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    Clinical Trial Results:
    A Randomized, Open-label, Multicenter, Phase 3 Study to Compare the Efficacy and Safety of Eribulin with Treatment of Physician's Choice in Subjects with Advanced Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2011-000724-15
    Trial protocol
    		 DE   GB   ES   PL   IT  
    Global end of trial date
    02 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jul 2019
    First version publication date
    03 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E7389-G000-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01454934
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Inc.
    Sponsor organisation address
    300 Tice Boulevard, Woodcliff Lake, 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
    Final
    Date of interim/final analysis
    29 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a randomized, open-label, multicenter, Phase 3 study, comparing efficacy and safety of eribulin with treatment of physician's choice (TPC) in subjects with advanced and disease progression following at least two prior regimens for advanced disease, which should have included a platinum-based regimen.
    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
    09 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 44
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Japan: 120
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    France: 98
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Singapore: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 50
    Country: Number of subjects enrolled
    Taiwan: 27
    Worldwide total number of subjects
    540
    EEA total number of subjects
    251
    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)
    338
    From 65 to 84 years
    201
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 735 subjects were screened. Of these, 195 screen failed due to failure to meet inclusion/exclusion criteria, adverse events, withdrawal of consent, or other reason and were not randomized into the study. A total of 540 subjects were randomized into the study. Of these, 3 were discontinued prior to 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
    		 Arm A: Eribulin Mesylate
    Arm description
    		 Eribulin mesylate (1.4 milligram per square meter [mg/m^2]) was administered intravenously (IV) over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesylate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eribulin mesylate was administered as an intravenous infusion at a dose of 1.4 mg/m^2, over 2 to 5 minutes on Days 1 and 8 of every cycle, where the duration of each cycle was 21 days.

    Arm title
    		 Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Arm description
    		 Treatment of Physician's Choice (TPC): Vinorelbine (30 mg/m^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Navelbine
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vinorelbine (30 mg/m^2) was administered by IV on Day 1, every 7 days.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Gemzar
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1250 mg/m^2) was administered by IV on Days 1 and 8, every 21 days (or 1000 mg/m^2 on Days 1, 8, and 15 every 28 days)

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere, Docefrez
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel (75 mg/m^2) was administered IV every 21 days

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Almita
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed (500 mg/m^2) was administered IV on Day 1 every 21 days (nonsquamous histology only)

    Number of subjects in period 1
    		Arm A: Eribulin Mesylate Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Started
    270
    270
    Completed
    0
    0
    Not completed
    270
    270
         Clinical progression
    28
    25
         Consent withdrawn by subject
    2
    5
         Disease progression
    194
    181
         Adverse event, non-fatal
    28
    24
         Other
    6
    17
         Withdrawal by participant
    11
    15
         Lost to follow-up
    -
    1
         Not treated
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Eribulin Mesylate
    Reporting group description
    		 Eribulin mesylate (1.4 milligram per square meter [mg/m^2]) was administered intravenously (IV) over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.

    Reporting group title
    Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Reporting group description
    		 Treatment of Physician's Choice (TPC): Vinorelbine (30 mg/m^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).

    Reporting group values
    		 Arm A: Eribulin Mesylate Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed Total
    Number of subjects
    		 270 270 540
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.4 ( 9.62 ) 60.8 ( 9.32 ) -
    Gender categorical
    Units: Subjects
        Female
    		 107 101 208
        Male
    		 163 169 332

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Eribulin Mesylate
    Reporting group description
    		 Eribulin mesylate (1.4 milligram per square meter [mg/m^2]) was administered intravenously (IV) over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.

    Reporting group title
    Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Reporting group description
    		 Treatment of Physician's Choice (TPC): Vinorelbine (30 mg/m^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The OS was defined as the time in months from the date of randomization to the date of death, regardless of cause. In the absence of confirmation of death, the subjects were censored either at the date that subject was last known to be alive or the date of study cut-off, whichever was earlier. The two treatment arms were compared using the log-rank test, stratified by histology, TPC option, and geographic region; and the treatment difference between eribulin and TPC was tested at a significance level of 0.05 (2-sided). Kaplan-Meier (K-M) survival probabilities for each arm were plotted over time. The treatment effect was estimated by fitting a Cox Proportional Hazards model to the OS times including treatment arm as a factor and histology, TPC option and geographic region as strata. Full analysis set (FAS) was the primary analysis set for all efficacy evaluations and included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Randomization (Day 1) until date of death from any cause, or 37 months
    End point values
    		 Arm A: Eribulin Mesylate Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Number of subjects analysed
    270
    270
    Units: months
        median (confidence interval 95%)
    9.5 (7.4 to 11.4)
    9.5 (8.5 to 11.3)
    Statistical analysis title
    		 Overall Survival
    Statistical analysis description
    OS was compared between eribulin and TPC testing the following null hypothesis: H0: OS in Arm A (eribulin) is equal to OS in Arm B (TPC) against the alternative: H1: OS in Arm A (eribulin) is not equal to OS in Arm B (TPC).
    Comparison groups
    Arm A: Eribulin Mesylate v Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Number of subjects included in analysis
    540
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1343 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.41
    Notes
    [1] - P-value was calculated from a 2-sided log-rank test stratified by histology, TPC option, and geographic region.

    Secondary: Progression Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST)

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    End point title
    		 Progression Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST)
    End point description
    PFS was defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first. The difference in PFS (based on the tumor response evaluation as determined by the investigator) between eribulin and TPC was evaluated using the log rank test, stratified by histology, TPC option, and geographic region, tested at an alpha level of 0.05 (2-sided). PFS censoring rules will be defined in the SAP and follow Federal Department of Agriculture (FDA) guidance. FAS was the primary analysis set for all efficacy evaluations and included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Randomization (Day 1) until date of disease progression or death (whichever occurred first), or 37 months
    End point values
    		 Arm A: Eribulin Mesylate Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Number of subjects analysed
    270
    270
    Units: months
        median (confidence interval 95%)
    3 (2.6 to 3.9)
    2.8 (2.6 to 3.6)
    Statistical analysis title
    		 PFS by RECIST
    Statistical analysis description
    OS was compared between eribulin and TPC testing the following null hypothesis: H0: OS in Arm A (eribulin) is equal to OS in Arm B (TPC) against the alternative: H1: OS in Arm A (eribulin) is not equal to OS in Arm B (TPC).
    Comparison groups
    Arm A: Eribulin Mesylate v Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Number of subjects included in analysis
    540
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3946 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.32
    Notes
    [2] - P-value was calculated from a 2-sided long-rank test stratified by histology, TPC option, and geographic region.

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    The ORR was defined as the proportion of subjects with best overall response of complete response (CR) or partial response (PR) per RECIST criteria. The ORR was estimated by study arm based on the tumor response evaluation as determined by the investigator, according to RECIST 1.1. Subjects with unknown response were treated as non-responders. The statistical difference in ORR between treatment arms was evaluated using the Cochran-Mantel-Haenszel (CMH) chi-square test with histology, TPC option, and geographic region as strata, tested at an alpha level of 0.05 (2-sided). The 95 percent CI was calculated using Clopper Pearson method. FAS was the primary analysis set for all efficacy evaluations and included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Randomization (Day 1) to CR or PR
    End point values
    		 Arm A: Eribulin Mesylate Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Number of subjects analysed
    270
    270
    Units: percentage of subjects
        number (confidence interval 95%)
    12.2 (8.6 to 16.7)
    15.2 (11.1 to 20)
    Statistical analysis title
    		 ORR
    Statistical analysis description
    OS was compared between eribulin and TPC testing the following null hypothesis: H0: OS in Arm A (eribulin) is equal to OS in Arm B (TPC) against the alternative: H1: OS in Arm A (eribulin) is not equal to OS in Arm B (TPC).
    Comparison groups
    Arm A: Eribulin Mesylate v Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Number of subjects included in analysis
    540
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3034 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - The P-value was stratified by histology, TPC option, and geographic region.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first dose up to 30 days after the last dose of study treatment, or up to data cutoff date (30 May 2014), up to approximately 37 months
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) were reported. The safety analysis set included all randomized subjects who received at least one dose of study treatment. Adverse event severity was graded on a 5-point scale according to Common Terminology for Adverse Events (CTCAE) version 4.0. All AEs graded 4 or 5 were considered serious.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Arm A: Eribulin Mesylate
    Reporting group description
    		 Eribulin mesylate (1.4 mg/m^2) was administered IV over 2 to 5 minutes on Day 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.

    Reporting group title
    Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Reporting group description
    		 TPC: Vinorelbine (30 mg/m^2) was administered IV on Day 1 every 7 days, Gemcitabine (1250 mg/m^2) was administered IV on Days 1 and 8 every 21 days (or 1000 mg/m^2 IV on Days 1, 8, and 15 every 28 days), Docetaxel (75 mg/m^2) was administered IV on Day 1 every 21 days, or Pemetrexed (500 mg/m^2) was administered IV on Day 1 every 21 days (nonsquamous histology only).

    Serious adverse events
    		 Arm A: Eribulin Mesylate Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Total subjects affected by serious adverse events
         subjects affected / exposed
    97 / 269 (36.06%)
    86 / 268 (32.09%)
         number of deaths (all causes)
    28
    21
         number of deaths resulting from adverse events
    22
    17
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant pleural effusion
         subjects affected / exposed
    1 / 269 (0.37%)
    4 / 268 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    2 / 269 (0.74%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    2 / 269 (0.74%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 269 (0.37%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 269 (0.00%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava stenosis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 269 (0.74%)
    3 / 268 (1.12%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 269 (0.00%)
    3 / 268 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    13 / 269 (4.83%)
    12 / 268 (4.48%)
         occurrences causally related to treatment / all
    1 / 21
    0 / 18
         deaths causally related to treatment / all
    0 / 7
    0 / 7
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 269 (0.74%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 269 (1.12%)
    3 / 268 (1.12%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 269 (0.74%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cough
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    9 / 269 (3.35%)
    10 / 268 (3.73%)
         occurrences causally related to treatment / all
    0 / 12
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 269 (0.74%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 269 (0.74%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 269 (0.74%)
    6 / 268 (2.24%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary hypertension
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 269 (0.37%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 269 (0.74%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fear
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 269 (0.37%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         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
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (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 coronary syndrome
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 269 (0.74%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Seizure
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (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 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 269 (0.74%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 269 (1.12%)
    7 / 268 (2.61%)
         occurrences causally related to treatment / all
    3 / 3
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 269 (1.49%)
    3 / 268 (1.12%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 269 (0.37%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 269 (0.74%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (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 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 269 (0.00%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (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 / 269 (0.00%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 269 (0.37%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 269 (0.74%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 269 (0.74%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 269 (4.46%)
    5 / 268 (1.87%)
         occurrences causally related to treatment / all
    4 / 13
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 269 (0.74%)
    3 / 268 (1.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 269 (0.37%)
    2 / 268 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         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
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection fungal
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (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 / 269 (0.37%)
    3 / 268 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    4 / 269 (1.49%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 269 (0.00%)
    1 / 268 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polydipsia
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 269 (0.37%)
    0 / 268 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Eribulin Mesylate Arm B: Vinorelbine, Gemcitabine, Docetaxel, or Pemetrexed
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    254 / 269 (94.42%)
    261 / 268 (97.39%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 269 (7.06%)
    23 / 268 (8.58%)
         occurrences all number
    35
    35
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 269 (6.32%)
    17 / 268 (6.34%)
         occurrences all number
    38
    24
    Neutrophil count decreased
         subjects affected / exposed
    60 / 269 (22.30%)
    58 / 268 (21.64%)
         occurrences all number
    347
    237
    Weight decreased
         subjects affected / exposed
    20 / 269 (7.43%)
    15 / 268 (5.60%)
         occurrences all number
    30
    18
    White blood cell count decreased
         subjects affected / exposed
    55 / 269 (20.45%)
    57 / 268 (21.27%)
         occurrences all number
    320
    208
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 269 (5.20%)
    19 / 268 (7.09%)
         occurrences all number
    17
    26
    Dysgeusia
         subjects affected / exposed
    25 / 269 (9.29%)
    16 / 268 (5.97%)
         occurrences all number
    27
    25
    Headache
         subjects affected / exposed
    35 / 269 (13.01%)
    21 / 268 (7.84%)
         occurrences all number
    57
    27
    Paraesthesia
         subjects affected / exposed
    21 / 269 (7.81%)
    6 / 268 (2.24%)
         occurrences all number
    33
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    44 / 269 (16.36%)
    24 / 268 (8.96%)
         occurrences all number
    69
    29
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    59 / 269 (21.93%)
    72 / 268 (26.87%)
         occurrences all number
    153
    157
    Leukopenia
         subjects affected / exposed
    27 / 269 (10.04%)
    28 / 268 (10.45%)
         occurrences all number
    101
    60
    Neutropenia
         subjects affected / exposed
    92 / 269 (34.20%)
    74 / 268 (27.61%)
         occurrences all number
    262
    187
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    59 / 269 (21.93%)
    56 / 268 (20.90%)
         occurrences all number
    112
    89
    Fatigue
         subjects affected / exposed
    66 / 269 (24.54%)
    62 / 268 (23.13%)
         occurrences all number
    135
    149
    Malaise
         subjects affected / exposed
    22 / 269 (8.18%)
    29 / 268 (10.82%)
         occurrences all number
    29
    70
    Oedema peripheral
         subjects affected / exposed
    40 / 269 (14.87%)
    31 / 268 (11.57%)
         occurrences all number
    54
    40
    Pyrexia
         subjects affected / exposed
    47 / 269 (17.47%)
    50 / 268 (18.66%)
         occurrences all number
    79
    59
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    17 / 269 (6.32%)
    17 / 268 (6.34%)
         occurrences all number
    21
    21
    Constipation
         subjects affected / exposed
    63 / 269 (23.42%)
    63 / 268 (23.51%)
         occurrences all number
    92
    81
    Diarrhoea
         subjects affected / exposed
    38 / 269 (14.13%)
    45 / 268 (16.79%)
         occurrences all number
    50
    65
    Nausea
         subjects affected / exposed
    73 / 269 (27.14%)
    78 / 268 (29.10%)
         occurrences all number
    111
    152
    Stomatitis
         subjects affected / exposed
    43 / 269 (15.99%)
    34 / 268 (12.69%)
         occurrences all number
    83
    54
    Vomiting
         subjects affected / exposed
    29 / 269 (10.78%)
    38 / 268 (14.18%)
         occurrences all number
    44
    45
    Abdominal pain
         subjects affected / exposed
    13 / 269 (4.83%)
    19 / 268 (7.09%)
         occurrences all number
    26
    24
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    42 / 269 (15.61%)
    42 / 268 (15.67%)
         occurrences all number
    49
    51
    Dyspnoea
         subjects affected / exposed
    57 / 269 (21.19%)
    52 / 268 (19.40%)
         occurrences all number
    81
    71
    Haemoptysis
         subjects affected / exposed
    19 / 269 (7.06%)
    20 / 268 (7.46%)
         occurrences all number
    25
    22
    Productive cough
         subjects affected / exposed
    16 / 269 (5.95%)
    14 / 268 (5.22%)
         occurrences all number
    18
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    81 / 269 (30.11%)
    42 / 268 (15.67%)
         occurrences all number
    106
    47
    Rash
         subjects affected / exposed
    17 / 269 (6.32%)
    24 / 268 (8.96%)
         occurrences all number
    21
    27
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 269 (5.95%)
    20 / 268 (7.46%)
         occurrences all number
    17
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 269 (5.58%)
    18 / 268 (6.72%)
         occurrences all number
    25
    20
    Back pain
         subjects affected / exposed
    24 / 269 (8.92%)
    21 / 268 (7.84%)
         occurrences all number
    32
    31
    Muscle Spasms
         subjects affected / exposed
    14 / 269 (5.20%)
    7 / 268 (2.61%)
         occurrences all number
    16
    8
    Muscular Weakness
         subjects affected / exposed
    14 / 269 (5.20%)
    9 / 268 (3.36%)
         occurrences all number
    15
    18
    Musculoskeletal chest pain
         subjects affected / exposed
    19 / 269 (7.06%)
    24 / 268 (8.96%)
         occurrences all number
    20
    27
    Musculoskeletal pain
         subjects affected / exposed
    22 / 269 (8.18%)
    14 / 268 (5.22%)
         occurrences all number
    27
    30
    Myalgia
         subjects affected / exposed
    28 / 269 (10.41%)
    26 / 268 (9.70%)
         occurrences all number
    48
    47
    Pain in extremity
         subjects affected / exposed
    13 / 269 (4.83%)
    14 / 268 (5.22%)
         occurrences all number
    17
    16
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 269 (4.83%)
    14 / 268 (5.22%)
         occurrences all number
    17
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    98 / 269 (36.43%)
    68 / 268 (25.37%)
         occurrences all number
    148
    129

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2012
    • Any hypokalemia or hypomagnesemia should be corrected before eribulin administration • Addition of a recommendation to monitor the QT interval during the treatment period • Introduction of an option to delay administration of eribulin for up to 2 weeks, to allow for resolution of any effects which would normally prevent eribulin dosing • Addition of an alternative dosing schedule for gemcitabine and clarification that the doses given for all treating physician choice (TPC) options were for reference only and country/regional Prescribing Information was to be followed. • Removal of the requirement to administer anti-emetic prophylaxis with eribulin mesylate. • Removal of the requirement for brain and bone scans to be conducted within 1 week of achieving a complete response (CR) or partial response (PR) in line with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 requirements.

    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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