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    Clinical Trial Results:
    The BEACON Study (BrEAst Cancer Outcomes with NKTR-102): A Phase 3 Open-Label, Randomized, Multicenter Study of NKTR-102 versus Treatment of Physician’s Choice (TPC) in Patients with Locally Recurrent or Metastatic Breast Cancer Previously Treated with an Anthracycline, a Taxane, and Capecitabine

    Summary
    EudraCT number
    2011-003832-30
    Trial protocol
    BE   GB   DE   ES   NL   IT  
    Global end of trial date
    08 Apr 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Aug 2017
    First version publication date
    05 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    11-PIR-11
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01492101
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Nektar Therapeutics
    Sponsor organisation address
    455 Mission Bay Boulevard South, San Francisco, United States, CA 94158
    Public contact
    Clinical Trial Information Desk, Quintiles Contact Center, +1 862 261 3634, StudyInquiry@nektar.com
    Scientific contact
    Clinical Trial Information Desk, Quintiles Contact Center, +1 862 261 3634, StudyInquiry@nektar.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
    12 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the overall survival (OS) of subjects who received NKTR-102 given once every 21 days to subjects who received treatment of physician’s choice (TPC) selected from the following list of 7 single-agent intravenous (IV) therapies: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel or nab-paclitaxel.
    Protection of trial subjects
    This study was carried out in compliance with the protocol and in accordance with standard operating procedures. These were designed to ensure adherence to Good Clinical Practice, as described in the following documents: International Council for Harmonisation Harmonized Tripartite Guidelines for Good Clinical Practice 1996; United States 21 Code of Federal Regulations dealing with clinical studies (including Parts 50 and 56 concerning informed consent and Institutional Review Board regulations, and parts 54 and 312); Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West, South Africa 1996, Edinburgh 2000, Washington 2002, Tokyo 2004, Seoul 2008).
    Background therapy
    -
    Evidence for comparator
    The TPC control arm consisted of a choice of one of the following 7 therapies: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel. Oncologists have a relatively broad range of potential chemotherapies that demonstrate some anti-cancer activity in the treatment of subjects with advanced breast cancer whose disease has progressed following therapy with anthracycline, a taxane, and capecitabine (ATC). Factors affecting the choice are often balanced between efficacy, toxicity, and treatment schedule and are based on tumor and subject characteristics, subject preference, and health care/regulatory and economics policies. Because there is no consensus in the oncology community on a single standard of care for advanced breast cancer subjects who have progressed after treatment with ATC (particularly across the countries that participated in this trial) and these 7 drugs are all routinely used in the treatment of advanced breast cancer, the TPC arm represented the current best chemotherapeutic standard of care. Anthracyclines (such as doxorubicin) and capecitabine, are also commonly used in the treatment of advanced breast cancer; however, they were not included as TPC drugs because this subject population had, per the inclusion criteria, already been treated with these and may have been refractory.
    Actual start date of recruitment
    19 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 97
    Country: Number of subjects enrolled
    United Kingdom: 42
    Country: Number of subjects enrolled
    Belgium: 92
    Country: Number of subjects enrolled
    France: 83
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    United States: 378
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 85
    Worldwide total number of subjects
    852
    EEA total number of subjects
    342
    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)
    683
    From 65 to 84 years
    169
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects had histologically or cytologically confirmed carcinoma of the breast; received a minimum of 2 and a maximum of 5 prior cytotoxic chemotherapy regimens for the treatment of locally recurrent or metastatic breast cancer, with the last dose of cytotoxic chemotherapy administered within 6 months of the date of randomization into this trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    NKTR-102
    Arm description
    NKTR-102 for injection was administered as an IV infusion over 90 ± 15 minutes, on Day 1 of each 21-day cycle) at a dose level of 145 mg/m^2.
    Arm type
    Experimental

    Investigational medicinal product name
    NKTR-102
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    NKTR-102 was administered as an IV infusion over 90 ± 15 minutes, on Day 1 of each 21-day cycle at a dose level of 145 mg/m^2. Body surface area was determined based on baseline height and current weight before the start of each cycle. The NKTR-102 was formulated as a sterile lyophilised powder of NKTR-102 in lactate buffer at pH 3.5. NKTR-102 for injection was reconstituted with commercially available 5% dextrose injection. Specific NKTR-102 dose modifications could be made for drug-related neutropenia, thrombocytopenia, anaemia, diarrhoea, dehydration, nausea/vomiting/abdominal pain and other drug-related, non-haematological toxicities. Trial drug was continued until disease progression, unacceptable toxicity, death, withdrawal by subject, Principal Investigator decision, lost to follow-up, protocol violation, or trial termination by Sponsor.

    Arm title
    TPC drugs
    Arm description
    The TPC drugs were administered in 21- or 28-day treatment cycles, depending on the institutional guidelines for the specific drug. The dosage and administration of the TPC drugs followed the institutional guidelines provided for each agent, with the exception of: Eribulin, which was administered in accordance with its local country Summary of Product Characteristics (SmPC) or Prescribing Information OR initially administered at no less than 1.4 mg/m^2 on Days 1 and 8 every 21 days; Ixabepilone, which was initially administered at 40 mg/m2 on Day 1 every 21 days, then per institutional guidelines.
    Arm type
    Active comparator

    Investigational medicinal product name
    TPC
    Investigational medicinal product code
    Other name
    Made up of 1 of 7 single-agent IV chemotherapies
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The TPC drugs were administered in 21- or 28-day treatment cycles, depending on the institutional guidelines for the specific drug. Some TPC drugs could be administered at weekly intervals. Body surface area was determined before the start of each cycle, based on baseline height and most recent weight. The dosage and administration of the TPC drugs followed the institutional guidelines provided for each agent, with the exception of: Eribulin which was administered in accordance with its local country SmPC or Prescribing Information or initially administered at no less than 1.4 mg/m^2 on Days 1 and 8 every 21 days; and Ixabepilone which was initially administered at 40 mg/m^2 on Day 1 every 21 days, then per institutional guidelines.

    Number of subjects in period 1
    NKTR-102 TPC drugs
    Started
    429
    423
    Completed
    92
    81
    Not completed
    337
    342
         Death
             323
             322
         Consent withdrawn by subject
             14
             18
         Lost to follow-up
             -
             2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NKTR-102
    Reporting group description
    NKTR-102 for injection was administered as an IV infusion over 90 ± 15 minutes, on Day 1 of each 21-day cycle) at a dose level of 145 mg/m^2.

    Reporting group title
    TPC drugs
    Reporting group description
    The TPC drugs were administered in 21- or 28-day treatment cycles, depending on the institutional guidelines for the specific drug. The dosage and administration of the TPC drugs followed the institutional guidelines provided for each agent, with the exception of: Eribulin, which was administered in accordance with its local country Summary of Product Characteristics (SmPC) or Prescribing Information OR initially administered at no less than 1.4 mg/m^2 on Days 1 and 8 every 21 days; Ixabepilone, which was initially administered at 40 mg/m2 on Day 1 every 21 days, then per institutional guidelines.

    Reporting group values
    NKTR-102 TPC drugs Total
    Number of subjects
    429 423 852
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    341 342 683
        From 65-84 years
    88 81 169
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.1 ± 10.29 55.2 ± 10.1 -
    Gender categorical
    Units: Subjects
        Female
    429 423 852
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    NKTR-102
    Reporting group description
    NKTR-102 for injection was administered as an IV infusion over 90 ± 15 minutes, on Day 1 of each 21-day cycle) at a dose level of 145 mg/m^2.

    Reporting group title
    TPC drugs
    Reporting group description
    The TPC drugs were administered in 21- or 28-day treatment cycles, depending on the institutional guidelines for the specific drug. The dosage and administration of the TPC drugs followed the institutional guidelines provided for each agent, with the exception of: Eribulin, which was administered in accordance with its local country Summary of Product Characteristics (SmPC) or Prescribing Information OR initially administered at no less than 1.4 mg/m^2 on Days 1 and 8 every 21 days; Ixabepilone, which was initially administered at 40 mg/m2 on Day 1 every 21 days, then per institutional guidelines.

    Primary: Kaplan-Meier Estimate of OS: Intention to Treat (ITT) Population

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    End point title
    Kaplan-Meier Estimate of OS: Intention to Treat (ITT) Population
    End point description
    Duration of OS was defined as the time from the date of randomisation to the date of death due to any cause. Subjects were followed until their date of death, loss to follow-up, withdrawal of consent for further follow-up for survival, or final database closure. OS was determined using the ITT population which included all subjects randomised into 1 of the 2 treatment arms. Subjects who were lost-to-follow-up or were not known to have died were censored at last date they were shown to be alive. Subjects who did not have any follow-up since the date of randomisation were censored at the date of randomization.
    End point type
    Primary
    End point timeframe
    From randomisation to death, loss to follow-up, withdrawal of consent for further follow-up for survival, or final database closure.
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    429
    423
    Units: Months
        median (confidence interval 95%)
    12.4 (11 to 13.6)
    10.3 (9 to 11.3)
    Statistical analysis title
    Analysis of OS
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.0835
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.872
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.747
         upper limit
    1.019
    Notes
    [1] - Two-sided log-rank test, stratified by geographic region, prior use of eribulin, and receptor status.

    Secondary: Kaplan-Meier Estimate of Progression-Free Survival (PFS): ITT Population

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    End point title
    Kaplan-Meier Estimate of Progression-Free Survival (PFS): ITT Population
    End point description
    PFS was defined as the time from the date of randomisation to the earliest date of disease progression (assessed by the investigator according to RECIST version 1.1) or death due to any cause. PFS was determined using the ITT population which included all subjects randomised into 1 of the 2 treatment arms. For subjects whose disease did not progress or who did not die, the PFS time was censored at the time of the last tumor assessment that demonstrated lack of disease progression. For subjects who received new anti-cancer therapy, the PFS time was censored at the start of the new anti-cancer therapy.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (± 7 days) from date of randomisation until earliest documented disease progression or death.
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    429
    423
    Units: Months
        median (confidence interval 95%)
    2.4 (2.1 to 3.5)
    2.8 (2.1 to 3.5)
    Statistical analysis title
    Analysis of PFS
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.3017
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.926
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.798
         upper limit
    1.075

    Secondary: Clinical benefit rate (CBR): ITT Population

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    End point title
    Clinical benefit rate (CBR): ITT Population
    End point description
    CBR was defined as the proportion of subjects with a CR, PR, or stable disease (SD) for at least 6 months (≥ 182 days).
    End point type
    Secondary
    End point timeframe
    At least 6 months (≥ 182 days).
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    429
    423
    Units: Percentage of subjects
        number (confidence interval 95%)
    20.5 (16.8 to 24.6)
    19.6 (15.9 to 23.7)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR): Efficacy Evaluable Population

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    End point title
    Duration of response (DOR): Efficacy Evaluable Population
    End point description
    DOR was defined as the time from first documented CR or PR until the earliest evidence of disease progression or death from any cause. Subjects who were alive without documented disease progression per RECIST version 1.1 were censored at the date of last tumor assessment without disease progression or start of new anti-cancer therapy for the study disease.
    End point type
    Secondary
    End point timeframe
    From the time measurement criteria for CR/PR (whichever was first recorded) were first met until the first date that recurrent disease or disease progression or death was objectively documented.
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    354
    358
    Units: Months
        median (confidence interval 95%)
    3.9 (3.5 to 5.1)
    3.7 (2.1 to 3.9)
    No statistical analyses for this end point

    Secondary: Incidence of Dose Reductions: Safety Population

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    End point title
    Incidence of Dose Reductions: Safety Population
    End point description
    Proportion of subjects who had a reduction in dose.
    End point type
    Secondary
    End point timeframe
    All cycles.
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    425
    406
    Units: Percentage of subjects
        number (not applicable)
    27.5
    28.3
    No statistical analyses for this end point

    Secondary: Quality of Life Questionnaire-Core 30 (QLQ-C30) individual scale, overall score: ITT Population

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    End point title
    Quality of Life Questionnaire-Core 30 (QLQ-C30) individual scale, overall score: ITT Population
    End point description
    The QLQ-C30 is composed of 5 multi-item functional scales (physical, role, social, emotional and cognitive functioning), a global health status/QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (financial impact, appetite loss, diarrhoea, constipation, insomnia and dyspnoea). Most items are scaled 1 to 4 except the items contributing to the global health status/QoL, which are 7-point questions. Raw scores were transformed using a linear transformation to standardise the results so that scores range from 0 to 100. n=number of subjects who completed each individual scale.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    429
    423
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Global health status/QoL (n=421;405)
    61.4 ± 21.76
    58 ± 20.43
        Physical functioning (n=422;406)
    74.5 ± 19.72
    72.3 ± 19.74
        Role functioning (n=422;405)
    71.8 ± 26.81
    67.3 ± 26.93
        Emotional functioning (n=421;405)
    72.4 ± 21.86
    71.9 ± 20.06
        Cognitive functioning (n=421;405)
    82.5 ± 18.7
    81.2 ± 19.04
        Social functioning (n=421;405)
    73 ± 26.69
    71 ± 25.06
        Fatigue (n=422;406)
    37.7 ± 23.68
    41.3 ± 22.98
        Nausea and vomiting (n=422;406)
    8.6 ± 13.39
    9.9 ± 16.17
        Pain (n=422;406)
    32.3 ± 27.2
    35.3 ± 28.01
        Dyspnoea (n=421;406)
    24.5 ± 27.44
    23.6 ± 26.2
        Insomnia (n=421;406)
    29.3 ± 28.94
    31.5 ± 27.11
        Appetite loss (n=422;406)
    24.3 ± 27.55
    26.6 ± 27.89
        Constipation (n=422;403)
    18 ± 25.9
    21 ± 28.15
        Diarrhoea (n=421;404)
    6.3 ± 13.64
    5.6 ± 11.14
        Financial difficulties (n=421;404)
    26.4 ± 31.29
    21.9 ± 28.95
    No statistical analyses for this end point

    Secondary: QLQ-C30 individual scale, change over time: ITT Population

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    End point title
    QLQ-C30 individual scale, change over time: ITT Population
    End point description
    The QLQ-C30 is composed of 5 multi-item functional scales (physical, role, social, emotional and cognitive functioning), a global health status/QoL scale, 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (financial impact, appetite loss, diarrhea, constipation, insomnia and dyspnea). Most items are scaled 1 to 4 except the items contributing to the global health status/QoL, which are 7-point questions. Raw scores were transformed using a linear transformation to standardise the results so that scores range from 0 to 100. n=number of subjects who completed each individual scale. Because the number of patients that completed the HRQoL questionnaires decreased to below 10% of the population beyond 32 weeks, meaningful HRQoL analyses were not reliable after Week 32.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56.
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    429
    423
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Global health status/QoL: Week 8 (n=337;311)
    -4.4 ± 22.57
    -4.7 ± 20.37
        Global health status/QoL: Week 16 (n=181;159)
    -2.5 ± 22.9
    -5.6 ± 21.86
        Global health status/QoL: Week 24 (n=116;90)
    -1.8 ± 24.99
    -6.6 ± 22.47
        Global health status/QoL: Week 32 (n=69;59)
    -0.2 ± 20.39
    -6.3 ± 26.66
        Global health status/QoL: Week 40 (n=48;31)
    -5.2 ± 22.27
    -2.6 ± 19.41
        Global health status/QoL: Week 48 (n=29;19)
    -2.3 ± 18.62
    -1.8 ± 20.71
        Global health status/QoL: Week 56 (n=26;15)
    2.9 ± 17.79
    -11.1 ± 29.36
        Physical functioning: Week 8 (n=340;315)
    -4.9 ± 17.98
    -7.1 ± 17.4
        Physical functioning: Week 16 (n=181;159)
    -3 ± 20.63
    -7 ± 18.26
        Physical functioning: Week 24 (n=116;92)
    0.3 ± 20.93
    -4.7 ± 15.9
        Physical functioning: Week 32 (n=68;60)
    -3 ± 18.88
    -8.5 ± 20.4
        Physical functioning: Week 40 (n=48;31)
    -1.9 ± 19.23
    -6.4 ± 18.81
        Physical functioning: Week 48 (n=30;19)
    0.2 ± 17.66
    -7.4 ± 16.46
        Physical functioning: Week 56 (n=26;16)
    2.2 ± 13.48
    -10.4 ± 24.28
        Role functioning: Week 8 (n=340;314)
    -6.6 ± 27.26
    -8.3 ± 27.37
        Role functioning: Week 16 (n=180;159)
    -4.8 ± 26.06
    -8.3 ± 24.41
        Role functioning: Week 24 (n=116;91)
    -7.8 ± 33.3
    -10.8 ± 26.72
        Role functioning: Week 32 (n=68;60)
    -9.7 ± 19.03
    -12.2 ± 29.81
        Role functioning: Week 40 (n=48;30)
    -8.7 ± 30.94
    -7.8 ± 27.93
        Role functioning: Week 48 (n=30;19)
    -3.1 ± 25.38
    -5.7 ± 21.7
        Role functioning: Week 56 (n=26;16)
    -2.6 ± 17.12
    -9.4 ± 35.08
        Emotional functioning: Week 8 (n=338;313)
    -0.5 ± 19.65
    -2 ± 19.95
        Emotional functioning: Week 16 (n=181;160)
    2.7 ± 18.93
    -1.6 ± 20.57
        Emotional functioning: Week 24 (n=116;91)
    -0.6 ± 22.34
    -3.7 ± 18.95
        Emotional functioning: Week 32 (n=69;59)
    -2.8 ± 21.02
    -7.6 ± 20.88
        Emotional functioning: Week 40 (n=48;31)
    -1.4 ± 26.12
    0.8 ± 19.11
        Emotional functioning: Week 48 (n=29;19)
    0.9 ± 21.37
    1.2 ± 18.83
        Emotional functioning: Week 56 (n=26;15)
    -3.6 ± 19.72
    -4.7 ± 25.29
        Cognitive functioning: Week 8 (n=339,313)
    -3.3 ± 18.46
    -3.2 ± 19.44
        Cognitive functioning: Week 16 (n=181,160)
    -1.4 ± 17.67
    -4.4 ± 20.81
        Cognitive functioning: Week 24 (n=116,91)
    -1.8 ± 17.26
    -2.2 ± 17.12
        Cognitive functioning: Week 32 (n=69,59)
    -4.6 ± 17.82
    -7.9 ± 20.14
        Cognitive functioning: Week 40 (n=48,31)
    -5.7 ± 18.61
    -3.5 ± 21.6
        Cognitive functioning: Week 48 (n=29,19)
    -4.6 ± 18.04
    2.2 ± 17.75
        Cognitive functioning: Week 56 (n=26,15)
    -2.9 ± 18.25
    -6.7 ± 22.97
        Social functioning: Week 8 (n=339,313)
    -4.9 ± 27.46
    -6.2 ± 24.04
        Social functioning: Week 16 (n=181,160)
    0.4 ± 27.57
    -6.4 ± 24.2
        Social functioning: Week 24 (n=116,90)
    -3.4 ± 25.68
    -7.2 ± 24.1
        Social functioning: Week 32 (n=69,59)
    -8.8 ± 20.61
    -7.2 ± 30.1
        Social functioning: Week 40 (n=48,31)
    -9.7 ± 26.09
    -7 ± 20.98
        Social functioning: Week 48 (n=29,19)
    -5.5 ± 17.86
    -6.6 ± 20.71
        Social functioning: Week 56 (n=26,15)
    -3.2 ± 22.25
    -24.4 ± 29.96
        Fatigue: Week 8 (n=340,315)
    6.7 ± 22.88
    6.6 ± 22.17
        Fatigue: Week 16 (n=180,161)
    3.7 ± 22.63
    7.7 ± 22.84
        Fatigue: Week 24 (n=116,92)
    3 ± 26.51
    3.6 ± 21.23
        Fatigue: Week 32 (n=69,60)
    5 ± 21.84
    6.6 ± 24.25
        Fatigue: Week 40 (n=48,31)
    4.1 ± 26.65
    2.3 ± 19.02
        Fatigue: Week 48 (n=30,19)
    0.9 ± 18.69
    6.7 ± 14.53
        Fatigue: Week 56 (n=26,16)
    2.1 ± 19.57
    4.5 ± 24.36
        Nausea and vomiting: Week 8 (n=340,315)
    12.8 ± 23.28
    4.2 ± 21.94
        Nausea and vomiting: Week 16 (n=180,160)
    8.8 ± 19.85
    -2 ± 19.1
        Nausea and vomiting: Week 24 (n=116,92)
    7.2 ± 22.57
    -0.1 ± 16.55
        Nausea and vomiting: Week 32 (n=69,60)
    6.5 ± 14.21
    3.5 ± 18.81
        Nausea and vomiting: Week 40 (n=48,31)
    4.5 ± 12.97
    5.6 ± 23.61
        Nausea and vomiting: Week 48 (n=30,19)
    5 ± 13.77
    3.9 ± 28.92
        Nausea and vomiting: Week 56 (n=26,16)
    8 ± 11.66
    1.6 ± 23.02
        Pain: Week 8 (n=341,315)
    -1.7 ± 26.08
    2.4 ± 27.03
        Pain: Week 16 (n=182,161)
    -5 ± 26.9
    1.9 ± 27.8
        Pain: Week 24 (n=116,92)
    -4.1 ± 29.35
    2.1 ± 27.78
        Pain: Week 32 (n=69,60)
    -1 ± 27.17
    3.9 ± 32.49
        Pain: Week 40 (n=48,31)
    1.6 ± 31.82
    1.3 ± 28.96
        Pain: Week 48 (n=30,19)
    -0.8 ± 30.82
    -0.4 ± 25.23
        Pain: Week 56 (n=26,16)
    -4.2 ± 22.88
    0.5 ± 33.95
        Dyspnoea: Week 8 (n=339,313)
    0.7 ± 25.02
    5.8 ± 24.59
        Dyspnoea: Week 16 (n=180,158)
    -1.1 ± 26.34
    4.6 ± 26.99
        Dyspnoea: Week 24 (n=116,92)
    -2 ± 25.65
    1.4 ± 20.47
        Dyspnoea: Week 32 (n=68,60)
    0 ± 24.77
    8.6 ± 29.67
        Dyspnoea: Week 40 (n=48,30)
    2.4 ± 27.93
    5 ± 25.95
        Dyspnoea: Week 48 (n=30,19)
    -5.6 ± 26.38
    -0.9 ± 19.62
        Dyspnoea: Week 56 (n=26,14)
    -7.1 ± 18.36
    -1.2 ± 22.13
        Insomnia: Week 8 (n=338,315)
    -1.5 ± 28.1
    3.3 ± 30.28
        Insomnia: Week 16 (n=180,160)
    -1.4 ± 24.4
    2.1 ± 27.2
        Insomnia: Week 24 (n=116,92)
    -2.7 ± 31.77
    1.3 ± 26.41
        Insomnia: Week 32 (n=68,59)
    1.5 ± 34.04
    2.5 ± 30.14
        Insomnia: Week 40 (n=48,30)
    0 ± 31.51
    4.4 ± 22.71
        Insomnia: Week 48 (n=30,19)
    2.8 ± 28.05
    0.9 ± 34.01
        Insomnia: Week 56 (n=26,16)
    -1.3 ± 35.57
    -1 ± 27.53
        Appetite loss: Week 8 (n=340,314)
    11.6 ± 32.03
    4 ± 30.26
        Appetite loss: Week 16 (n=180,159)
    9.4 ± 32.16
    -2.1 ± 29.75
        Appetite loss: Week 24 (n=116,92)
    4.6 ± 36.55
    -1.6 ± 30.57
        Appetite loss: Week 32 (n=69,60)
    8.9 ± 35.42
    0 ± 32.04
        Appetite loss: Week 40 (n=48,31)
    6.9 ± 38.57
    5.4 ± 38.58
        Appetite loss: Week 48 (n=30,18)
    2.2 ± 34.67
    13 ± 45.93
        Appetite loss: Week 56 (n=26,16)
    14.7 ± 35.38
    1 ± 39.19
        Constipation: Week 8 (n=337,310)
    2.1 ± 29.95
    6.7 ± 27.81
        Constipation: Week 16 (n=181,158)
    0.2 ± 31.03
    3.1 ± 30.96
        Constipation: Week 24 (n=116,90)
    0.6 ± 29.65
    -2 ± 28.14
        Constipation: Week 32 (n=69,59)
    4.6 ± 29.83
    0.3 ± 26.53
        Constipation: Week 40 (n=48,31)
    1 ± 28.44
    -3.2 ± 29.32
        Constipation: Week 48 (n=29,19)
    -0.6 ± 31.65
    7 ± 33.48
        Constipation: Week 56 (n=26,15)
    1.9 ± 34.42
    -4.4 ± 35.34
        Diarrhoea: Week 8 (n=339,311)
    10.2 ± 27.98
    1.8 ± 16.87
        Diarrhoea: Week 16 (n=181,158)
    10.8 ± 26.97
    3.4 ± 19.07
        Diarrhoea: Week 24 (n=114,89)
    9.4 ± 26.43
    2.4 ± 16.39
        Diarrhoea: Week 32 (n=69,59)
    9.2 ± 21.3
    0.8 ± 17.07
        Diarrhoea: Week 40 (n=48,30)
    8.3 ± 23.06
    7.8 ± 27.93
        Diarrhoea: Week 48 (n=29,19)
    12.1 ± 22.23
    0 ± 17.57
        Diarrhoea: Week 56 (n=26,15)
    4.5 ± 14.57
    6.7 ± 31.37
        Financial difficulties: Week 8 (n=339,312)
    -0.7 ± 22.87
    0.6 ± 22.42
        Financial difficulties: Week 16 (n=181,159)
    0.8 ± 23.26
    1 ± 22.48
        Financial difficulties: Week 24 (n=115,90)
    1 ± 21.09
    4.6 ± 28.38
        Financial difficulties: Week 32 (n=69,59)
    1.2 ± 20.28
    10.2 ± 26.81
        Financial difficulties: Week 40 (n=48,30)
    4.2 ± 21.61
    -1.7 ± 19.74
        Financial difficulties: Week 48 (n=29,19)
    0 ± 22.27
    3.5 ± 18.9
        Financial difficulties: Week 56 (n=26,15)
    -1.9 ± 21.25
    5.6 ± 25.72
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Global health status/QoL: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [2]
    P-value
    = 0.635
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.65
         upper limit
    4.33
    Notes
    [2] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Physical functioning: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [3]
    P-value
    = 0.1656
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.88
         upper limit
    5.14
    Notes
    [3] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Role functioning: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [4]
    P-value
    = 0.8356
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.9
         upper limit
    4.82
    Notes
    [4] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Emotional functioning: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [5]
    P-value
    = 0.7727
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.88
         upper limit
    3.88
    Notes
    [5] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Cognitive functioning: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [6]
    P-value
    = 0.7446
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.56
         upper limit
    3.59
    Notes
    [6] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Social functioning: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [7]
    P-value
    = 0.9169
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    4.45
    Notes
    [7] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Fatigue: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [8]
    P-value
    = 0.9731
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.66
         upper limit
    3.79
    Notes
    [8] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Nausea and vomiting: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [9]
    P-value
    < 0.0001
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.88
         upper limit
    10.67
    Notes
    [9] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Pain: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [10]
    P-value
    = 0.1252
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.59
         upper limit
    0.93
    Notes
    [10] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Dyspnoea: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [11]
    P-value
    = 0.1717
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.83
         upper limit
    1.22
    Notes
    [11] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Insomnia: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [12]
    P-value
    = 0.5513
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.95
         upper limit
    3.18
    Notes
    [12] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Appetite loss: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [13]
    P-value
    = 0.0009
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    8.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.57
         upper limit
    13.72
    Notes
    [13] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Constipation: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [14]
    P-value
    = 0.2337
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.35
         upper limit
    1.8
    Notes
    [14] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Diarrhoea: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [15]
    P-value
    < 0.0001
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    10.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.6
         upper limit
    13.98
    Notes
    [15] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-C30 Change from Baseline
    Statistical analysis description
    Financial difficulties: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [16]
    P-value
    = 0.99
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.74
         upper limit
    3.69
    Notes
    [16] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.

    Secondary: Quality of Life Questionnaire-breast cancer-specific module (BR23) score value: ITT Population

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    End point title
    Quality of Life Questionnaire-breast cancer-specific module (BR23) score value: ITT Population
    End point description
    The QLQ-BR23 incorporates 5 multi-item scales to assess systemic therapy side effects, arm symptoms, breast symptoms, body image and sexual functioning, and 3 single items to assess sexual enjoyment, upset by hair loss and future perspective. n=number of subjects who completed each individual scale.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    429
    423
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Body image (n=421,408)
    69.5 ± 28.94
    69.9 ± 27.91
        Sexual functioning (n=410,388)
    14.1 ± 19.24
    13.3 ± 18.91
        Sexual enjoyment (n=184,166)
    36.1 ± 29.25
    34.2 ± 30.77
        Future perspective (n=421,406)
    38.7 ± 30.53
    36.1 ± 29
        Systemic therapy side effects (n=423,408)
    21.9 ± 16.37
    22.3 ± 15.15
        Breast symptoms (n=423,408)
    15.3 ± 21.55
    15.8 ± 20.79
        Arm symptoms (n=423,409)
    20.8 ± 23.4
    22.2 ± 22.75
        Upset by hair loss (n=244,225)
    33.2 ± 34.15
    30.5 ± 33.29
    No statistical analyses for this end point

    Secondary: BR23 score change over time: ITT Population

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    End point title
    BR23 score change over time: ITT Population
    End point description
    The QLQ-BR23 incorporates 5 multi-item scales to assess systemic therapy side effects, arm symptoms, breast symptoms, body image and sexual functioning, and 3 single items assess sexual enjoyment, upset by hair loss and future perspective. n=number of subjects who completed each individual scale. Because the number of patients that completed the HRQoL questionnaires decreased to below 10% of the population beyond 32 weeks, meaningful HRQoL analyses were not reliable after Week 32.
    End point type
    Secondary
    End point timeframe
    Change from Baseline to End-of -Treatment
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    429
    423
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Body image: Week 8 (n=342,310)
    -0.8 ± 21.99
    -2.2 ± 20.49
        Body image: Week 16 (n=178,162)
    -0.8 ± 24.31
    -2.3 ± 20.91
        Body image: Week 24 (n=113,96)
    0.8 ± 23.58
    -4.7 ± 20.97
        Body image: Week 32 (n=68,62)
    -1.2 ± 26.27
    -0.3 ± 22.23
        Body image: Week 40 (n=48,30)
    3.3 ± 22.63
    -2.4 ± 20.98
        Body image: Week 48 (n=29,20)
    -0.3 ± 25.47
    -1.1 ± 28.93
        Body image: Week 56 (n=27,16)
    3.9 ± 25.53
    -10.2 ± 26.61
        Sexual functioning: Week 8 (n=320,286)
    -0.8 ± 16.07
    -2.2 ± 16.26
        Sexual functioning: Week 16 (n=166,143)
    0.1 ± 16.67
    -0.8 ± 17.28
        Sexual functioning: Week 24 (n=100,82)
    -2.8 ± 16.72
    -1.4 ± 15.7
        Sexual functioning: Week 32 (n=61,57)
    -2.2 ± 19.12
    -0.7 ± 12.82
        Sexual functioning: Week 40 (n=43,25)
    -5.4 ± 16.66
    2.7 ± 16.27
        Sexual functioning: Week 48 (n=26,16)
    -9.6 ± 19.68
    1.6 ± 15.88
        Sexual functioning: Week 56 (n=25,15)
    -5.3 ± 17.33
    1.7 ± 13.06
        Sexual enjoyment: Week 8 (n=96,68)
    2.6 ± 19.84
    -4.2 ± 23.64
        Sexual enjoyment: Week 16 (n=51,33)
    -0.3 ± 18.41
    -8.6 ± 21.7
        Sexual enjoyment: Week 24 (n=27,19)
    1.9 ± 29.72
    -3.5 ± 28.1
        Sexual enjoyment: Week 32 (n=17,13)
    2 ± 23.48
    -2.6 ± 20.24
        Sexual enjoyment: Week 40 (n=12,7)
    -15.3 ± 29.69
    7.1 ± 13.11
        Sexual enjoyment: Week 48 (n=6,5)
    -27.8 ± 25.09
    6.7 ± 14.91
        Sexual enjoyment: Week 56 (n=7,4)
    -9.5 ± 16.27
    0 ± 0
        Future perspective: Week 8 (n=342,309)
    3.5 ± 28.3
    1.5 ± 27.21
        Future perspective: Week 16 (n=180,162)
    6.9 ± 27.17
    3.6 ± 29.18
        Future perspective: Week 24 (n=113,94)
    9.3 ± 31.1
    6.6 ± 29.55
        Future perspective: Week 32 (n=66,61)
    6.1 ± 30.19
    4.4 ± 35.86
        Future perspective: Week 40 (n=49,30)
    7.1 ± 28.05
    13.3 ± 37.75
        Future perspective: Week 48 (n=29,19)
    9.2 ± 27.31
    6.1 ± 35.66
        Future perspective: Week 56 (n=25,16)
    16 ± 28.25
    -3.1 ± 45.22
        Systemic therapy side effects: Week 8 (n=345,312)
    2.3 ± 13.74
    7.9 ± 16.03
        Systemic therapy side effects: Week 16 (n=181,162)
    3 ± 14.95
    9.1 ± 17.7
        Systemic therapy side effects: Week 24 (n=115,96)
    2.2 ± 15.55
    6.9 ± 17.39
        Systemic therapy side effects: Week 32 (n=69,62)
    3.5 ± 13.5
    7.3 ± 18.01
        Systemic therapy side effects: Week 40 (n=49,30)
    3.2 ± 16.62
    10.1 ± 18.33
        Systemic therapy side effects: Week 48 (n=30,20)
    0.3 ± 11.74
    6.4 ± 15.68
        Systemic therapy side effects: Week 56 (n=27,16)
    -1.1 ± 11.06
    6.8 ± 21.84
        Breast symptoms: Week 8 (n=342,310)
    -1.7 ± 15.21
    -0.2 ± 13.82
        Breast symptoms: Week 16 (n=177,159)
    -3.5 ± 14.6
    0.1 ± 14.64
        Breast symptoms: Week 24 (n=115,97)
    -4.8 ± 10.52
    -1.1 ± 13.48
        Breast symptoms: Week 32 (n=69,60)
    -2.5 ± 14.26
    -2.8 ± 13.63
        Breast symptoms: Week 40 (n=48,30)
    -1.9 ± 14.59
    -0.2 ± 11.02
        Breast symptoms: Week 48 (n=29,20)
    -2.7 ± 12.16
    0 ± 13.79
        Breast symptoms: Week 56 (n=26,16)
    -3.4 ± 13.28
    2.5 ± 12.15
        Arm symptoms: Week 8 (n=342,312)
    -3 ± 16.72
    -0.9 ± 15.01
        Arm symptoms: Week 16 (n=178,159)
    -5.1 ± 17.24
    1.1 ± 18.24
        Arm symptoms: Week 24 (n=115,97)
    -4.9 ± 20.06
    -0.3 ± 19.56
        Arm symptoms: Week 32 (n=69,60)
    -4.4 ± 18.39
    -0.5 ± 19.03
        Arm symptoms: Week 40 (n=48,30)
    -6 ± 21.86
    5.2 ± 18.39
        Arm symptoms: Week 48 (n=29,20)
    -5.6 ± 20.89
    -1.4 ± 12.98
        Arm symptoms: Week 56 (n=26,16)
    -5.6 ± 19.44
    -1.4 ± 19.51
        Upset by hair loss: Week 8 (n=102,122)
    -4.7 ± 32.28
    0.1 ± 28.63
        Upset by hair loss: Week 16 (n=54,58)
    8.3 ± 33.61
    2.9 ± 31.24
        Upset by hair loss: Week 24 (n=37,38)
    6.8 ± 35.02
    3.5 ± 30.3
        Upset by hair loss: Week 32 (n=17,22)
    6.9 ± 31.76
    -2.3 ± 29.68
        Upset by hair loss: Week 40 (n=20,14)
    -4.2 ± 30.05
    20.2 ± 29.37
        Upset by hair loss: Week 48 (n=7,10)
    -16.7 ± 31.91
    21.7 ± 36.89
        Upset by hair loss: Week 56 (n=8,5)
    -14.6 ± 30.13
    16.7 ± 44.1
    Statistical analysis title
    Analysis for HRQoL QLQ-BR23 Change from Baseline
    Statistical analysis description
    Body image: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [17]
    P-value
    = 0.5833
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.42
         upper limit
    4.29
    Notes
    [17] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-BR23 Change from Baseline
    Statistical analysis description
    Sexual functioning: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [18]
    P-value
    = 0.3098
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.24
         upper limit
    3.9
    Notes
    [18] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-BR23 Change from Baseline
    Statistical analysis description
    Future perspective: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [19]
    P-value
    = 0.6264
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.39
         upper limit
    5.63
    Notes
    [19] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-BR23 Change from Baseline
    Statistical analysis description
    Systemic therapy side effects: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [20]
    P-value
    = 0.0003
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.11
         upper limit
    -2.1
    Notes
    [20] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-BR23 Change from Baseline
    Statistical analysis description
    Breast symptoms: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [21]
    P-value
    = 0.2473
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.84
         upper limit
    0.99
    Notes
    [21] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-BR23 Change from Baseline
    Statistical analysis description
    Arm symptoms: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [22]
    P-value
    = 0.0333
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.54
         upper limit
    -0.23
    Notes
    [22] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-BR23 Change from Baseline
    Statistical analysis description
    Upset by hair loss: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [23]
    P-value
    = 0.2575
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.2
         upper limit
    3.28
    Notes
    [23] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.
    Statistical analysis title
    Analysis for HRQoL QLQ-BR23 Change from Baseline
    Statistical analysis description
    Sexual enjoyment: change from baseline to last assessment (Week 56)
    Comparison groups
    NKTR-102 v TPC drugs
    Number of subjects included in analysis
    852
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [24]
    P-value
    = 0.1072
    Method
    F-test
    Parameter type
    Mean difference (final values)
    Point estimate
    5.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.22
         upper limit
    12.34
    Notes
    [24] - Analysis of variance with change from baseline in linear transformed score at the last visit as the dependent variable and treatment arm, geographic region, prior use of eribulin, and receptor status as fixed effects.

    Secondary: Population Mean ± Standard Deviation (SD) Area Under the Concentration-Time Curve (AUC) for NKTR-102 and Metabolites after Multiple Administration of 145 mg/m^2 NKTR-102

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    End point title
    Population Mean ± Standard Deviation (SD) Area Under the Concentration-Time Curve (AUC) for NKTR-102 and Metabolites after Multiple Administration of 145 mg/m^2 NKTR-102 [25]
    End point description
    Plasma concentrations of NKTR-102 and its major metabolites irinotecan, SN38, SN38G, and APC were measured using validated analytical methods. The population pharmacokinetic (PK) model-derived mean AUC values were computed by integration from t = 0 (start of first dose) to 21 days after the last dose. Integration was implemented using a separate compartment defined as the amount of drug or metabolite in the central compartment divided by the model-estimated volume of distribution.
    End point type
    Secondary
    End point timeframe
    From the first dose up to 21 days after the last dose.
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants from “NKTR-102” treatment arm were planned to be analysed for this end point.
    End point values
    NKTR-102
    Number of subjects analysed
    95
    Units: μg·h/mL
    arithmetic mean (standard deviation)
        NKTR-102
    4619 ± 4874
        Irinotecan
    18.8 ± 22.1
        SN38
    5.32 ± 6.74
        SN38G
    40.6 ± 39.2
        APC
    4 ± 5.1
    No statistical analyses for this end point

    Secondary: Population Mean ± SD Maximum Plasma Concentration (Cmax) for NKTR-102 and Metabolites after Multiple Administration of 145 mg/m^2 NKTR-102

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    End point title
    Population Mean ± SD Maximum Plasma Concentration (Cmax) for NKTR-102 and Metabolites after Multiple Administration of 145 mg/m^2 NKTR-102 [26]
    End point description
    Plasma concentrations of NKTR-102 and its major metabolites irinotecan, SN38, SN38G, and APC were measured using validated analytical methods. The population PK model-derived mean Cmax values were computed by integration from t = 0 (start of first dose) to 21 days after the last dose. Integration was implemented using a separate compartment defined as the amount of drug or metabolite in the central compartment divided by the model-estimated volume of distribution.
    End point type
    Secondary
    End point timeframe
    From the first dose up to 21 days after the last dose.
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants from “NKTR-102” treatment arm were planned to be analysed for this end point.
    End point values
    NKTR-102
    Number of subjects analysed
    95
    Units: ng/mL
    arithmetic mean (standard deviation)
        NKTR-102
    62701 ± 14576
        Irinotecan
    138 ± 61.8
        SN38
    4.45 ± 1.82
        SN38G
    47.7 ± 43.1
        APC
    7.3 ± 6.7
    No statistical analyses for this end point

    Secondary: Population Mean ± SD Elimination Half-life (t½) for NKTR-102 after Multiple Administration of 145 mg/m^2 NKTR-102

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    End point title
    Population Mean ± SD Elimination Half-life (t½) for NKTR-102 after Multiple Administration of 145 mg/m^2 NKTR-102 [27]
    End point description
    Plasma concentrations of NKTR-102 and its major metabolites irinotecan, SN38, SN38G, and APC were measured using validated analytical methods. The population PK model-derived mean t½ values were computed by integration from t = 0 (start of first dose) to 21 days after the last dose. Integration was implemented using a separate compartment defined as the amount of drug or metabolite in the central compartment divided by the model-estimated volume of distribution. The t½ of all analytes was primarily driven by NKTR-102. Thus, the NKTR-102 t½ of 37 days also applies to all NKTR-102 metabolites.
    End point type
    Secondary
    End point timeframe
    From the first dose up to 21 days after the last dose.
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants from “NKTR-102” treatment arm were planned to be analysed for this end point.
    End point values
    NKTR-102
    Number of subjects analysed
    95
    Units: days
        arithmetic mean (standard deviation)
    36.8 ± 1.4
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR): Efficacy Evaluable Population

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    End point title
    Objective Response Rate (ORR): Efficacy Evaluable Population
    End point description
    ORR was defined as the proportion of subjects with a complete response (CR) or a partial response (PR), assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 The analyses were performed for subjects in the efficacy evaluable population who had measurable disease as determined by the investigator at baseline.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks (± 7 days) from date of randomisation until protocol-defined disease progression.
    End point values
    NKTR-102 TPC drugs
    Number of subjects analysed
    354
    358
    Units: Percentage of subjects
        number (confidence interval 95%)
    16.4 (12.7 to 20.7)
    17 (13.3 to 21.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were reported from the time the patient received the first dose of study drug through the End-of-Treatment Visit (i.e., 30 ± 3 days after the last dose of study drug).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    NKTR-102
    Reporting group description
    NKTR-102 for injection was administered as an IV infusion over 90 ± 15 minutes, on Day 1 of each 21-day cycle) at a dose level of 145 mg/m^2.

    Reporting group title
    TPC drugs
    Reporting group description
    The TPC drugs were administered in 21- or 28-day treatment cycles, depending on the institutional guidelines for the specific drug. The dosage and administration of the TPC drugs followed the institutional guidelines provided for each agent, with the exception of: Eribulin, which was administered in accordance with its local country Summary of Product Characteristics (SmPC) or Prescribing Information OR initially administered at no less than 1.4 mg/m^2 on Days 1 and 8 every 21 days; Ixabepilone, which was initially administered at 40 mg/m2 on Day 1 every 21 days, then per institutional guidelines.

    Serious adverse events
    NKTR-102 TPC drugs
    Total subjects affected by serious adverse events
         subjects affected / exposed
    128 / 425 (30.12%)
    129 / 406 (31.77%)
         number of deaths (all causes)
    323
    322
         number of deaths resulting from adverse events
    3
    2
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    6 / 425 (1.41%)
    10 / 406 (2.46%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Metastases to meninges
         subjects affected / exposed
    2 / 425 (0.47%)
    4 / 406 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to spine
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 425 (0.71%)
    5 / 406 (1.23%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 425 (0.71%)
    3 / 406 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Asthenia
         subjects affected / exposed
    1 / 425 (0.24%)
    3 / 406 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 425 (0.47%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium test positive
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    15 / 425 (3.53%)
    18 / 406 (4.43%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 21
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Dyspnoea
         subjects affected / exposed
    2 / 425 (0.47%)
    7 / 406 (1.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 425 (0.24%)
    5 / 406 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    4 / 425 (0.94%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 425 (0.47%)
    6 / 406 (1.48%)
         occurrences causally related to treatment / all
    2 / 3
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 425 (0.47%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 425 (0.47%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathic haemolytic anaemia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    3 / 425 (0.71%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 425 (0.24%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    3 / 425 (0.71%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholinergic syndrome
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysgraphia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gliosis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal chord compression
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 425 (4.00%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    18 / 18
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 425 (2.35%)
    6 / 406 (1.48%)
         occurrences causally related to treatment / all
    5 / 10
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    4 / 425 (0.94%)
    5 / 406 (1.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    4 / 425 (0.94%)
    3 / 406 (0.74%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 425 (0.47%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colonic obstruction
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileitis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    3 / 425 (0.71%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Bile duct obstruction
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatomegaly
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    3 / 425 (0.71%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 425 (0.47%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 425 (0.24%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    8 / 425 (1.88%)
    6 / 406 (1.48%)
         occurrences causally related to treatment / all
    7 / 8
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hypercalcaemia
         subjects affected / exposed
    2 / 425 (0.47%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 425 (0.47%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyponatraemia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 425 (0.94%)
    4 / 406 (0.99%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 425 (0.94%)
    3 / 406 (0.74%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 425 (0.24%)
    3 / 406 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 425 (0.24%)
    3 / 406 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 425 (0.24%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 425 (0.47%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 425 (0.24%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urosepsis
         subjects affected / exposed
    0 / 425 (0.00%)
    2 / 406 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 425 (0.24%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute haemorrhagic conjunctivitis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast infection
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Moraxella infection
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Oral herpes
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 425 (0.00%)
    1 / 406 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 425 (0.24%)
    0 / 406 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    NKTR-102 TPC drugs
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    417 / 425 (98.12%)
    404 / 406 (99.51%)
    Investigations
    Weight decreased
         subjects affected / exposed
    57 / 425 (13.41%)
    24 / 406 (5.91%)
         occurrences all number
    65
    25
    Neutrophil count decreased
         subjects affected / exposed
    26 / 425 (6.12%)
    50 / 406 (12.32%)
         occurrences all number
    41
    126
    Aspartate aminotransferase increased
         subjects affected / exposed
    23 / 425 (5.41%)
    29 / 406 (7.14%)
         occurrences all number
    24
    31
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    58 / 425 (13.65%)
    70 / 406 (17.24%)
         occurrences all number
    68
    87
    Cough
         subjects affected / exposed
    59 / 425 (13.88%)
    52 / 406 (12.81%)
         occurrences all number
    64
    55
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    92 / 425 (21.65%)
    126 / 406 (31.03%)
         occurrences all number
    174
    244
    Anaemia
         subjects affected / exposed
    64 / 425 (15.06%)
    82 / 406 (20.20%)
         occurrences all number
    83
    105
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    55 / 425 (12.94%)
    41 / 406 (10.10%)
         occurrences all number
    75
    51
    Dysgeusia
         subjects affected / exposed
    34 / 425 (8.00%)
    28 / 406 (6.90%)
         occurrences all number
    41
    44
    Neuropathy peripheral
         subjects affected / exposed
    9 / 425 (2.12%)
    50 / 406 (12.32%)
         occurrences all number
    9
    62
    Eye disorders
    Vision blurred
         subjects affected / exposed
    68 / 425 (16.00%)
    12 / 406 (2.96%)
         occurrences all number
    161
    13
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    145 / 425 (34.12%)
    130 / 406 (32.02%)
         occurrences all number
    241
    163
    Asthenia
         subjects affected / exposed
    91 / 425 (21.41%)
    114 / 406 (28.08%)
         occurrences all number
    142
    170
    Pyrexia
         subjects affected / exposed
    30 / 425 (7.06%)
    63 / 406 (15.52%)
         occurrences all number
    39
    98
    Oedema peripheral
         subjects affected / exposed
    20 / 425 (4.71%)
    42 / 406 (10.34%)
         occurrences all number
    22
    49
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 425 (6.82%)
    33 / 406 (8.13%)
         occurrences all number
    45
    35
    Anxiety
         subjects affected / exposed
    20 / 425 (4.71%)
    22 / 406 (5.42%)
         occurrences all number
    26
    23
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    255 / 425 (60.00%)
    155 / 406 (38.18%)
         occurrences all number
    479
    249
    Diarrhoea
         subjects affected / exposed
    277 / 425 (65.18%)
    79 / 406 (19.46%)
         occurrences all number
    1202
    128
    Vomiting
         subjects affected / exposed
    172 / 425 (40.47%)
    72 / 406 (17.73%)
         occurrences all number
    342
    109
    Constipation
         subjects affected / exposed
    112 / 425 (26.35%)
    126 / 406 (31.03%)
         occurrences all number
    167
    152
    Abdominal pain
         subjects affected / exposed
    89 / 425 (20.94%)
    47 / 406 (11.58%)
         occurrences all number
    147
    52
    Abdominal pain upper
         subjects affected / exposed
    56 / 425 (13.18%)
    37 / 406 (9.11%)
         occurrences all number
    71
    45
    Dyspepsia
         subjects affected / exposed
    34 / 425 (8.00%)
    32 / 406 (7.88%)
         occurrences all number
    45
    50
    Stomatitis
         subjects affected / exposed
    17 / 425 (4.00%)
    34 / 406 (8.37%)
         occurrences all number
    23
    43
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    44 / 425 (10.35%)
    95 / 406 (23.40%)
         occurrences all number
    49
    102
    Rash
         subjects affected / exposed
    23 / 425 (5.41%)
    24 / 406 (5.91%)
         occurrences all number
    28
    28
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    26 / 425 (6.12%)
    59 / 406 (14.53%)
         occurrences all number
    30
    89
    Back pain
         subjects affected / exposed
    39 / 425 (9.18%)
    39 / 406 (9.61%)
         occurrences all number
    45
    41
    Arthralgia
         subjects affected / exposed
    29 / 425 (6.82%)
    42 / 406 (10.34%)
         occurrences all number
    35
    55
    Pain in extremity
         subjects affected / exposed
    27 / 425 (6.35%)
    35 / 406 (8.62%)
         occurrences all number
    32
    43
    Bone pain
         subjects affected / exposed
    17 / 425 (4.00%)
    35 / 406 (8.62%)
         occurrences all number
    20
    38
    Musculoskeletal pain
         subjects affected / exposed
    25 / 425 (5.88%)
    26 / 406 (6.40%)
         occurrences all number
    28
    29
    Muscle spasms
         subjects affected / exposed
    29 / 425 (6.82%)
    16 / 406 (3.94%)
         occurrences all number
    60
    16
    Musculoskeletal chest pain
         subjects affected / exposed
    16 / 425 (3.76%)
    26 / 406 (6.40%)
         occurrences all number
    16
    31
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    130 / 425 (30.59%)
    98 / 406 (24.14%)
         occurrences all number
    169
    116
    Hypokalaemia
         subjects affected / exposed
    39 / 425 (9.18%)
    37 / 406 (9.11%)
         occurrences all number
    54
    39
    Dehydration
         subjects affected / exposed
    34 / 425 (8.00%)
    19 / 406 (4.68%)
         occurrences all number
    39
    25
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    26 / 425 (6.12%)
    26 / 406 (6.40%)
         occurrences all number
    27
    28
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 425 (3.53%)
    27 / 406 (6.65%)
         occurrences all number
    18
    32

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2012
    The major changes made to the protocol were: 1. The requirement for the Xeloda® brand of capecitabine was amended to permit patients to receive generic capecitabine where available and approved by the local country Competent Authority. 2. Clarify that investigators selected a TPC that was approved by the Local Competent Authority and commercially available in that country. 3. A tissue acquisition protocol sub-study was added to the main study. 4. Clarification of Eligibility Criteria. 5. The United States Adopted Name for NKTR-102 (etirinotecan pegol) was added to the protocol. References to United States Pharmacopeia (USP) for diluents were removed. Documentation of the lot number of NKTR-102 administered to each patient was required in the electronic case report form. Shelf-life increased from 30 to 36 months based on additional stability data. Changes were also made to Dosing Modification, Supportive Care and Prohibited Medications. 6. For the TPC, nab-albumin paclitaxel was changed to nab-paclitaxel throughout the protocol, information regarding diluents (locally sourced) was added and references regarding USP were removed. 7. Modifications were made to the following procedures: the definition of human epidermal growth factor receptor 2-positive disease was removed; added that patients received a Patient Information Card at time of consent; updated the instructions for bone scans; updated the text for laboratory tests for screening and treatment; updated the timing of PK sample collection; updated text relating to biomarkers, brain imaging, positron emission tomography–computed tomography, health-related quality of life and Health Economics questionnaires, and Safety.

    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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