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    Clinical Trial Results:
    A Phase 1b/2, Multicenter, Open-label, Dose-escalation and Confirmation Study of Eribulin in Combination with Capecitabine

    Summary
    EudraCT number
    		 2009-011217-24
    Trial protocol
    		 GB   BG  
    Global end of trial date
    13 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2020
    First version publication date
    04 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    E7389-E044-203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01323530
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd.
    Sponsor organisation address
    Mosquito Way, Hatfield, Hertfordshire, United Kingdom, AL10 9SN UK
    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
    13 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of the study is to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of eribulin mesilate when administered in combination with capecitabine in two different dosing schedules in subjects with advanced and/or metastatic cancer in Dose Escalation Cohorts (Phase 1b), and to evaluate the activity of the combination of eribulin mesilate and capecitabine when administered in the selected schedule at the MTD (determined during dose escalation) in female subjects with advanced and/or metastatic breast cancer (Phase 2).
    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
    26 Jan 2010
    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
    United Kingdom: 47
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Russian Federation: 23
    Worldwide total number of subjects
    76
    EEA total number of subjects
    53
    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)
    61
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 13 investigative sites in Bulgaria, Russia, and United Kingdom from 26 January 2010 to 13 October 2015.

    Pre-assignment
    Screening details
    		 In Phase 1b (Dose Escalation Phase), a total of 43 subjects with solid tumors were screened, of which 9 were screen failures and 34 received study treatment, and in Phase 2 (Dose Confirmation Phase), a total of 54 female subjects with breast cancer were screened, of which 12 were screen failures and 42 received study treatment.

    Period 1
    Period 1 title
    Phase 1b (Dose Escalation Phase)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2)
    Arm description
    		 Subjects received eribulin mesilate 1.2 milligrams per square meter (mg/m^2), injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of progressive disease (PD), undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesilate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received eribulin mesilate 1.2 mg/m^2, injection, intravenously, once, on Day 1 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    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
    Subjects received capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Arm title
    		 Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2)
    Arm description
    		 Subjects received eribulin mesilate 1.6 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesilate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received eribulin mesilate 1.6 mg/m^2, injection, intravenously, once, on Day 1 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    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
    Subjects received capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Arm title
    		 Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2)
    Arm description
    		 Subjects received eribulin mesilate 2.0 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesilate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received eribulin mesilate 2.0 mg/m^2, injection, intravenously, once, on Day 1 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    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
    Subjects received capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Arm title
    		 Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2)
    Arm description
    		 Subjects received eribulin mesilate 0.7 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesilate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received eribulin mesilate 0.7 mg/m^2, injection, intravenously, once, on Days 1 and 8 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    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
    Subjects received capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Arm title
    		 Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2)
    Arm description
    		 Subjects received eribulin mesilate 1.1 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesilate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received eribulin mesilate 1.1 mg/m^2, injection, intravenously, once, on Days 1 and 8 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    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
    Subjects received capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Arm title
    		 Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2)
    Arm description
    		 Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesilate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    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
    Subjects received capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Number of subjects in period 1
    		Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2)
    Started
    8
    6
    5
    3
    6
    6
    Completed
    5
    4
    4
    3
    3
    3
    Not completed
    3
    2
    1
    0
    3
    3
         Adverse event, serious fatal
    2
    -
    -
    -
    -
    2
         Consent withdrawn by subject
    1
    1
    1
    -
    2
    -
         Clinical Progression
    -
    1
    -
    -
    1
    1
    Period 2
    Period 2 title
    Phase 2 (Dose-confirmation Phase)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Arm description
    		 Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eribulin mesilate
    Investigational medicinal product code
    E7389
    Other name
    Halaven
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 2.

    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
    Subjects received capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 2.

    Number of subjects in period 2
    		Phase 2: Eribulin mesilate 1.4 mg/m^2
    Started
    42
    Completed
    25
    Not completed
    17
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    8
         Development of bladder cancer
    1
         Investigators decision
    3
         Clinical Progression
    3

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.2 milligrams per square meter (mg/m^2), injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of progressive disease (PD), undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.6 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 2.0 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 0.7 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.1 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The baseline period is the Dose-escalation Phase with 34 subjects. The baseline characteristics for remaining 42 subjects in Dose-confirmation Phase is reported using subject analysis set.
    Reporting group values
    		 Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2) Total
    Number of subjects
    		 8 6 5 3 6 6 34
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 7 4 3 2 5 3 24
        From 65-84 years
    		 1 2 2 1 1 3 10
        85 years and over
    		 0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 6 0 3 2 3 5 19
        Male
    		 2 6 2 1 3 1 15
    Race
    Units: Subjects
        White
    		 8 6 5 3 6 6 34
        Black or African American
    		 0 0 0 0 0 0 0
    Ethinicity
    Units: Subjects
        Non Hispanic or Latino
    		 8 6 5 3 6 6 34
    Subject analysis sets

    Subject analysis set title
    Phase 2: Eribulin mesilate 1.4 mg/m^2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 2.

    Subject analysis sets values
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects
    42
    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)
    37
        From 65-84 years
    5
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    Gender categorical
    Units: Subjects
        Female
    42
        Male
    0
    Race
    Units: Subjects
        White
    41
        Black or African American
    1
    Ethinicity
    Units: Subjects
        Non Hispanic or Latino
    42

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.2 milligrams per square meter (mg/m^2), injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of progressive disease (PD), undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.6 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 2.0 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 0.7 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.1 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).
    Reporting group title
    Phase 2: Eribulin mesilate 1.4 mg/m^2
    Reporting group description
    		 Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 2.

    Subject analysis set title
    Phase 2: Eribulin mesilate 1.4 mg/m^2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 2.

    Primary: Phase 1b: Number of Subjects with DLTs as per National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0)

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    End point title
    		 Phase 1b: Number of Subjects with DLTs as per National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0) [1]
    End point description
    DLTs per NCI CTCAE v3.0 were defined as:1)Neutropenia Grade 4 that lasted 7 days, 2) Neutropenia Grade 3 or 4 complicated by fever or infection(absolute neutrophil count[ANC] less than 1.0*10^9/liter [L], fever of 38.5 degree celsius [°C]), 3)Thrombocytopenia Grade 4, 4)Thrombocytopenia Grade 3 complicated by bleeding or requiring platelet or blood transfusion, 5)Non-hematological toxicity Grade 3 or higher(excluding Grade 3 nausea, and Grade 3 or 4 vomiting or diarrhea in subjects who had not received optimal treatment with antiemetic or antidiarrheal medication; excluding laboratory abnormalities without clinical symptoms),6) Delayed recovery from treatment-related toxicity resulting in dose delay greater than 14 days,7)Failure to administer at least 75 percent(%) planned drugs during Cycle 1 as result of Grade 2 or higher treatment-related toxicity that constituted increase of at least 2 grades from baseline. Safety set: subjects who received drug, had 1 postdose safety assessment.
    End point type
    Primary
    End point timeframe
    Cycle 1 (21 days)
    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
    		 Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2)
    Number of subjects analysed
    8
    6
    5
    3
    6
    6
    Units: subjects
    1
    1
    2
    0
    1
    1
    No statistical analyses for this end point

    Primary: Phase 2: Objective Response Rate (ORR)

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    End point title
    		 Phase 2: Objective Response Rate (ORR) [2]
    End point description
    ORR was defined as the percentage of subjects who had either a confirmed complete response (CR) or partial response (PR). ORR was assessed based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1). CR was defined as disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. ORR was summarized using the Clopper-Pearson method. The Dose-confirmation full analysis set included all subjects who enrolled in the Dose-confirmation Cohort (Phase 2) and received at least 1 dose of drug.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug until PD or up to 30 days after the last dose of study treatment
    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
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    42
    Units: percentage of subjects
        number (confidence interval 95%)
    42.9 (27.7 to 59.0)
    No statistical analyses for this end point

    Secondary: Phase 2: Time to Response

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    End point title
    		 Phase 2: Time to Response
    End point description
    Time to response (CR or PR) was defined as the time from the first dose until first documented evidence of CR or PR (whichever status was recorded first). Time to response was assessed based on RECIST v 1.1. CR was defined as disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. Time to response was summarized using the Kaplan-Meier method. The Dose-confirmation full analysis set included all subjects who enrolled in the Dose-confirmation Cohort (Phase 2) and received at least 1 dose of drug. Here "subjects analysed" signifies subjects who had CR or PR.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug treatment start date until date of first documented evidence of CR or PR or up to 30 days after the last dose of study treatment
    End point values
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    18
    Units: days
        median (confidence interval 95%)
    44.0 (42.0 to 84.0)
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response (DOR)

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    End point title
    		 Phase 2: Duration of Response (DOR)
    End point description
    DOR: time from first documented evidence of CR or PR until first documented sign of PD or death. DOR was assessed based on RECIST v 1.1. CR: disappearance of all target lesions. All pathological lymph nodes (whether target/non-target) must have a reduction in their short axis to >10 mm. PR: at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this includes baseline sum if that is smallest on study). DOR was summarized using Kaplan-Meier method. The Dose-confirmation full analysis set included all subjects who enrolled in Dose-confirmation Cohort (Phase 2) and received at least 1 dose of drug. Here "subjects analysed" signifies subjects who had CR or PR. Here, 99999 means that upper limit of 95% confidence interval (CI) was not estimable due to an insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From date of the first CR or PR until the date of first documentation of PD or death or up to 30 days after the last dose of study treatment
    End point values
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    18
    Units: days
        median (confidence interval 95%)
    261.0 (161.0 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 2: Stable Disease (SD) Rate

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    End point title
    		 Phase 2: Stable Disease (SD) Rate
    End point description
    SD rate was defined as the percentage of subjects with a SD that lasted for a minimum of 5 weeks. SD rate was assessed based on RECIST version 1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR: at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). The Dose-confirmation full analysis set included all subjects who enrolled in the Dose-confirmation Cohort (Phase 2) and received at least 1 dose of drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until PD or up to 30 days after the last dose of study treatment
    End point values
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    42
    Units: percentage of subjects
        number (not applicable)
    38.1
    No statistical analyses for this end point

    Secondary: Phase 1b and Phase 2: Percentage of Subjects with Non-CR/Non-PD

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    End point title
    		 Phase 1b and Phase 2: Percentage of Subjects with Non-CR/Non-PD
    End point description
    Non-CR/Non-PD was for subjects who had non-target disease only (minimum duration from randomization to Non-CR/Non-PD >=7 weeks) and assessed by investigator based on RECIST v1.1. Non-CR/Non-PD: persistence of one or more non-target lesions, maintenance of tumor marker level above the normal limits. Full Analysis Set included all subjects who were enrolled and received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until PD or up to 30 days after the last dose of study treatment
    End point values
    		 Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2) Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    8
    6
    5
    3
    6
    6
    42
    Units: percentage of subjects
        number (not applicable)
    0
    0
    0
    0
    16.7
    0
    0
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Stable Disease (SD)

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    End point title
    		 Phase 2: Duration of Stable Disease (SD)
    End point description
    Duration of SD was measured from date of the first dose until progression. Duration of SD was assessed based on RECIST v1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR: at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). Duration of SD was summarized using the Kaplan-Meier method. The Dose-confirmation full analysis set included all subjects who enrolled in the Dose-confirmation Cohort (Phase 2) and received at least 1 dose of drug. Here "subjects analysed" signifies subjects who had SD.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until PD or 30 days after the last dose of study treatment
    End point values
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    16
    Units: days
        median (confidence interval 95%)
    162.0 (91.0 to 330.0)
    No statistical analyses for this end point

    Secondary: Phase 2: Disease Control Rate (DCR)

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    End point title
    		 Phase 2: Disease Control Rate (DCR)
    End point description
    DCR:percentage of subjects with a confirmed CR, PR, or SD divided by number of subjects in analysis set. DCR was assessed by an investigator based on RECIST v1.1. CR: disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have reduction in their short axis to <10 mm. PR: at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). DCR was summarized using the Clopper-Pearson method. The Dose-confirmation full analysis set included all subjects who enrolled in the Dose-confirmation Cohort (Phase 2) and received at least 1 dose of drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until PD or 30 days after the last dose of study treatment
    End point values
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    42
    Units: percentage of subjects
        number (confidence interval 95%)
    81.0 (65.9 to 91.4)
    No statistical analyses for this end point

    Secondary: Phase 2: Clinical Benefit Rate (CBR)

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    End point title
    		 Phase 2: Clinical Benefit Rate (CBR)
    End point description
    CBR:percentage of subjects with confirmed CR, PR, or SD of at least 6 months duration(durable SD)divided by number of subjects in analysis set. CBR was determined by an investigator based on RECIST v1.1. CR:disappearance of all target lesions. All pathological lymph nodes(whether target or non-target)must have reduction in their short axis to <10 mm. PR:at least 30% decrease in sum of longest diameter of target lesions,taking as reference baseline sum of the longest diameter.SD:neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD,taking as reference the smallest sum diameters while on study.PD:at least 20% increase in sum of diameters of target lesions,taking as reference the smallest sum on study(this includes baseline sum if that is the smallest on study).CBR was summarized using the Clopper-Pearson method. Dose-confirmation full analysis set: all subjects who enrolled in the Dose-confirmation Cohort (Phase 2) and received at least 1 dose of drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until PD or 30 days after the last dose of study treatment
    End point values
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    42
    Units: percentage of subjects
        number (confidence interval 95%)
    57.1 (41.0 to 72.3)
    No statistical analyses for this end point

    Secondary: Phase 2: Progression-free Survival (PFS)

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    End point title
    		 Phase 2: Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from the first dose date until PD or death due to any cause. PFS was determined by an investigator based on RECIST v1.1. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). PFS was summarized using the Kaplan-Meier method. The Dose-confirmation full analysis set included all subjects who enrolled in the Dose-confirmation Cohort (Phase 2) and received at least 1 dose of drug.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug until PD or death due to any cause or 30 days after the last dose of study treatment
    End point values
    		 Phase 2: Eribulin mesilate 1.4 mg/m^2
    Number of subjects analysed
    42
    Units: days
        median (confidence interval 95%)
    219.0 (138.0 to 330.0)
    No statistical analyses for this end point

    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
    Adverse event reporting additional description
    The safety set included the group of subjects who received study drug and had at least 1 post dose safety assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.2 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.6 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 2.0 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 0.7 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.1 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Reporting group title
    Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2)
    Reporting group description
    		 Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).

    Reporting group title
    Phase 2: Eribulin mesilate 1.4 mg/m^2
    Reporting group description
    		 Subjects received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 2.

    Serious adverse events
    		 Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2) Phase 2: Eribulin mesilate 1.4 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 6 (66.67%)
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    10 / 42 (23.81%)
         number of deaths (all causes)
    1
    1
    0
    0
    1
    2
    3
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant Ascites
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolongation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Spinal Cord Compression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heparin-induced Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    1 / 1
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal Ischaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestine obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b (Schedule 1): Eribulin mesilate (1.2 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (1.6 mg/m^2) Phase 1b (Schedule 1): Eribulin mesilate (2.0 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (0.7 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.1 mg/m^2) Phase 1b (Schedule 2): Eribulin mesilate (1.4 mg/m^2) Phase 2: Eribulin mesilate 1.4 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    6 / 6 (100.00%)
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    39 / 42 (92.86%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Lymphoedema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    6 / 42 (14.29%)
         occurrences all number
    0
    0
    1
    0
    5
    1
    16
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    6 / 42 (14.29%)
         occurrences all number
    2
    1
    7
    0
    1
    3
    10
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 42 (11.90%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    3
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Catheter site erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Catheter site related reaction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    2
    Influenza like illness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    3
    0
    1
    0
    2
    0
    5
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    4
    Dyspnoea
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
    2 / 3 (66.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
         occurrences all number
    2
    2
    2
    3
    2
    3
    4
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    3
    2
    1
    Haemoptysis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Rales
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Throat tightness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Depressed mood
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Parasomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    6 / 42 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    15
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    6 / 42 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    9
    Weight decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    7
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    Cardiac Murmur
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Electrocardiogram Abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Electrocardiogram T Wave Abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Soft tissue injury
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    0
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 6 (66.67%)
    2 / 5 (40.00%)
    2 / 3 (66.67%)
    4 / 6 (66.67%)
    4 / 6 (66.67%)
    8 / 42 (19.05%)
         occurrences all number
    3
    7
    4
    5
    22
    15
    66
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    8 / 42 (19.05%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    21
    Headache
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    3
    0
    0
    0
    1
    0
    7
    Neurotoxicity
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    5
    0
    0
    2
    0
    3
    Ageusia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    11
    1
    3
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
         occurrences all number
    0
    4
    0
    0
    0
    1
    3
    Paraesthesia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    5 / 6 (83.33%)
    34 / 42 (80.95%)
         occurrences all number
    2
    4
    0
    0
    3
    19
    238
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    20 / 42 (47.62%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    73
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    12 / 42 (28.57%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    24
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    Lymphadenopathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    Eye pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 8 (50.00%)
    4 / 6 (66.67%)
    4 / 5 (80.00%)
    2 / 3 (66.67%)
    3 / 6 (50.00%)
    6 / 6 (100.00%)
    12 / 42 (28.57%)
         occurrences all number
    5
    9
    6
    4
    15
    24
    28
    Diarrhoea
         subjects affected / exposed
    6 / 8 (75.00%)
    3 / 6 (50.00%)
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    8 / 42 (19.05%)
         occurrences all number
    7
    3
    5
    6
    6
    13
    30
    Stomatitis
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 6 (50.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    4 / 6 (66.67%)
    8 / 42 (19.05%)
         occurrences all number
    4
    6
    0
    0
    3
    6
    35
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    6 / 42 (14.29%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    7
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 6 (50.00%)
    3 / 5 (60.00%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    6 / 6 (100.00%)
    6 / 42 (14.29%)
         occurrences all number
    0
    5
    6
    0
    7
    18
    9
    Constipation
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    4 / 42 (9.52%)
         occurrences all number
    2
    3
    3
    3
    0
    3
    6
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 42 (7.14%)
         occurrences all number
    0
    2
    2
    1
    3
    2
    3
    Abdominal discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    Abdominal tenderness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Lip pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    7
    0
    0
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    4
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    3 / 5 (60.00%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    15 / 42 (35.71%)
         occurrences all number
    2
    2
    3
    1
    3
    3
    26
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    11 / 42 (26.19%)
         occurrences all number
    1
    5
    0
    0
    11
    0
    19
    Dry skin
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    1
    0
    0
    1
    2
    0
    2
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    Night sweats
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    2
    Rash macular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Skin mass
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Plantar Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    Urine flow decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    5 / 42 (11.90%)
         occurrences all number
    3
    1
    0
    1
    0
    3
    7
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    4
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    3
    Joint swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    4
    Muscle spasms
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    Muscular weakness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    2
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    4
    3
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    8
    Cellulitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Localised infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 42 (2.38%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    3
    Oral herpes
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    4
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    5 / 5 (100.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    1
    6
    2
    2
    3
    6
    Hypomagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Dec 2010
    Protocol Amendment 1: The main purpose of this amendment was to remove randomization from the study design for the Dose Escalation Cohorts (Phase 1b) as it was considered to be impractical and unnecessary for a Phase 1b study.
    21 Jun 2011
    Protocol Amendment 2: The main purpose of this amendment was to change the study design to include only 1 treatment arm in the Dose-Confirmation (Phase 2) part of the study. It was decided that the observed and tolerated dose levels in Schedule 2 could provide a better dose intensity than even the highest dose level in Schedule 1; therefore, only the MTD determined during Schedule 2 was selected for further exploration. As a result of this, the term “Randomized” was deleted from the title of the study; to delete Holter monitoring and revise the timing of the postdose electrocardiogram (ECG) for subjects included in the Dose Confirmation Cohort. The postdose 12-lead safety ECG time point was revised in accordance with the updated PK information available for eribulin; to delete an Exclusion Criterion based on new study results showing that no drug–drug interactions were expected with CYP 3A4 inhibitors, substrates, or inducers.
    16 Jun 2014
    Protocol Amendment 3: The main purpose of Amendment 3 was to reduce the frequency of tumor assessments for subjects (Dose-Confirmation Cohort, Extension Phase only) who had been in the study for 12 months or longer. This reduced the radiation risk for these subjects, as well as risks associated with the administration of contrast dye at the time of tumor assessments.
    18 Aug 2015
    Protocol Amendment 4: The main purpose of Amendment 4 was to further reduce the frequency of tumor assessments for subjects (Extension Phase only) who had been in the study for 12 months or longer. This further reduced the radiation risk for these subjects, as well as risks associated with the administration of contrast dye at the time of tumor assessments.

    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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