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    Clinical Trial Results:
    Phase III trial of IV vinflunine versus an alkylating agent in patients with metastatic breast cancer previously treated with or resistant to an anthracycline, a taxane, an antimetabolite, and a vinca-alkaloid (study L00070 IN 308 B0)

    Summary
    EudraCT number
    		 2009-011118-47
    Trial protocol
    		 FR   PT   IT   ES   BE   DE   AT   HU   GB   BG  
    Global end of trial date
    17 Jan 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Jun 2019
    First version publication date
    08 Jan 2017
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Update of safety data of subjects still ongoing treatment at the primary cut-off

    Trial information

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    Trial identification
    Sponsor protocol code
    L00070 IN 3 08 B0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01091168
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PIERRE FABRE MEDICAMENT
    Sponsor organisation address
    45, place Abel Gance, Boulogne Billancourt, France,
    Public contact
    Dr Karim Keddad, INSTITUT DE RECHERCHE PIERRE FABRE, karim.keddad@pierre-fabre.com
    Scientific contact
    Dr Karim Keddad, Centre de Recherche et Développement clinique. 3 avenue Hubert CURIEN - 31000 TOULOUSE, karim.keddad@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
    27 Aug 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Aug 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the overall survival in patients treated with i.v. vinflunine versus those receiving an alkylating agent of physician’s choice.
    Protection of trial subjects
    Antiemetic (corticosteroids) in both arms Laxatives in test drug arm All best supportive treatment: analgesics for pain, biphosphonates for bone metastasis localized radiotheray in case of bone pain, transfusion, erythropoietin, GCSF in case of neutropenia gr 4 lasting at least 7 days or febrile neutropenia or neutropenic infection and then prophylactically in further cycles
    Background therapy
    		 Antiemetic (corticosteroids) in both arms Laxatives in test drug arm All best supportive treatment: analgesics for pain, biphosphonates for bone metatstasis, localized radiotheray in case of bone pain, transfusion, erythropoietin, GCSF in case of neutropenia gr 4 lasting at least 7 days or febrile neutropenia or neutropenic infection and then prophylactically in further cycles
    Evidence for comparator
    		 Alkylating agents (cyclophosphamide, carboplatin, cisplatine, melphalan, thiotepa, mitomycin C) are according to investigators acceptable treatment MBC in patients having exhausted the most active cytotoxics because they have shown some activity in this setting
    Actual start date of recruitment
    15 Jul 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 15
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Taiwan: 26
    Country: Number of subjects enrolled
    Belarus: 54
    Country: Number of subjects enrolled
    Russian Federation: 57
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    Ukraine: 10
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Spain: 78
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    France: 162
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 54
    Worldwide total number of subjects
    594
    EEA total number of subjects
    396
    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)
    463
    From 65 to 84 years
    131
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was randomized on 15 July 2009 and the last patient was randomized on 11 October 2011. The recruitment period lasted 27 months. A total of 594 patients with metastatic breast cancer were randomized in the study in 130 sites over 20 countries.

    Pre-assignment
    Screening details
    		 Inclusion criteria included: women ≥ 18 years and ≤ 75 years, with histologically or cytologically confirmed breast cancer; at least two prior chemotherapy regimens for the treatment of locally recurrent and/or metastatic disease excluding chemotherapy received in the neo/adjuvant setting; prior treatment included an anthracycline (A), a taxane (T)

    Pre-assignment period milestones
    Number of subjects started
    		 594
    Number of subjects completed
    		 594

    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
    		 Vinflunine
    Arm description
    		 vinflunine 280 mg/m2/day on day 1 of a 3 week cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vinflunine
    Investigational medicinal product code
    L0070
    Other name
    Javlor®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    280 mg/m2/day on day 1 of each 3 weeks cycle, over a 20-minute intravenous (IV) infusion

    Arm title
    		 Alkylating agent
    Arm description
    		 alkylating agent of physician choice
    Arm type
    		 Active comparator

    Investigational medicinal product name
    cyclophosphamide or cisplatin or carboplatin or thiotepa or melphalan or mitomycin C
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal tablet, Solution for injection/infusion
    Routes of administration
    Buccal use, Intravenous use
    Dosage and administration details
    All comparator drugs were commercially available and approved for the treatment of cancer in the country where they were used. Alkylating agents which were received as single agent every 3 weeks, included cyclophosphamide (IV or oral), melphalan (IV or oral), mitomycin C, thiotepa, cisplatin and carboplatin according to SPCs

    Number of subjects in period 1
    		Vinflunine Alkylating agent
    Started
    298
    296
    cut-off date
    243
    229
    Completed
    0
    0
    Not completed
    298
    296
         Consent withdrawn by subject
    1
    3
         Physician decision
    15
    12
         Adverse event, non-fatal
    21
    24
         Other
    2
    -
         progressive disease
    250
    234
         Lost to follow-up
    -
    1
         patient's decision
    9
    20
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vinflunine
    Reporting group description
    		 vinflunine 280 mg/m2/day on day 1 of a 3 week cycle

    Reporting group title
    Alkylating agent
    Reporting group description
    		 alkylating agent of physician choice

    Reporting group values
    		 Vinflunine Alkylating agent Total
    Number of subjects
    		 298 296 594
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 236 227 463
        From 65-84 years
    		 62 69 131
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 57.2 ( 9.1 ) 56.5 ( 10.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 298 296 594
    WHO Performance status
    Units: Subjects
        WHO 0
    		 103 110 213
        WHO 1
    		 164 155 319
        WHO 2
    		 31 31 62
    Menopausal status
    Units: Subjects
        Menopaused
    		 237 211 448
        Non Menaopaused
    		 61 85 146
    Main histopathological type
    Units: Subjects
        Ductal
    		 220 220 440
        Lobular
    		 25 28 53
        Carcinoma NOS
    		 36 38 74
        Others
    		 17 10 27
    Time from diagnosis to study entry
    Units: years
        median (full range (min-max))
    		 1.2 (0 to 9.8) 1.3 (0 to 10.7) -

    End points

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    End points reporting groups
    Reporting group title
    Vinflunine
    Reporting group description
    		 vinflunine 280 mg/m2/day on day 1 of a 3 week cycle

    Reporting group title
    Alkylating agent
    Reporting group description
    		 alkylating agent of physician choice

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomisation to death.
    End point type
    Primary
    End point timeframe
    from Baseline to cut-off date (August, 27 th 2012)
    End point values
    		 Vinflunine Alkylating agent
    Number of subjects analysed
    298
    296
    Units: months
        median (confidence interval 95%)
    9.1 (7.7 to 10.4)
    9.3 (7.5 to 10.9)
    Statistical analysis title
    		 Primary efficacy analysis
    Statistical analysis description
    Kaplan-Meier curves and life tables by treatment arm were provided. Confidence intervals on the median were calculated using the Brookmeyer and Crowley method. Hazard ratio and 95% confidence intervals were 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
    Comparison groups
    Alkylating agent v Vinflunine
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.673 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.25
    Notes
    [1] - As a secondary analysis of the OS, a Multivariate analysis was conducted in the ITT population using the Cox proportional hazard model to estimate the simultaneous effect of the following prognosis factors: age, number of organs involved, time from initial diagnosis to randomisation, prior hormonal therapy, prior neo/adjuvant chemotherapy, hormone receptors and Her-2 status. The only prognostic factor which was significant was the number of organs involved : P < 0.0001 when the number was > 2
    [2] - The median OS was similar in the 2 study arms : 9.1 months in the VFL arm and 9.3 months in the aniti alkylating agents arm (HR = 1.04, 95% CI = 0.86 - 1.25, P = 0.6730)

    Secondary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    PFS was defined as the time from randomisation to the first tumour progression or death due to any cause in the absence of previous documentation of objective tumour progression. PFS was performed in the ITT and eligible populations. For patients lost of follow up, or whithout a known record of progression or death, PFS was censored at the date of last tumour assessment or the date of last contact of a follow-up showing no progression which ever occured last
    End point type
    Secondary
    End point timeframe
    From baseline to cut-off date
    End point values
    		 Vinflunine Alkylating agent
    Number of subjects analysed
    298 [3]
    296 [4]
    Units: months
        median (confidence interval 95%)
    2.5 (1.7 to 2.7)
    1.9 (1.5 to 2.6)
    Notes
    [3] - 291 events-7 censored
    [4] - 286 events-10 censored
    Statistical analysis title
    		 PFS secondary analysis
    Statistical analysis description
    PFS was compared between the 2 treatment arms by the log-rank test procedure with the 5 % significant level, stratified on the stratification factors (except study site) as specified at the time of randomisation. Os was analysed using Kaplan-Meir ethod and summarized with median and 95% CI of the median
    Comparison groups
    Vinflunine v Alkylating agent
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4927 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.12
    Notes
    [5] - Investigator-assessed median PFS was slightly longer in the VFL arm without statistically signicant difference : 2.5 months in the VFL arm and 1.9 months in the AA arm, p=0.4927

    Secondary: Disease Control Rate

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    End point title
    		 Disease Control Rate
    End point description
    DCR was defined as the proportion of patients with CR, PR and stable disease (SD), relative to the total number of patients in the analysed population.
    End point type
    Secondary
    End point timeframe
    From baseline to cut-off date
    End point values
    		 Vinflunine Alkylating agent
    Number of subjects analysed
    298
    296
    Units: percent
        median (confidence interval 95%)
    43.6 (37.9 to 49.3)
    35.5 (30 to 41.2)
    Statistical analysis title
    		 DCR: Secondary efficay analysis
    Statistical analysis description
    the disease control rate (DCR) were compared in the ITT population and in the population evaluable for response between the 2 arms with a cochran Mantel Haenszel, stratified on WHO performance status at baseline, number of prior chemotherapy lines for the treatement of disease and desease measurability at baseline
    Comparison groups
    Vinflunine v Alkylating agent
    Number of subjects included in analysis
    594
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0424 [6]
    Method
    		 Logrank
    Confidence interval
    Notes
    [6] - Disease control rates (DCRs) were significantly higher in the Vinflunine arm compared to the AA arm whatever the population considered. In the ITT population, DCRs were 43.6% in the VFL arm and 35.5% in the AA arm (P = 0.0424).

    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 exception of SAEs occured after discontinuation and start of a further treatment.
    Adverse event reporting additional description
    The same event may appear as both an AE and SAE. However what is presented are distincts events. An event may be categorized as serious in 1 subject and as non serious in anothe. Specific AE tables were generated separately as per Eu format. we report here all "on study" SAEs and 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
    Alkylating agent
    Reporting group description
    		 alkylating agent of physician choice

    Reporting group title
    Vinflunine
    Reporting group description
    		 vinflunine 280 mg/m2/day on day 1 of a 3-week cycle

    Serious adverse events
    		 Alkylating agent Vinflunine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    66 / 290 (22.76%)
    82 / 297 (27.61%)
         number of deaths (all causes)
    229
    243
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    43 / 290 (14.83%)
    38 / 297 (12.79%)
         occurrences causally related to treatment / all
    0 / 43
    0 / 38
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    suamous cell carninoma
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (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
    Asthenia
         subjects affected / exposed
    0 / 290 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 290 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 290 (0.69%)
    4 / 297 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 290 (0.69%)
    6 / 297 (2.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 290 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    confusional state
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 290 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriospasm coronary
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (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 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachial plexopathy
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (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
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (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
    Neutropenia
         subjects affected / exposed
    0 / 290 (0.00%)
    6 / 297 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 290 (0.00%)
    6 / 297 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 290 (0.34%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 290 (0.69%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis staphylococcal
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 290 (0.00%)
    5 / 297 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 290 (1.03%)
    6 / 297 (2.02%)
         occurrences causally related to treatment / all
    2 / 3
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 290 (0.34%)
    4 / 297 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 290 (0.00%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ileus paralytic
         subjects affected / exposed
    0 / 290 (0.00%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 290 (0.00%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 290 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 290 (0.34%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain upper
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagial Stenosis
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bile duct obstruction
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (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
    Arthralgia
         subjects affected / exposed
    1 / 290 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Neutropenic infection
         subjects affected / exposed
    1 / 290 (0.34%)
    4 / 297 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoniae
         subjects affected / exposed
    1 / 290 (0.34%)
    3 / 297 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 290 (0.69%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 290 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchitis
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    influenza
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 290 (0.00%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central line infection
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (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 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 290 (0.00%)
    2 / 297 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 290 (0.34%)
    1 / 297 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 290 (0.34%)
    0 / 297 (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
    		 Alkylating agent Vinflunine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    262 / 290 (90.34%)
    197 / 297 (66.33%)
    Investigations
    Weight decreased
         subjects affected / exposed
    17 / 290 (5.86%)
    26 / 297 (8.75%)
         occurrences all number
    23
    34
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    5 / 290 (1.72%)
    21 / 297 (7.07%)
         occurrences all number
    9
    48
    Headache
         subjects affected / exposed
    5 / 290 (1.72%)
    7 / 297 (2.36%)
         occurrences all number
    7
    15
    Dizziness
         subjects affected / exposed
    4 / 290 (1.38%)
    3 / 297 (1.01%)
         occurrences all number
    7
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    43 / 290 (14.83%)
    89 / 297 (29.97%)
         occurrences all number
    62
    177
    Injection site reaction
         subjects affected / exposed
    2 / 290 (0.69%)
    29 / 297 (9.76%)
         occurrences all number
    2
    58
    Fatigue
         subjects affected / exposed
    25 / 290 (8.62%)
    23 / 297 (7.74%)
         occurrences all number
    35
    55
    Pain
         subjects affected / exposed
    0 / 290 (0.00%)
    4 / 297 (1.35%)
         occurrences all number
    0
    4
    Pyrexia
         subjects affected / exposed
    3 / 290 (1.03%)
    10 / 297 (3.37%)
         occurrences all number
    5
    19
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    31 / 290 (10.69%)
    37 / 297 (12.46%)
         occurrences all number
    46
    56
    Thrombocytopenia
         subjects affected / exposed
    39 / 290 (13.45%)
    3 / 297 (1.01%)
         occurrences all number
    64
    3
    Anaemia
         subjects affected / exposed
    6 / 290 (2.07%)
    2 / 297 (0.67%)
         occurrences all number
    9
    2
    Gastrointestinal disorders
    Constipation
    Additional description: related TEAES are provided
         subjects affected / exposed
    23 / 290 (7.93%)
    102 / 297 (34.34%)
         occurrences all number
    34
    181
    Nausea
         subjects affected / exposed
    67 / 290 (23.10%)
    70 / 297 (23.57%)
         occurrences all number
    126
    131
    Abdominal pain
         subjects affected / exposed
    16 / 290 (5.52%)
    66 / 297 (22.22%)
         occurrences all number
    58
    170
    Stomatitis
         subjects affected / exposed
    18 / 290 (6.21%)
    52 / 297 (17.51%)
         occurrences all number
    23
    98
    Vomiting
         subjects affected / exposed
    33 / 290 (11.38%)
    34 / 297 (11.45%)
         occurrences all number
    45
    44
    Diarrhoea
         subjects affected / exposed
    19 / 290 (6.55%)
    16 / 297 (5.39%)
         occurrences all number
    35
    24
    Abdominal pain upper
         subjects affected / exposed
    4 / 290 (1.38%)
    14 / 297 (4.71%)
         occurrences all number
    5
    24
    Abdominal distension
         subjects affected / exposed
    1 / 290 (0.34%)
    5 / 297 (1.68%)
         occurrences all number
    1
    5
    Dyspepsia
         subjects affected / exposed
    1 / 290 (0.34%)
    4 / 297 (1.35%)
         occurrences all number
    1
    4
    gastritis
         subjects affected / exposed
    0 / 290 (0.00%)
    4 / 297 (1.35%)
         occurrences all number
    0
    4
    Paraesthesia
         subjects affected / exposed
    0 / 290 (0.00%)
    4 / 297 (1.35%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    9 / 290 (3.10%)
    30 / 297 (10.10%)
         occurrences all number
    12
    31
    Pruritus
         subjects affected / exposed
    2 / 290 (0.69%)
    7 / 297 (2.36%)
         occurrences all number
    1
    11
    Dry skin
         subjects affected / exposed
    3 / 290 (1.03%)
    4 / 297 (1.35%)
         occurrences all number
    3
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 290 (0.00%)
    10 / 297 (3.37%)
         occurrences all number
    0
    18
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    5 / 290 (1.72%)
    38 / 297 (12.79%)
         occurrences all number
    5
    78
    Arthralgia
         subjects affected / exposed
    3 / 290 (1.03%)
    21 / 297 (7.07%)
         occurrences all number
    3
    53
    Pain in Jaw
         subjects affected / exposed
    0 / 290 (0.00%)
    12 / 297 (4.04%)
         occurrences all number
    0
    24
    Muscle spasms
         subjects affected / exposed
    2 / 290 (0.69%)
    6 / 297 (2.02%)
         occurrences all number
    2
    6
    Musculoskeletal pain
         subjects affected / exposed
    1 / 290 (0.34%)
    4 / 297 (1.35%)
         occurrences all number
    1
    8
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    24 / 290 (8.28%)
    31 / 297 (10.44%)
         occurrences all number
    29
    62

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 May 2009
    The extra label on the commercial packaging of the alkylating agent used as comparator drugs was deleted. The HER2 and hormonal receptors status was required to be obtained at baseline
    23 Sep 2009
    The use of GCSF had to follow local (Taiwan) guidelines and medical practice
    15 Dec 2009
    - Inclusion criterion n°4: the upper limit of number of prior chemotherapy lines (no more than 5) was deleted because approximatively 1/3 of screened patients were found ineligible - Inclusion criterion n° 9: the delay between discontinuation of anti HER2 targeted therapy was shortened from 4 to 3 weeks as far as no additional toxicity was expected - Inclusion criterion n° 10: the delay between discontinuation of radiation therapy was shortened from 4 to 3 weeks because only localised palliative radiotherapy was performed at this far advanced stage of breast cancer - Inclusion criterion n° 15: To add as prohibited treatment during the month preceding first study drug administration,transfusions except if medically indicated - Exclusion criterion n° 1: symptomatic ascites (grade ≥ 2) requiring active treatment was added To adapt the stratification factor concerning the number of prior lines for the treatment of locally recurrent/metastatic disease excluding chemotherapy given in the neo/adjuvant setting. To add complementary information to vinflunine reconstitution procedure (possibility to use G5% solution) To modify restriction of use of alkylating agents in order to stick to local practice in each countries. (Alkylating agents approved for the treatment of cancer in general in the country and not only in breast cancer were prescribed) To define the cycle for alkylating agent as a 3 week period in order to homogenize periodicity of tumour assessments between the 2 arms

    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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    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
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