    Notes
    [3] - The primary efficacy analysis of the PFS was performed in the intent-to-treat (ITT) population
    [4] - According to the IRC, the median PFS was of 5.6 months for the VFL+CAPE arm and 4.3 months for the CAPE single agent arm and the difference was statistically significant (HR= 0.84, 95%CI 0.71-0.99; P=0.0426)

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    The overall survival (OS) was defined as the duration between the date of randomisation and the date of death from any cause. The OS analysis was performed in the ITT population and the eligible and perprotocol populations once the required number of events (631 deaths) was observed Patients lost to follow-up, or without a known record of death at time of analysis had the OS censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    Baseline up to the cut-off date set on 15 March, 2013 (final analysis). At the cut-off date 83.5% of all patients had progressed or died (death as first event)
    End point values
    Capecitabine single agent Vinflunine + capecitabine
    Number of subjects analysed
    386 [5]
    384 [6]
    Units: Months
        median (confidence interval 95%)
    11.7 (10.8 to 13.5)
    13.9 (11.9 to 15)
    Notes
    [5] - 319 events-67 censored
    [6] - 324 events 60 censored
    Statistical analysis title
    Overall survival analysis
    Statistical analysis description
    OS is defined as time from date of randomization to date of death due to any cause The final analysis of survival was conducted in the ITT population after 643 deaths have been observed (83.5% of all patients, 84.4% in the VFL+CAPE arm and 82.6% in the CAPE arm respectively).
    Comparison groups
    Capecitabine single agent v Vinflunine + capecitabine
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.7657 [8]
    Method
    stratified Log rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.15
    Notes
    [7] - To describe time dependent parameters, Kaplan-Meier curves and life tables by treatment arm are provided. Confidence intervals on the median were calculated using the Brookmeyer and Crowley method. Hazard ratio and 95% confidence intervals are reported. A stratified Cox proportional model was performed to compare the two treatment arms taking into account the stratification factors (except centre) used at the time of randomisation.
    [8] - The IRC assessed ORR was higher in the VFL+CAPE arm compared to the CAPE arm in ITT (and in all studied populations) even though this difference (+2.2 months) did not reach statistical significance.

    Secondary: Overall Response rate (ORR=CR+PR)

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    End point title
    Overall Response rate (ORR=CR+PR)
    End point description
    ORR defined as documentation of complete or partial response that was subsequently confirmed to first documentation of disease progression or to death due to any cause, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    From baseline to 1st cut-off date
    End point values
    Capecitabine single agent Vinflunine + capecitabine
    Number of subjects analysed
    386
    384
    Units: percent
        median (confidence interval 95%)
    17.9 (14.2 to 22.1)
    22.9 (18.8 to 27.5)
    Statistical analysis title
    Overall response rate at 1st cut off date
    Statistical analysis description
    The analyses of tumour response were performed in the ITT population and in the population evaluable for response in the two treatment. Tumour response rate (overall response rate, ORR) defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) as best overall (across all time points) response from the date of randomisation until disease progression but within 30 days from the last administration.
    Comparison groups
    Capecitabine single agent v Vinflunine + capecitabine
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.103 [10]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Median difference (final values)
    Confidence interval
    Notes
    [9] - The overall response rate (ORR) was first evaluated according to IRC and compared between the two arms with a Cochran-Mantel-Haenszel test stratified on the stratification factors at randomisation (except centre). Furthermore, the ORR was estimated
    [10] - ORR was higher in the VFL+CAPE arm compared to the CAPE arm in all studied populations even though this difference did not reach statistical significance

    Secondary: Disease Control rate

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    End point title
    Disease Control rate
    End point description
    Disease control rate defined (DCR) as the proportion of patients who achieved at least a stabilisation of the disease not counting patients with only non-measurable disease at baseline and best overall response of non-CR/non-PD.
    End point type
    Secondary
    End point timeframe
    from Baseline to first cut-off date
    End point values
    Capecitabine single agent Vinflunine + capecitabine
    Number of subjects analysed
    386
    384
    Units: percent
        median (confidence interval 95%)
    47.9 (42.9 to 53)
    57.3 (52.2 to 62.3)
    Statistical analysis title
    disease control rate analysis
    Statistical analysis description
    Disease control rate defined (DCR) as the proportion of patients who achieved at least a stabilisation of the disease not counting patients with only non-measurable disease at baseline and best overall response of non-CR/non-PD.
    Comparison groups
    Capecitabine single agent v Vinflunine + capecitabine
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.0089 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Median difference (final values)
    Confidence interval
    Notes
    [11] - The 95% confidence interval for proportions was computed following the exact method. Stratified analyses were performed using a Cochran-Mantel-Haenszel
    [12] - The DCR as per IRC in the ITT population was significantly increased (+9.4%; p=0.0089) in the VFL+CAPE arm compared to the CAPE arm (57.3% and 47.9% respectively)

    Secondary: Duration of response

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    End point title
    Duration of response
    End point description
    Measured from the first time that measurement criteria were first met for objective response (documented CR or PR) until recurrence/progression or death whatever the cause.
    End point type
    Secondary
    End point timeframe
    from Baseline to cut-off date
    End point values
    Capecitabine single agent Vinflunine + capecitabine
    Number of subjects analysed
    386
    384
    Units: Months
        median (confidence interval 95%)
    5.5 (4.1 to 6.9)
    8.4 (4.9 to 9.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs are reported from time of first dose of study treatment up to 30 days after last dose of study treatment at the exceptions of SAEs occurring after discontinuation and start of a further treatment
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 subject and as nonserious in another. Specific AE tables were generated separately as per EU format. We report here all on study SAEs and only Treatment related AEs by SOC and PT (PT>=1%)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Capecitabine single agent
    Reporting group description
    Overall 90.1% of "all treated Capecitabine patients" (N=383) experienced at least one AE and 73.6% at least one related AE. 21.7% experienced at least one SAE of which 6% were treatment related Among them we will detail and report AEs related to treatment (PT >=1%) and all SAEs experienced during the treatment period whatever the Relationship with treatment

    Reporting group title
    Vinflunine + capecitabine
    Reporting group description
    Overall 94% of "all treated Vinflunine + Capecitabine patients" (N=383) experienced at least one AE and 79.6% at least one related AE. 26.9% experienced at least one SAE of which 13.3% were treatment related. We report here AEs related to treatment (PT >=1%) and all SAEs experienced during the treatment period whatever the Relationship with treatment

    Serious adverse events
    Capecitabine single agent Vinflunine + capecitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    83 / 383 (21.67%)
    103 / 383 (26.89%)
         number of deaths (all causes)
    235
    232
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    32 / 383 (8.36%)
    34 / 383 (8.88%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 34
         deaths causally related to treatment / all
    0 / 18
    0 / 20
    Malignant pleural effusion
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (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 / 383 (0.26%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Central venous catheterisation
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula excision
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stent insertion
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoid operation
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related complication
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 383 (0.52%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Condition aggravated
         subjects affected / exposed
    6 / 383 (1.57%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Death
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 383 (0.00%)
    3 / 383 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (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
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (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
    Pulmonary embolism
         subjects affected / exposed
    3 / 383 (0.78%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 383 (1.31%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Biopsy
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (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
    Femur fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medication error
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (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
    Cerebrovascular accident
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Brachial plexopathy
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 383 (0.78%)
    4 / 383 (1.04%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 383 (0.52%)
    7 / 383 (1.83%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Neutropenia
         subjects affected / exposed
    1 / 383 (0.26%)
    6 / 383 (1.57%)
         occurrences causally related to treatment / all
    1 / 1
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 383 (0.00%)
    9 / 383 (2.35%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 383 (0.26%)
    6 / 383 (1.57%)
         occurrences causally related to treatment / all
    0 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 383 (0.26%)
    4 / 383 (1.04%)
         occurrences causally related to treatment / all
    1 / 1
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 383 (0.00%)
    6 / 383 (1.57%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 383 (0.78%)
    5 / 383 (1.31%)
         occurrences causally related to treatment / all
    1 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    6 / 383 (1.57%)
    4 / 383 (1.04%)
         occurrences causally related to treatment / all
    6 / 8
    5 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 383 (0.26%)
    3 / 383 (0.78%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 383 (0.00%)
    3 / 383 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reflux gastritis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    musculoskeletal chest pain
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 383 (0.52%)
    3 / 383 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 383 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 383 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 383 (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: 1%
    Non-serious adverse events
    Capecitabine single agent Vinflunine + capecitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    262 / 383 (68.41%)
    257 / 383 (67.10%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    33 / 383 (8.62%)
    34 / 383 (8.88%)
         occurrences all number
    0
    0
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 383 (0.00%)
    4 / 383 (1.04%)
         occurrences all number
    0
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    92 / 383 (24.02%)
    111 / 383 (28.98%)
         occurrences all number
    0
    0
    Asthenia
         subjects affected / exposed
    39 / 383 (10.18%)
    66 / 383 (17.23%)
         occurrences all number
    0
    0
    Injection site reaction
         subjects affected / exposed
    0 / 383 (0.00%)
    63 / 383 (16.45%)
         occurrences all number
    0
    0
    Pyrexia
         subjects affected / exposed
    35 / 383 (9.14%)
    46 / 383 (12.01%)
         occurrences all number
    0
    0
    Oedema peripheral
         subjects affected / exposed
    22 / 383 (5.74%)
    21 / 383 (5.48%)
         occurrences all number
    0
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 383 (0.52%)
    5 / 383 (1.31%)
         occurrences all number
    3
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    51 / 383 (13.32%)
    52 / 383 (13.58%)
         occurrences all number
    0
    0
    Cough
         subjects affected / exposed
    34 / 383 (8.88%)
    40 / 383 (10.44%)
         occurrences all number
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 383 (0.26%)
    6 / 383 (1.57%)
         occurrences all number
    2
    8
    Insomnia
         subjects affected / exposed
    14 / 383 (3.66%)
    26 / 383 (6.79%)
         occurrences all number
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    74 / 383 (19.32%)
    113 / 383 (29.50%)
         occurrences all number
    0
    0
    Weight increased
         subjects affected / exposed
    48 / 383 (12.53%)
    55 / 383 (14.36%)
         occurrences all number
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 383 (9.92%)
    59 / 383 (15.40%)
         occurrences all number
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    19 / 383 (4.96%)
    33 / 383 (8.62%)
         occurrences all number
    0
    0
    Dizziness
         subjects affected / exposed
    23 / 383 (6.01%)
    33 / 383 (8.62%)
         occurrences all number
    0
    0
    Dysgeusia
         subjects affected / exposed
    5 / 383 (1.31%)
    8 / 383 (2.09%)
         occurrences all number
    5
    11
    Tremor
         subjects affected / exposed
    0 / 383 (0.00%)
    4 / 383 (1.04%)
         occurrences all number
    0
    5
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    32 / 383 (8.36%)
    73 / 383 (19.06%)
         occurrences all number
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    10 / 383 (2.61%)
    10 / 383 (2.61%)
         occurrences all number
    18
    28
    Anaemia
         subjects affected / exposed
    9 / 383 (2.35%)
    3 / 383 (0.78%)
         occurrences all number
    12
    3
    Leukopenia
         subjects affected / exposed
    4 / 383 (1.04%)
    3 / 383 (0.78%)
         occurrences all number
    7
    4
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    7 / 383 (1.83%)
    4 / 383 (1.04%)
         occurrences all number
    9
    6
    Conjunctivitis
         subjects affected / exposed
    6 / 383 (1.57%)
    0 / 383 (0.00%)
         occurrences all number
    9
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    97 / 383 (25.33%)
    123 / 383 (32.11%)
         occurrences all number
    0
    0
    Abdominal pain
         subjects affected / exposed
    78 / 383 (20.37%)
    119 / 383 (31.07%)
         occurrences all number
    0
    0
    Constipation
         subjects affected / exposed
    30 / 383 (7.83%)
    108 / 383 (28.20%)
         occurrences all number
    0
    0
    Vomiting
         subjects affected / exposed
    62 / 383 (16.19%)
    106 / 383 (27.68%)
         occurrences all number
    64
    126
    Stomatitis
         subjects affected / exposed
    39 / 383 (10.18%)
    82 / 383 (21.41%)
         occurrences all number
    62
    156
    Diarrhoea
         subjects affected / exposed
    96 / 383 (25.07%)
    70 / 383 (18.28%)
         occurrences all number
    234
    138
    Abdominal pain upper
         subjects affected / exposed
    11 / 383 (2.87%)
    39 / 383 (10.18%)
         occurrences all number
    21
    77
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 383 (0.00%)
    5 / 383 (1.31%)
         occurrences all number
    0
    6
    Hyperbilirubinaemia
         subjects affected / exposed
    10 / 383 (2.61%)
    4 / 383 (1.04%)
         occurrences all number
    15
    10
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    180 / 383 (47.00%)
    90 / 383 (23.50%)
         occurrences all number
    0
    0
    Alopecia
         subjects affected / exposed
    3 / 383 (0.78%)
    42 / 383 (10.97%)
         occurrences all number
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    7 / 383 (1.83%)
    1 / 383 (0.26%)
         occurrences all number
    8
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 383 (3.66%)
    48 / 383 (12.53%)
         occurrences all number
    0
    0
    Myalgia
         subjects affected / exposed
    5 / 383 (1.31%)
    36 / 383 (9.40%)
         occurrences all number
    0
    0
    Pain in extremity
         subjects affected / exposed
    23 / 383 (6.01%)
    37 / 383 (9.66%)
         occurrences all number
    0
    0
    Bone pain
         subjects affected / exposed
    30 / 383 (7.83%)
    39 / 383 (10.18%)
         occurrences all number
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    11 / 383 (2.87%)
    20 / 383 (5.22%)
         occurrences all number
    0
    0
    Back pain
         subjects affected / exposed
    25 / 383 (6.53%)
    21 / 383 (5.48%)
         occurrences all number
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 383 (1.04%)
    3 / 383 (0.78%)
         occurrences all number
    4
    3
    Bronchitis
         subjects affected / exposed
    1 / 383 (0.26%)
    4 / 383 (1.04%)
         occurrences all number
    1
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    37 / 383 (9.66%)
    63 / 383 (16.45%)
         occurrences all number
    0
    0
    Dehydration
         subjects affected / exposed
    5 / 383 (1.31%)
    3 / 383 (0.78%)
         occurrences all number
    6
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2009
    Implementation of the revised RECIST guideline version 1.1 (instead of the previous version 1.0), Introduction of systematic antiemetic prophylaxis guidelines, Modification of constipation prophylaxis Deletion of unnecessary biological exams such as prothrombin time or partial thromboplastin time replaced by the INR for patients on coumadin or warfarin, Modification of treatment labelling.
    07 Dec 2009
    Modification of recommendations for capecitabine dose adjustment in consistency with a new version of Xeloda SmPC, Minimum delay between discontinuation of the anti-HER-2 therapy and randomisation shortened from 4 to 3 weeks, Clarification of inclusion criteria about resistance to taxane therapy (restricted to patient with at least 2 cycles of taxane-based therapy), Clarification about acceptable imaging based procedures for confirmation of bone lesions (CT-scan, MRI and X-ray), • Addition of dose adaptation rules for total bilirubin level increase, • Update of the number of expected participating countries and sites"
    19 May 2011
    Modification of the inclusion criteria number 15, limiting the inclusion to patients of less than 80 year-old in agreement with recent results and modification of the Javlor SmPC, Modification of secondary efficacy analysis with pooling of 3 independent factors (hormonal receptor to oestrogen status, hormonal receptor to progesterone status and HER-2 status) for PFS, OS and ORR multivariate analysis."

    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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