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    Clinical Trial Results:
    A Phase III Open Label, Randomized Two-Parallel-Arm Multicenter Study of E7389 versus Capecitabine in subjects with Locally Advanced or Metastatic Breast Cancer Previously Treated with Anthracyclines and Taxanes

    Summary
    EudraCT number
    		 2005-004009-26
    Trial protocol
    		 HU   BE   CZ   LT   DE   FR   IT   GR   BG   ES  
    Global end of trial date
    11 Dec 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Jun 2020
    First version publication date
    20 Feb 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Results were initially posted at primary completion date cut-off. Updated version includes new data added to full data set at study completion date.

    Trial information

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    Trial identification
    Sponsor protocol code
    E7389-G000-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00337103
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Inc.
    Sponsor organisation address
    Woodcliff Lake, New Jersey, United States, 07677
    Public contact
    Eisai Medical Information, Eisai Inc., +1 888-274-2378, esi_oncmedinfo@eisai.com
    Scientific contact
    Eisai Medical Information, Eisai Inc., +1 888-274-2378, esi_oncmedinfo@eisai.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
    Interim
    Date of interim/final analysis
    12 Mar 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of E7389 versus capecitabine monotherapy, in terms of overall survival (OS) and progression-free survival (PFS) in subjetcs with locally advanced or metastatic breast cancer.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Sep 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 63
    Country: Number of subjects enrolled
    Belgium: 42
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Lithuania: 6
    Country: Number of subjects enrolled
    Russian Federation: 300
    Country: Number of subjects enrolled
    Argentina: 67
    Country: Number of subjects enrolled
    Brazil: 120
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Croatia: 9
    Country: Number of subjects enrolled
    Poland: 41
    Country: Number of subjects enrolled
    Romania: 34
    Country: Number of subjects enrolled
    Serbia: 20
    Country: Number of subjects enrolled
    Ukraine: 122
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    United States: 62
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Taiwan: 19
    Country: Number of subjects enrolled
    South Africa: 12
    Worldwide total number of subjects
    1102
    EEA total number of subjects
    296
    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)
    944
    From 65 to 84 years
    158
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 210 sites across geographic regions (6 regions: North America, Western Europe, Eastern Europe, Latin America, South Africa and Asia) from 01 Apr 2006 to 12 Mar 2012.

    Pre-assignment
    Screening details
    		 A total of 1276 participants were enrolled and screened, of which 174 were screen failures and 1102 were randomized in the study. Of the randomized participants, 1090 participants received the study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eribulin Mesylate 1.4 mg/m^2
    Arm description
    		 Eribulin mesylate 1.4 milligram per square meter (mg/m^2) intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin Mesylate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Eribulin mesylate 1.4 mg/m^2 IV infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

    Arm title
    		 Capecitabine 2.5 g/m^2/Day
    Arm description
    		 Capecitabine : Capecitabine 2.5 gram per square meter (g/m^2) per (/) day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 2.5 g/m^2/day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.

    Number of subjects in period 1
    		Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Started
    554
    548
    Treated (Safety Population)
    544
    546
    Completed
    0
    0
    Not completed
    554
    548
         Physician decision
    15
    14
         Consent withdrawn by subject
    8
    5
         Adverse event, non-fatal
    45
    59
         Subject Choice
    34
    27
         Death
    1
    -
         Progressive Disease
    414
    410
         Not specified
    5
    6
         Lost to follow-up
    1
    2
         Clinical Progression
    27
    24
         Entry Criteria Not Met
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eribulin Mesylate 1.4 mg/m^2
    Reporting group description
    		 Eribulin mesylate 1.4 milligram per square meter (mg/m^2) intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

    Reporting group title
    Capecitabine 2.5 g/m^2/Day
    Reporting group description
    		 Capecitabine : Capecitabine 2.5 gram per square meter (g/m^2) per (/) day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.

    Reporting group values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day Total
    Number of subjects
    		 554 548 1102
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.8 ± 10.37 52.8 ± 10.20 -
    Gender categorical
    Units: Subjects
        Female
    		 554 548 1102
        Male
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 18 18 36
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 15 16 31
        White
    		 496 495 991
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 25 19 44

    End points

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    End points reporting groups
    Reporting group title
    Eribulin Mesylate 1.4 mg/m^2
    Reporting group description
    		 Eribulin mesylate 1.4 milligram per square meter (mg/m^2) intravenous (IV) infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

    Reporting group title
    Capecitabine 2.5 g/m^2/Day
    Reporting group description
    		 Capecitabine : Capecitabine 2.5 gram per square meter (g/m^2) per (/) day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [1]
    End point description
    OS was measured from the date of randomization until the date of death from any cause, or the last date the subject was known to be alive. Subjects who were lost to follow-up or who were alive at the date of data cutoff were censored. The censoring rules for OS were as follows: 1) if the subject was still alive at data cutoff, the date of data cutoff was considered the end date, and 2) if the subject was lost to follow-up before data cutoff, the date they were last known to be alive was considered the end date. Subjects who survived past the end of the study were counted as in the full study period. If death occurred after data cutoff, the end date was to be censored at the time of data cutoff. Data was analyzed using the Intent-to-Treat (ITT) Population defined as all subject who were randomized.
    End point type
    Primary
    End point timeframe
    From date of randomization until date of death from any cause, assessed up to data cutoff date of 12 Mar 2012, or up to approximately 6 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analysed for this endpoint.
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    554
    548
    Units: Days
        median (confidence interval 95%)
    484 (462 to 536)
    440 (400 to 487)
    No statistical analyses for this end point

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS) [2]
    End point description
    PFS was defined as the time (in days) from the date of randomization to the date of the first sign of disease progression based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 (v 1.1) or date of death, regardless of cause. Disease progression was measured by computed tomography (CT) and magnetic resonance imaging (MRI) performed on lesions targeted at baseline for tumor assessment. Disease progression (as assessed by independent review of the imaging scans) per RECIST v 1.1 was defined as at least a 20% increase in the sum of the diameters of the target lesions (taking as reference the smallest sum on study, including the baseline sum if that is the smallest), and an absolute increase of at least 5 millimeter (mm). Note that the appearance of one or more new lesions was also considered as disease progression. Data was analyzed using the ITT Population defined as all subject who were randomized.
    End point type
    Primary
    End point timeframe
    From date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date of 12 Mar 2012 or up to approximately 6 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analysed for this endpoint.
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    554
    548
    Units: Days
        median (confidence interval 95%)
    126 (106 to 131)
    129 (120 to 147)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by European Organization for the Treatment of Cancer Quality of Life Core Questionnaire Scores Based on Core 30 Items (EORTC-QLQ-C30) at Week 6

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    End point title
    		 Change From Baseline in Global Health Status/Quality of Life (QoL) Measured by European Organization for the Treatment of Cancer Quality of Life Core Questionnaire Scores Based on Core 30 Items (EORTC-QLQ-C30) at Week 6
    End point description
    EORTCQLQ-C30:cancer-specific instrument with 30 questions to assess the subject QoL. First 28 questions used to evaluate 5 functional scales(physical, role, cognitive, emotional, social),3 symptom scales(fatigue, nausea and vomiting, pain)and single items(dysponea, appetite loss, insomnia, constipation, diarrhea, financial difficulties).Each of these 28 questions assessed on 4-point scale(1=not at all, 2=a little, 3=quite a bit, 4=very much);functional scales: higher score=better level of functioning; symptom scale: higher score=more severe symptoms; for single items: higher score=more severe problem. Last 2 questions used to evaluate global health status(GHS)/QoL. Each question was assessed on 7-point scale(1=very poor to 7=excellent). Scores averaged, transformed to 0-100 scale; higher score=better quality of life/better level of functioning. ITT Population: subjects who were randomized. Here, overall number of subjects analyzed are those who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    438
    406
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.1 ± 19.23
    1.7 ± 20.69
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for the Treatment of Cancer Quality of Life Core Questionnaire Scores Based on Breast Cancer Specific 23 Items (EORTC-QLQ- BR 23) at Week 6

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    End point title
    		 Change From Baseline in European Organization for the Treatment of Cancer Quality of Life Core Questionnaire Scores Based on Breast Cancer Specific 23 Items (EORTC-QLQ- BR 23) at Week 6
    End point description
    EORTC-QLQ-BR23:disease-specific module for breast cancer developed as a supplement for the EORTC-QLQ-C30 to assess quality of life of participants with breast cancer. The scores from 23 items of QLQ-BR23 included functional scales (body image, sexual functioning, sexual enjoyment, future perspective), symptom scales (systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss). Each item was rated on a scale of 1 to 4 to record level of intensity (1= not at all, 2= a little, 3= quite a bit, 4= very much) within each scales. Scores averaged and transformed to 0-100 scale. High score indicated high/better level of functioning/healthy functioning. Negative change from Baseline indicated deterioration in QOL and positive change from Baseline indicated an improvement in QOL. ITT Population: all subjects who were randomized. Here, “number analyzed” signifies the subjects who were evaluable for this outcome measure for individual row.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    554
    548
    Units: units on a scale
    arithmetic mean (standard deviation)
        Body Image: (n=441, 411)
    0.7 ± 21.26
    4.8 ± 21.80
        Sexual functioning: (n=418, 381)
    1.2 ± 14.75
    -0.1 ± 16.62
        Sexual enjoyment: (n=82, 96)
    0.8 ± 21.58
    3.1 ± 17.49
        Future perspective: (n=439, 410)
    7.7 ± 28.48
    10.0 ± 30.84
        Systemic therapy side effects: (n=440, 415)
    4.5 ± 15.55
    -1.2 ± 14.73
        Breast Symptoms: (n=434, 407)
    -3.4 ± 16.55
    -3.6 ± 16.20
        Arm Symptoms: (n=437, 411)
    -4.2 ± 17.94
    -3.4 ± 18.65
        Upset by hair loss: (n=91, 56)
    -4.4 ± 32.66
    -10.1 ± 29.76
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR): Independent Review

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    End point title
    		 Objective Response Rate (ORR): Independent Review
    End point description
    ORR was defined as the percentage of subjects with a best overall response of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v 1.1). CR is defined as disappearance of all target legions and non-target lesions. All pathological lymph nodes (whether target and non-target), must have reduction in their short axis to less than 10 mm. PR is defined as at least 30% decrease in the sum of the long diameter LD (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of first documentation of CR or PR, assessed up to data cutoff date of 12 Mar 2012 or up to approximately 6 years
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    554
    548
    Units: percentage of subjects
        number (confidence interval 90%)
    11.0 (8.5 to 13.9)
    11.5 (8.9 to 14.5)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR): Independent Review

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    End point title
    		 Duration of Response (DOR): Independent Review
    End point description
    DOR was defined as the time from first documented CR or PR until disease progression or death from any cause for those subjects with a confirmed PR or CR measured by RECIST v1.1. CR defined as disappearance of all target and non-target lesions . All pathological lymph nodes(whether target and non-target), must have reduction in their short axis to less than 10 mm. PR defined as at least 30% decrease in the sum of the long diameter LD (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD. Data was analyzed using for a subset of subjects in the ITT Population who had a response. Here, “overall number of subjects analyzed” are the subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From first documented CR or PR until date of recurrent or progressive disease or death, assessed up to data cutoff date of 12 Mar 2012 or up to approximately 6 years
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    61
    63
    Units: days
        median (confidence interval 95%)
    198 (150 to 273)
    330 (208 to 541)
    No statistical analyses for this end point

    Secondary: Overall Survival Rate

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    End point title
    		 Overall Survival Rate
    End point description
    One-, two-, and three- year’s survival rates were defined as the percentage of subjects who were alive at one, two, and three years respectively, and estimated using the Kaplan−Meier method and Greenwood Formula. ITT population included all subjects who were randomized.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to Year 1, 2 and 3
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    554
    548
    Units: percentage of subjects
    number (confidence interval 95%)
        At 1-year
    0.644 (0.604 to 0.684)
    0.580 (0.538 to 0.622)
        At 2-years
    0.328 (0.289 to 0.368)
    0.298 (0.259 to 0.337)
        At 3-years
    0.178 (0.144 to 0.212)
    0.145 (0.113 to 0.177)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) until 30 Days after the Last Dose of Study Drug

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    End point title
    		 Change From Baseline in Pain Intensity by Visual Analog Scale (VAS) until 30 Days after the Last Dose of Study Drug
    End point description
    Pain intensity was measured by marking a single vertical line that crosses a 1-100 mm unmarked VAS scale. The left-end of the visual analog scale was labelled “least possible pain” and the right-end of the visual analog scale was labelled “worst possible pain”. The pain rating ranged from 0 to 100, with a higher score indicating more pain. A negative change score indicated improvement. ITT Population included all subjects who were randomized. Here, “overall number of subjects analyzed” are the subjects who were evaluable for the outcome measure.
    End point type
    Secondary
    End point timeframe
    First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    431
    431
    Units: units on a scale
        arithmetic mean (standard deviation)
    -3.7 ± 22.80
    0.4 ± 22.90
    No statistical analyses for this end point

    Secondary: Number of Subjects With Consumption of Analgesics During the Study

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    End point title
    		 Number of Subjects With Consumption of Analgesics During the Study
    End point description
    Subjects took analgesics as concomitant pain medications which are defined as pain medications that (1) started before the first dose of study drug and were continuing at the time of the first dose of study drug, or (2) started on/after the day of the first dose of study drug up to 30 days after the last dose of study drug medication.Safety population included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    544
    546
    Units: subjects
    222
    196
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    Safety population defined as all subjects who received at least one dose of study treatment. TEAEs included both SAEs as well as non-SAEs.
    End point type
    Secondary
    End point timeframe
    First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    544
    546
    Units: subjects
        TEAEs
    512
    494
        SAEs
    95
    115
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Markedly Abnormal Parameter Values

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    End point title
    		 Number of Subjects With Treatment-emergent Markedly Abnormal Parameter Values
    End point description
    Safety population defined as all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    544
    546
    Units: subjects
    362
    224
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Took at Least One Concomitant Medication

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    End point title
    		 Number of Subjects Who Took at Least One Concomitant Medication
    End point description
    Concomitant medications included medications that either (1) started before the first dose of study drug and were continuing at the time of the first dose of study drug, or (2) started on or after the first dose of study drug up to 30 days after the last dose of study drug. Safety population included all subjects who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    544
    546
    Units: subjects
    496
    483
    No statistical analyses for this end point

    Secondary: Duration of Eribulin mesylate Exposure

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    End point title
    		 Duration of Eribulin mesylate Exposure
    End point description
    Data have been reported per primary analysis completion stage and final analysis completion stage. After primary analysis completion (at cutoff date of 12 March 2012), only 10 subjects were still receiving study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 6 years for primary analysis completion stage, Up to approximately 6 years 2 months for final analysis completion stage
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Number of subjects analysed
    554
    548
    Units: days
    median (full range (min-max))
        At primary analysis completion stage (n= 544, 546)
    125.0 (21 to 1372)
    119.0 (21 to 1442)
        At final analysis completion stage (n=5, 5)
    1743.0 (1561 to 2219)
    1506.0 (1175 to 2296)
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Eribulin mesylate

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    End point title
    		 Plasma Concentrations of Eribulin mesylate [3]
    End point description
    Pharmacokinetic (PK) analysis set included all subjects who have received at least one dose of E7389 and have at least one quantifiable E7389 concentration. Here, “number analyzed” signifies the subjects who were evaluable for this outcome measure for given time points.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 5-10 minutes(min), 15-30 min, 30-60 min, 60-90 min, 2-4 hours(hrs), 4-8 hrs, 10-24 hrs, 48-72 hrs, 72-96 hrs, 96-120 hrs after the start of infusion of Eribulin mesylate (Duration of each cycle is 21 days)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive data was planned to be analysed for this endpoint.
    End point values
    		 Eribulin Mesylate 1.4 mg/m^2
    Number of subjects analysed
    173
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        5-10 minutes (n=172)
    415.8 ± 719.5
        15-30 minutes (n=57)
    152.6 ± 70.51
        30-60 minutes (n=58)
    95.5 ± 87.90
        60-90 minutes (n=58)
    52.7 ± 79.33
        2-4 hours (n=85)
    20.7 ± 32.81
        4-8 hours (n=78)
    10.0 ± 5.40
        10-24 hours (n=44)
    5.8 ± 3.72
        48-72 hours (n=40)
    3.7 ± 2.58
        72-96 hours (n=37)
    2.4 ± 1.60
        96-120 hours (n=41)
    7.6 ± 38.75
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug (Baseline) up to 30 days after last dose of study drug (up to approximately 6 years 3 months)
    Adverse event reporting additional description
    Data was analyzed using Safety Population defined as all subjects who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Eribulin Mesylate 1.4 mg/m^2
    Reporting group description
    		 Eribulin mesylate 1.4 mg/m^2 IV infusion given over 2-5 minutes on Days 1 and 8 every 21 days.

    Reporting group title
    Capecitabine 2.5 g/m^2/Day
    Reporting group description
    		 Capecitabine : Capecitabine 2.5 g/m^2/day administered orally twice daily in two equal doses on Days 1 to 14 every 21 days.

    Serious adverse events
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    95 / 544 (17.46%)
    115 / 546 (21.06%)
         number of deaths (all causes)
    442
    459
         number of deaths resulting from adverse events
    26
    36
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant Ascites
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Pleural Effusion
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Central Nervous System
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Liver
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastases to Meninges
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Ovary
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Peritoneum
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Pleura
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm Malignant
         subjects affected / exposed
    7 / 544 (1.29%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 6
    0 / 4
    Oncologic Complication
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal Cancer
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Pain
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    2 / 544 (0.37%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombophlebitis
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Malignant Breast Lump Removal
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 544 (0.55%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 544 (0.37%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Extravasation
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 544 (0.55%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    2 / 544 (0.37%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Generalized Oedema
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza Like Illness
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection Site Extravasation
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal Inflammation
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-Organ Failure
         subjects affected / exposed
    1 / 544 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Oedema peripheral
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 544 (0.55%)
    5 / 546 (0.92%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal Haemorrhage
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    13 / 544 (2.39%)
    17 / 546 (3.11%)
         occurrences causally related to treatment / all
    4 / 20
    2 / 22
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (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 / 544 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    2 / 544 (0.37%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 544 (0.18%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory Failure
         subjects affected / exposed
    5 / 544 (0.92%)
    7 / 546 (1.28%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Tracheal Stenosis
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 544 (0.37%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    2 / 544 (0.37%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemoglobin Decreased
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin Increased
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 544 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac Tamponade
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory Arrest
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic Shock
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Left Ventricular Dysfunction
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (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
    Aphasia
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebellar Infarction
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular Accident
         subjects affected / exposed
    2 / 544 (0.37%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Coma Hepatic
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    1 / 544 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Depressed Level of Consciousness
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysgeusia
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial Paresis
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 544 (0.37%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial Pressure Increased
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lethargy
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonic Epilepsy
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial Seizures
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Motor Neuropathy
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (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
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Simple Partial Seizures
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    2 / 544 (0.37%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (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 / 544 (0.55%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    7 / 544 (1.29%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    7 / 8
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    4 / 544 (0.74%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    10 / 544 (1.84%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    10 / 10
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Thrombocytopenia
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 544 (0.37%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 544 (0.18%)
    15 / 546 (2.75%)
         occurrences causally related to treatment / all
    1 / 1
    14 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 544 (0.18%)
    7 / 546 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 544 (0.37%)
    9 / 546 (1.65%)
         occurrences causally related to treatment / all
    0 / 2
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatitis Toxic
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    2 / 544 (0.37%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (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
    Bronchitis
         subjects affected / exposed
    0 / 544 (0.00%)
    3 / 546 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 544 (0.00%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 544 (0.74%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    1 / 4
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia Klebsiella
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 544 (0.37%)
    4 / 546 (0.73%)
         occurrences causally related to treatment / all
    2 / 4
    4 / 5
         deaths causally related to treatment / all
    1 / 2
    1 / 1
    Soft Tissue Infection
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous Abscess
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 544 (0.18%)
    0 / 546 (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
    Decreased Appetite
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 544 (0.18%)
    9 / 546 (1.65%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte Imbalance
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 544 (0.18%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    1 / 544 (0.18%)
    2 / 546 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatremia
         subjects affected / exposed
    0 / 544 (0.00%)
    1 / 546 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Eribulin Mesylate 1.4 mg/m^2 Capecitabine 2.5 g/m^2/Day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    509 / 544 (93.57%)
    489 / 546 (89.56%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    47 / 544 (8.64%)
    23 / 546 (4.21%)
         occurrences all number
    103
    41
    Aspartate aminotransferase increased
         subjects affected / exposed
    43 / 544 (7.90%)
    27 / 546 (4.95%)
         occurrences all number
    113
    49
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    29 / 544 (5.33%)
    22 / 546 (4.03%)
         occurrences all number
    38
    43
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 544 (5.51%)
    29 / 546 (5.31%)
         occurrences all number
    38
    31
    Headache
         subjects affected / exposed
    67 / 544 (12.32%)
    55 / 546 (10.07%)
         occurrences all number
    133
    94
    Peripheral sensory neuropathy
         subjects affected / exposed
    73 / 544 (13.42%)
    38 / 546 (6.96%)
         occurrences all number
    131
    47
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    102 / 544 (18.75%)
    96 / 546 (17.58%)
         occurrences all number
    237
    194
    Leukopenia
         subjects affected / exposed
    171 / 544 (31.43%)
    57 / 546 (10.44%)
         occurrences all number
    537
    170
    Neutropenia
         subjects affected / exposed
    292 / 544 (53.68%)
    87 / 546 (15.93%)
         occurrences all number
    914
    211
    Thrombocytopenia
         subjects affected / exposed
    27 / 544 (4.96%)
    29 / 546 (5.31%)
         occurrences all number
    48
    42
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    83 / 544 (15.26%)
    79 / 546 (14.47%)
         occurrences all number
    165
    113
    Fatigue
         subjects affected / exposed
    91 / 544 (16.73%)
    82 / 546 (15.02%)
         occurrences all number
    193
    116
    Mucosal inflammation
         subjects affected / exposed
    26 / 544 (4.78%)
    35 / 546 (6.41%)
         occurrences all number
    37
    60
    Oedema peripheral
         subjects affected / exposed
    35 / 544 (6.43%)
    36 / 546 (6.59%)
         occurrences all number
    42
    41
    Pyrexia
         subjects affected / exposed
    67 / 544 (12.32%)
    27 / 546 (4.95%)
         occurrences all number
    124
    33
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    32 / 544 (5.88%)
    46 / 546 (8.42%)
         occurrences all number
    51
    68
    Abdominal Pain Upper
         subjects affected / exposed
    31 / 544 (5.70%)
    39 / 546 (7.14%)
         occurrences all number
    38
    52
    Constipation
         subjects affected / exposed
    42 / 544 (7.72%)
    46 / 546 (8.42%)
         occurrences all number
    70
    58
    Diarrhoea
         subjects affected / exposed
    77 / 544 (14.15%)
    154 / 546 (28.21%)
         occurrences all number
    124
    363
    Nausea
         subjects affected / exposed
    121 / 544 (22.24%)
    131 / 546 (23.99%)
         occurrences all number
    259
    226
    Stomatitis
         subjects affected / exposed
    27 / 544 (4.96%)
    31 / 546 (5.68%)
         occurrences all number
    38
    42
    Vomiting
         subjects affected / exposed
    63 / 544 (11.58%)
    89 / 546 (16.30%)
         occurrences all number
    87
    141
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    45 / 544 (8.27%)
    44 / 546 (8.06%)
         occurrences all number
    56
    61
    Dyspnoea
         subjects affected / exposed
    49 / 544 (9.01%)
    51 / 546 (9.34%)
         occurrences all number
    62
    77
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    9 / 544 (1.65%)
    38 / 546 (6.96%)
         occurrences all number
    12
    82
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    188 / 544 (34.56%)
    22 / 546 (4.03%)
         occurrences all number
    263
    24
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 544 (0.18%)
    244 / 546 (44.69%)
         occurrences all number
    1
    735
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    42 / 544 (7.72%)
    31 / 546 (5.68%)
         occurrences all number
    76
    53
    Back pain
         subjects affected / exposed
    55 / 544 (10.11%)
    43 / 546 (7.88%)
         occurrences all number
    86
    75
    Bone pain
         subjects affected / exposed
    50 / 544 (9.19%)
    42 / 546 (7.69%)
         occurrences all number
    94
    75
    Myalgia
         subjects affected / exposed
    30 / 544 (5.51%)
    8 / 546 (1.47%)
         occurrences all number
    38
    9
    Pain in extremity
         subjects affected / exposed
    47 / 544 (8.64%)
    37 / 546 (6.78%)
         occurrences all number
    91
    68
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    29 / 544 (5.33%)
    26 / 546 (4.76%)
         occurrences all number
    35
    32
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    68 / 544 (12.50%)
    80 / 546 (14.65%)
         occurrences all number
    91
    120

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2005
    Amendment 01: The protocol was amended to update PFS from secondary objective to primary objective, pharmacogenomic analysis was deleted and Eastern Cooperative Oncology Group (ECOG) performance status was removed from symptom assessments and included as a separate assessment.
    02 Mar 2006
    Amendment 02: The protocol was amended to update number of subjects included in the PK analysis to include a minimum of 200 subjects, requirement for previous exposure to trastuzumab was modified to allow subjects to participate in the study without previous exposure to trastuzumab, confirmation of the frequency of additional bone scans, stability data for E7389, addition of more comprehensive information regarding bone marrow exposure in relation to exclusion criterion #4 and provisions under which the use of bisphosphonates was permitted during the study.
    11 May 2006
    Amendment 03: Storage conditions for E7389 were updated according to new stability data.
    05 Dec 2006
    Amendment 04: The protocol was amended to include all subjects, not just those subjects who had measurable lesions for imaging review process by independent review, eligibility criteria were changed to include a more complete representation of the breast cancer population, level of renal function was changed for greater than (>) 50 milliliter/minute creatinine clearance in order to administer the full 2.5 g/m2 starting dose of capecitabine, washout period was added for prior experimental treatments, removed restriction on subjects with prior high dose chemotherapy, added requirement for confirmation of stable brain metastases by scan at screening to ensure scan is available for independent review and allowed for continuation of treatment with E7389 for as long as subjects continue to experience clinical benefit.
    31 Oct 2007
    Amendment 05: The protocol was amendment to update The number of sites participating in the study was increased from 180 to 210. Storage conditions for E7389 were updated to reflect new stability data.
    06 Mar 2008
    Amendment 06: The protocol was amended to update title of the study to remove the requirement for subject’s tumors to be refractory to the most recent chemotherapy, eligibility for enrollment into the study was widened to comply with current medical practices in the use of capecitabine, allowed inclusion of subjects with ECOG performance status of up to 2 and complete response (CR) or partial response (PR) was to be assessed a minimum of 5 weeks after start of treatment with a subsequent PD without a confirmation of PR or CR at least 4 weeks later by follow-up scans, allowed investigator more discretion for dose reductions of capecitabine on the first instance of Grade 2 toxicity and specified requirements for bone lesion assessment to note the use of x-ray to confirm whether or not lesions are malignant. Complete response or PR was to be assessed a minimum of 5 weeks after start of treatment with a subsequent PD without a confirmation of PR or CR at least 4 weeks later by follow-up scans but having a subsequent PD assessment was considered SD for the best response. However, CR or PR assessed less than 5 weeks of start of treatment with a subsequent PD was considered PD for the best response.
    03 Mar 2009
    Amendment 07: The protocol was amended to update study timeline to change the date of the end of the study from 31 Mar 2010 to Apr 2012.
    15 Sep 2014
    Amendment 08: The protocol was amended to update that no further collection of survival follow-up data, quality of life data, pain intensity data, and images by the independent imaging vendor was deemed necessary for the study. 

    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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