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    Clinical Trial Results:
    Investigating Denosumab as an add-on to neoadjuvant chemotherapy in RANK/L-positive or RANK/L-negative primary breast cancer and two different nab-Paclitaxel schedules in a 2x2 factorial design (GeparX)

    Summary
    EudraCT number
    		 2015-001755-72
    Trial protocol
    		 DE  
    Global end of trial date
    28 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2021
    First version publication date
    16 Sep 2021
    Other versions
    Summary report(s)
    		 GeparX CSR synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    GBG88
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02682693
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GBG Forschungs GmbH
    Sponsor organisation address
    Martin Behaim Str. 12, Neu-Isenburg, Germany, 63263
    Public contact
    Medicine and Research, GBG Forschungs GmbH, +49 610274800, publications@gbg.de, Medicine and Research, GBG Forschungs GmbH, +49 610274800, publications@gbg.de, +49 610274800, publications@gbg.de
    Scientific contact
    Medicine and Research, GBG Forschungs GmbH, +49 610274800, publications@gbg.de, Medicine and Research, GBG Forschungs GmbH, +49 610274800, publications@gbg.de, +49 610274800, publications@gbg.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Jan 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Co-Primary Objectives • To compare the pathological complete response (pCR, ypT0 ypN0) rates of neoadjuvant treatment with or without denosumab in addition to backbone treatment consisting of nab-Paclitaxel 125mg/m² weekly (plus carboplatin in triple-negative disease) followed by epirubicin/cyclophosphamide or of nab-Paclitaxel 125mg/m² day 1,8 q22 (plus carboplatin in triple-negative disease) followed by epirubicin/cyclophosphamide plus anti-HER2 treatment (i. e. trastuzumab/pertuzumab in case of positive HER2-status) in patients with early breast cancer. • To compare the pCR (ypT0 ypN0) rates of nab-Paclitaxel 125mg/m² weekly (plus carboplatin in triple-negative disease) followed by epirubicin/cyclophosphamide or nab-Paclitaxel 125mg/m² day 1,8 q22 (plus carboplatin in triple-negative disease) followed by epirubicin/cyclophosphamide plus anti-HER2 treatment (i. e. trastuzumab/pertuzumab in case of positive HER2-status) in patients with early breast cancer.
    Protection of trial subjects
    The trial protocol including amendments, the patient information and the informed consent were reviewed and approved from a properly constituted IRB/IEC for each site prior to the study start. The trial was in compliance with the International Conference on Harmonization (ICH) - Harmonized Tripartite Guideline for Good Clinical Practice (GCP) (E6), and the Commission Directives in the European Community as well as with the applicable German national laws and regulations, and with Declaration of Helsinki and its revisions in all aspects of preparation, monitoring, reporting, auditing, and archiving. IDMC was to ensure the ethical conduct of the trial and to protect patients' safety interests in this study.
    Background therapy
    		 For all patients Epirubicin 90 mg/m² i.v. on day 1 every 2 or 3 weeks for 4 cycles in combination with Cyclophosphamide 600 mg/m² i.v. on day 1 every 2 or 3 weeks for 4 cycles.. For patients with TNBC only Carboplatin AUC 2.0 i.v. on day 1, 8, 15 every 3 weeks for 4 cycles For patients with HER2-positive disease Pertuzumab at 840mg (loading dose) and 420mg (maintenance dose) i.v. on the day before the first nab-Paclitaxel cycle and denosumab administration (loading dose) and on day 1 q day 22 (maintenance dose) for a minimum of 4 cycles (according to label)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Feb 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 780
    Worldwide total number of subjects
    780
    EEA total number of subjects
    780
    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)
    710
    From 65 to 84 years
    70
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Approximately 25 months (Q-I 2017 –Q-I 2019). 780 patients were randomized (390 in denosumab arm and 390 in no denosumab arm, thereafter 390 to nab-paclitaxel weekly and 390 to nab-paclitaxel d1, 8 q3w), and started therapy. 756/780 (96.9%) patients underwent surgery

    Pre-assignment
    Screening details
    		 Patients with unilateral or bilateral primary breast cancer with stages cT2 - cT4a-d or cT1c with either clinically node positive or pathologically nodal positive or estrogen receptor (ER)-negative/ progesterone receptor (PR)-negative or Ki-67 >20% or HER2+ breast cancer.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Denosumab
    Arm description
    		 A total of 390 patients were randomized to receive denosumab plus nab-paclitaxel (randomized secondarily to two schedules) followed by epirubicin and cyclophosphamide and started treatment; 371 patients received surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab (XGEVA®)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Denosumab was administered s.c. into the thigh, abdomen or upper arm. The schedule of administration was 120 mg given on day 1 (+/- 3 days) every 4 weeks for 6 cycles. The first injection was to be given on day 2 after the administration of anti-HER2 treatments.

    Investigational medicinal product name
    Trastuzumab (ABP 980)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab (ABP 980) was administered i.v. (for all patients with HER2 positive tumors and concomitantly with pertuzumab) over 90 min with 4.5 h monitoring of the patient (loading dose) or over 30-90 min with 30 min monitoring of the patient (maintenance dose). The schedule of administration was 8 mg/kg body weight (loading dose), thereafter 6 mg/kg body weight (maintenance dose), with the first injection given the day before the application of nab-Paclitaxel and denosumab. The following injections on day 1 q day 22 for 8 cycles (8 infusions) together with nab-Paclitaxel-EC.

    Arm title
    		 No denosumab
    Arm description
    		 A total of 390 patients were randomized to receive no denosumab plus nab-paclitaxel (randomized secondarily to two schedules) followed by epirubicin and cyclophosphamide and started treatment; 385 patients received surgery.
    Arm type
    		 no Denosumab

    Investigational medicinal product name
    Trastuzumab (ABP 980)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab (ABP 980) was administered i.v. (for all patients with HER2 positive tumors and concomitantly with pertuzumab) over 90 min with 4.5 h monitoring of the patient (loading dose) or over 30-90 min with 30 min monitoring of the patient (maintenance dose). The schedule of administration was 8 mg/kg body weight (loading dose), thereafter 6 mg/kg body weight (maintenance dose), with the first injection given the day before the application of nab-Paclitaxel and denosumab. The following injections on day 1 q day 22 for 8 cycles (8 infusions) together with nab-Paclitaxel-EC.

    Number of subjects in period 1
    		Denosumab No denosumab
    Started
    390
    390
    Completed
    390
    390

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 A total of 390 patients were randomized to receive denosumab plus nab-paclitaxel (randomized secondarily to two schedules) followed by epirubicin and cyclophosphamide and started treatment; 371 patients received surgery.

    Reporting group title
    No denosumab
    Reporting group description
    		 A total of 390 patients were randomized to receive no denosumab plus nab-paclitaxel (randomized secondarily to two schedules) followed by epirubicin and cyclophosphamide and started treatment; 385 patients received surgery.

    Reporting group values
    		 Denosumab No denosumab Total
    Number of subjects
    		 390 390 780
    Age categorical
    Units: Subjects
        <30
    		 8 11 19
        30-<40
    		 66 68 134
        40-<50
    		 122 132 254
        50-<60
    		 123 108 231
        60-<70
    		 59 61 120
        >=70
    		 12 10 22
    Age continuous
    Units: years
        median (full range (min-max))
    		 49 (23 to 78) 48.5 (22 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 389 390 779
        Male
    		 1 0 1
    Tumor stage, sonography
    Units: Subjects
        cT1
    		 135 156 291
        cT2
    		 222 213 435
        cT3
    		 18 11 29
        cT4
    		 11 6 17
        missing
    		 4 4 8
    Nodal stage, sonography
    Units: Subjects
        cN0
    		 232 233 465
        cN1
    		 134 136 270
        cN2
    		 18 12 30
        cN3
    		 3 6 9
        missing
    		 3 3 6
    Tumor grading
    Units: Subjects
        G1
    		 7 7 14
        G2
    		 128 119 247
        G3
    		 255 264 519
    Nodal stage, sonography
    Units: Subjects
        Invasive carcinoma NST
    		 374 375 749
        Invasive lobular carcinoma or mixed lobular carcin
    		 6 9 15
        other
    		 10 6 16
    ER/PgR, central
    Units: Subjects
        both ER and PgR negative
    		 185 180 365
        ER and/or PgR positive
    		 205 210 415
    HER2, central
    Units: Subjects
        negative
    		 313 314 627
        positive
    		 77 76 153
    Subtype (stratification)
    Units: Subjects
        HER2-/HR+
    		 153 157 310
        TNBC
    		 160 157 317
        HER2+
    		 77 76 153
    Ki-67, central (stratification)
    Units: Subjects
        ≤20%
    		 73 59 132
        >20%
    		 317 331 648
    LPBC, central (stratification)
    Units: Subjects
        no LPBC (≤50% sTILs)
    		 359 359 718
        LPBC (>50% sTILs)
    		 31 31 62
    Planned EC schedule (stratification)
    Units: Subjects
        2-weekly
    		 206 208 414
        3-weekly
    		 184 182 366
    Subject analysis sets

    Subject analysis set title
    nab-Paclitaxel weekly
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    nab-Paclitaxel weekly

    Subject analysis set title
    nab-Paclitaxel d1,8 q3w
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    nab-Paclitaxel d1,8 q3w

    Subject analysis sets values
    		 nab-Paclitaxel weekly nab-Paclitaxel d1,8 q3w
    Number of subjects
    390
    390
    Age categorical
    Units: Subjects
        <30
    7
    12
        30-<40
    71
    63
        40-<50
    127
    127
        50-<60
    112
    119
        60-<70
    63
    57
        >=70
    10
    12
    Age continuous
    Units: years
        median (full range (min-max))
    49 (23 to 78)
    49.5 (22 to 80)
    Gender categorical
    Units: Subjects
        Female
    389
    390
        Male
    1
    0
    Tumor stage, sonography
    Units: Subjects
        cT1
    132
    159
        cT2
    230
    205
        cT3
    13
    16
        cT4
    9
    8
        missing
    6
    2
    Nodal stage, sonography
    Units: Subjects
        cN0
    238
    227
        cN1
    131
    139
        cN2
    16
    14
        cN3
    5
    4
        missing
    0
    6
    Tumor grading
    Units: Subjects
        G1
    7
    7
        G2
    126
    121
        G3
    257
    262
    Nodal stage, sonography
    Units: Subjects
        Invasive carcinoma NST
    380
    369
        Invasive lobular carcinoma or mixed lobular carcin
    5
    10
        other
    5
    11
    ER/PgR, central
    Units: Subjects
        both ER and PgR negative
    177
    188
        ER and/or PgR positive
    213
    202
    HER2, central
    Units: Subjects
        negative
    314
    313
        positive
    76
    77
    Subtype (stratification)
    Units: Subjects
        HER2-/HR+
    155
    155
        TNBC
    159
    158
        HER2+
    76
    77
    Ki-67, central (stratification)
    Units: Subjects
        ≤20%
    63
    69
        >20%
    327
    321
    LPBC, central (stratification)
    Units: Subjects
        no LPBC (≤50% sTILs)
    359
    359
        LPBC (>50% sTILs)
    31
    31
    Planned EC schedule (stratification)
    Units: Subjects
        2-weekly
    207
    207
        3-weekly
    183
    183

    End points

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    End points reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 A total of 390 patients were randomized to receive denosumab plus nab-paclitaxel (randomized secondarily to two schedules) followed by epirubicin and cyclophosphamide and started treatment; 371 patients received surgery.

    Reporting group title
    No denosumab
    Reporting group description
    		 A total of 390 patients were randomized to receive no denosumab plus nab-paclitaxel (randomized secondarily to two schedules) followed by epirubicin and cyclophosphamide and started treatment; 385 patients received surgery.

    Subject analysis set title
    nab-Paclitaxel weekly
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    nab-Paclitaxel weekly

    Subject analysis set title
    nab-Paclitaxel d1,8 q3w
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    nab-Paclitaxel d1,8 q3w

    Primary: pCR (ypT0 ypN0)

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    End point title
    		 pCR (ypT0 ypN0)
    End point description
    End point type
    Primary
    End point timeframe
    from start of treatment to surgery, 24 weeks
    End point values
    		 Denosumab No denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q3w
    Number of subjects analysed
    390
    390
    390
    390
    Units: percent
        number (confidence interval 90%)
    41.0 (36.9 to 45.1)
    42.8 (38.7 to 46.9)
    44.9 (40.7 to 49.0)
    39.0 (34.9 to 43.0)
    Statistical analysis title
    		 continuity corrected χ2-test denosumab
    Statistical analysis description
    Co-primary objectives were tested (stratified) according to the improved Bonferroni procedure: the smaller of the two p-values was compared with α = 0.1 and the larger p-value was compared with α = 0.2 to keep the overall significance level of the study of α = 0.2. The primary endpoint was summarized as pathological complete response rate for each treatment group for both randomizations. Two-sided 90% confidence intervals were calculated according to Pearson and Clopper.
    Comparison groups
    No denosumab v Denosumab
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.582
    Method
    		 Chi-squared corrected
    Confidence interval
    Notes
    [1] - The null hypothesis was that there was no difference in pCR rates between treatment arms; the alternative hypothesis was that there was a difference for both randomizations.
    Statistical analysis title
    		 continuity corrected χ2-test nab-Paclitaxel
    Statistical analysis description
    Co-primary objectives were tested (stratified) according to the improved Bonferroni procedure (stratified test) : the smaller of the two p-values was compared with α = 0.1 and the larger p-value was compared with α = 0.2 to keep the overall significance level of the study of α = 0.2. The primary endpoint was summarized as pathological complete response rate for each treatment group for both randomizations.
    Comparison groups
    nab-Paclitaxel weekly v nab-Paclitaxel d1,8 q3w
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.062
    Method
    		 Chi-squared corrected
    Confidence interval
    Notes
    [2] - The null hypothesis was that there was no difference in pCR rates between treatment arms; the alternative hypothesis was that there was a difference for both randomizations.

    Secondary: pCR (ypT0/is, ypN0)

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    End point title
    		 pCR (ypT0/is, ypN0)
    End point description
    End point type
    Secondary
    End point timeframe
    from start of treatment to surgery, 12 weeks
    End point values
    		 Denosumab No denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q3w
    Number of subjects analysed
    390
    390
    390
    390
    Units: percent
        number (confidence interval 90%)
    45.9 (41.7 to 50.0)
    48.5 (44.3 to 52.6)
    50.5 (46.3 to 54.7)
    43.8 (39.7 to 48.0)
    Statistical analysis title
    		 pCR (ypT0/is ypN0)
    Comparison groups
    No denosumab v Denosumab
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.436
    Method
    		 Chi-squared corrected
    Confidence interval
    Statistical analysis title
    		 pCR (ypT0/is, ypN0)
    Comparison groups
    nab-Paclitaxel weekly v nab-Paclitaxel d1,8 q3w
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 Chi-squared corrected
    Confidence interval

    Secondary: pCR (ypT0 ypN0/+)

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    End point title
    		 pCR (ypT0 ypN0/+)
    End point description
    End point type
    Secondary
    End point timeframe
    from start of treatment to surgery, 24 weeks
    End point values
    		 Denosumab No denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q3w
    Number of subjects analysed
    390
    390
    390
    390
    Units: percent
        number (confidence interval 90%)
    42.6 (38.4 to 46.7)
    46.4 (42.3 to 50.6)
    47.4 (43.3 to 51.6)
    41.5 (37.4 to 45.6)
    Statistical analysis title
    		 continuity corrected χ2-test denosumab
    Comparison groups
    Denosumab v No denosumab
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 Chi-squared corrected
    Confidence interval
    Statistical analysis title
    		 continuity corrected χ2-test nab-Paclitaxel
    Comparison groups
    nab-Paclitaxel weekly v nab-Paclitaxel d1,8 q3w
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.055
    Method
    		 Chi-squared corrected
    Confidence interval

    Secondary: pCR (ypT0/is, ypN0/+)

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    End point title
    		 pCR (ypT0/is, ypN0/+)
    End point description
    End point type
    Secondary
    End point timeframe
    from start of treatment to surgery, 24 weeks
    End point values
    		 Denosumab No denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q3w
    Number of subjects analysed
    390
    390
    390
    390
    Units: percent
        number (confidence interval 90%)
    48.7 (44.6 to 52.9)
    53.3 (49.2 to 57.5)
    54.9 (50.7 to 59.0)
    47.2 (43.0 to 51.3)
    Statistical analysis title
    		 continuity corrected χ2-test denosumab
    Comparison groups
    Denosumab v No denosumab
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 Chi-squared corrected
    Confidence interval
    Statistical analysis title
    		 continuity corrected χ2-test nab-Paclitaxel
    Comparison groups
    nab-Paclitaxel d1,8 q3w v nab-Paclitaxel weekly
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Chi-squared corrected
    Confidence interval

    Secondary: pCR (ypT(any), ypN0)

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    End point title
    		 pCR (ypT(any), ypN0)
    End point description
    End point type
    Secondary
    End point timeframe
    from start of treatment to surgery, 24 weeks
    End point values
    		 Denosumab No denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q3w
    Number of subjects analysed
    390
    390
    390
    390
    Units: percent
        number (confidence interval 90%)
    74.6 (71.0 to 78.2)
    76.2 (72.6 to 79.7)
    77.4 (74.0 to 80.9)
    73.3 (69.7 to 77.0)
    Statistical analysis title
    		 continuity corrected χ2-test denosumab
    Comparison groups
    Denosumab v No denosumab
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.588
    Method
    		 Chi-squared corrected
    Confidence interval
    Statistical analysis title
    		 continuity corrected χ2-test nab-Paclitaxel
    Comparison groups
    nab-Paclitaxel weekly v nab-Paclitaxel d1,8 q3w
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.261
    Method
    		 Chi-squared corrected
    Confidence interval

    Secondary: pCR (ypT0 ypN0) in predefined subgroups

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    End point title
    		 pCR (ypT0 ypN0) in predefined subgroups
    End point description
    End point type
    Secondary
    End point timeframe
    from start of treatment to surgery, 24 weeks
    End point values
    		 Denosumab No denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q3w
    Number of subjects analysed
    390
    390
    390
    390
    Units: percent
    number (confidence interval 90%)
        HER2-/HR+
    21.6 (16.1 to 27.0)
    22.3 (16.8 to 27.8)
    22.6 (17.1 to 28.1)
    21.3 (15.9 to 26.7)
        TNBC
    52.5 (46.0 to 59.0)
    58.0 (51.5 to 64.4)
    60.4 (54.0 to 66.8)
    50.0 (43.5 to 56.5)
        HER2+
    55.8 (46.5 to 65.2)
    53.9 (44.5 to 63.4)
    57.9 (48.6 to 67.2)
    51.9 (42.6 to 61.3)
        no LPBC
    38.4 (34.2 to 42.7)
    41.2 (37.0 to 45.5)
    42.6 (38.3 to 46.9)
    37.0 (32.9 to 41.2)
        LPBC
    71.0 (57.6 to 84.4)
    61.3 (46.9 to 75.7)
    71.0 (57.6 to 84.4)
    61.3 (46.9 to 75.7)
        EC 2-weekly
    40.3 (34.7 to 45.9)
    43.3 (37.6 to 48.9)
    46.9 (41.2 to 52.6)
    36.7 (31.2 to 42.2)
        EC 3-weekly
    41.8 (35.9 to 47.8)
    42.3 (36.3 to 48.3)
    42.6 (36.6 to 48.6)
    41.5 (35.5 to 47.5)
        with Dmab
    0 (0 to 0)
    0 (0 to 0)
    48.2 (42.3 to 54.1)
    33.8 (28.3 to 39.4)
        without Dmab
    0 (0 to 0)
    0 (0 to 0)
    41.5 (35.7 to 47.3)
    44.1 (38.3 to 50.0)
    No statistical analyses for this end point

    Secondary: Breast conserving surgery

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    End point title
    		 Breast conserving surgery
    End point description
    End point type
    Secondary
    End point timeframe
    from start of treatment to surgery, 24 weeks
    End point values
    		 Denosumab No denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q3w
    Number of subjects analysed
    390
    390
    390
    390
    Units: percent
        number (not applicable)
    70.4
    76.1
    74.5
    72.1
    Statistical analysis title
    		 continuity corrected χ2-test denosumab
    Comparison groups
    Denosumab v No denosumab
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.078
    Method
    		 Chi-squared corrected
    Confidence interval
    Statistical analysis title
    		 continuity corrected χ2-test nab-Paclitaxel
    Comparison groups
    nab-Paclitaxel weekly v nab-Paclitaxel d1,8 q3w
    Number of subjects included in analysis
    780
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.444
    Method
    		 Chi-squared corrected
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events occurring during the study treatment period were reported.
    Adverse event reporting additional description
    Non-serious AEs are reported per patient; any grade (1-4) during the complete treatment duration for the overall safety population. AEs per patient occurring more frequently (> 20%) in all arms are shown. Note, overall number of single AE occurrences per term was not assessed, only per Patient. AEs reported as free text are not shown
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 A total of 390 patients were randomized to receive denosumab plus nab-paclitaxel (randomized secondarily to two schedules) followed by epirubicin and cyclophosphamide and started treatment; 371 patients received surgery.

    Reporting group title
    no Denosumab
    Reporting group description
    		 -

    Reporting group title
    nab-Paclitaxel weekly
    Reporting group description
    		 -

    Reporting group title
    nab-Paclitaxel d1,8 q22
    Reporting group description
    		 -

    Serious adverse events
    		 Denosumab no Denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q22
    Total subjects affected by serious adverse events
         subjects affected / exposed
    108 / 377 (28.65%)
    110 / 391 (28.13%)
    126 / 395 (31.90%)
    92 / 373 (24.66%)
         number of deaths (all causes)
    1
    0
    0
    1
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial cancer
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 377 (0.27%)
    1 / 391 (0.26%)
    2 / 395 (0.51%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 377 (0.80%)
    3 / 391 (0.77%)
    4 / 395 (1.01%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 377 (0.00%)
    2 / 391 (0.51%)
    0 / 395 (0.00%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Administration site extravasation
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 377 (0.00%)
    2 / 391 (0.51%)
    2 / 395 (0.51%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 377 (0.27%)
    3 / 391 (0.77%)
    3 / 395 (0.76%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    6 / 377 (1.59%)
    2 / 391 (0.51%)
    5 / 395 (1.27%)
    3 / 373 (0.80%)
         occurrences causally related to treatment / all
    6 / 6
    2 / 2
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    16 / 377 (4.24%)
    15 / 391 (3.84%)
    19 / 395 (4.81%)
    12 / 373 (3.22%)
         occurrences causally related to treatment / all
    13 / 16
    15 / 15
    17 / 19
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    23 / 377 (6.10%)
    14 / 391 (3.58%)
    26 / 395 (6.58%)
    11 / 373 (2.95%)
         occurrences causally related to treatment / all
    15 / 23
    13 / 14
    20 / 26
    8 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    3 / 377 (0.80%)
    0 / 391 (0.00%)
    2 / 395 (0.51%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 377 (0.00%)
    2 / 391 (0.51%)
    1 / 395 (0.25%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Abortion missed
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Alveolitis
         subjects affected / exposed
    1 / 377 (0.27%)
    2 / 391 (0.51%)
    2 / 395 (0.51%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 377 (1.59%)
    0 / 391 (0.00%)
    3 / 395 (0.76%)
    3 / 373 (0.80%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 377 (0.53%)
    0 / 391 (0.00%)
    2 / 395 (0.51%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 377 (0.27%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anastomotic stenosis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    19 / 395 (4.81%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 377 (0.53%)
    1 / 391 (0.26%)
    3 / 395 (0.76%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    19 / 395 (4.81%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 377 (0.27%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 377 (0.00%)
    4 / 391 (1.02%)
    0 / 395 (0.00%)
    4 / 373 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Acoustic neuritis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 377 (2.65%)
    7 / 391 (1.79%)
    12 / 395 (3.04%)
    5 / 373 (1.34%)
         occurrences causally related to treatment / all
    10 / 10
    7 / 7
    12 / 12
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    15 / 377 (3.98%)
    29 / 391 (7.42%)
    23 / 395 (5.82%)
    21 / 373 (5.63%)
         occurrences causally related to treatment / all
    15 / 15
    29 / 29
    23 / 23
    21 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    7 / 377 (1.86%)
    4 / 391 (1.02%)
    9 / 395 (2.28%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    7 / 7
    4 / 4
    9 / 9
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    16 / 377 (4.24%)
    8 / 391 (2.05%)
    10 / 395 (2.53%)
    14 / 373 (3.75%)
         occurrences causally related to treatment / all
    16 / 16
    8 / 8
    10 / 10
    14 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    5 / 377 (1.33%)
    3 / 391 (0.77%)
    5 / 395 (1.27%)
    3 / 373 (0.80%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 377 (0.00%)
    3 / 391 (0.77%)
    1 / 395 (0.25%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 377 (0.53%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 377 (0.27%)
    5 / 391 (1.28%)
    3 / 395 (0.76%)
    3 / 373 (0.80%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 377 (0.53%)
    5 / 391 (1.28%)
    5 / 395 (1.27%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 5
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 377 (0.27%)
    1 / 391 (0.26%)
    2 / 395 (0.51%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 377 (0.27%)
    5 / 391 (1.28%)
    5 / 395 (1.27%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 377 (0.53%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    2 / 377 (0.53%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    2 / 377 (0.53%)
    0 / 391 (0.00%)
    2 / 395 (0.51%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 377 (0.80%)
    4 / 391 (1.02%)
    3 / 395 (0.76%)
    4 / 373 (1.07%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 377 (0.27%)
    1 / 391 (0.26%)
    2 / 395 (0.51%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 377 (0.27%)
    1 / 391 (0.26%)
    2 / 395 (0.51%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 377 (0.00%)
    3 / 391 (0.77%)
    3 / 395 (0.76%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 377 (0.53%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 377 (0.00%)
    3 / 391 (0.77%)
    3 / 395 (0.76%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    2 / 377 (0.53%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 377 (1.59%)
    1 / 391 (0.26%)
    5 / 395 (1.27%)
    2 / 373 (0.54%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 1
    4 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 377 (0.27%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 377 (0.00%)
    4 / 391 (1.02%)
    0 / 395 (0.00%)
    4 / 373 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Denosumab no Denosumab nab-Paclitaxel weekly nab-Paclitaxel d1,8 q22
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    377 / 377 (100.00%)
    391 / 391 (100.00%)
    395 / 395 (100.00%)
    373 / 373 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 377 (6.90%)
    30 / 391 (7.67%)
    26 / 395 (6.58%)
    30 / 373 (8.04%)
         occurrences all number
    26
    30
    26
    30
    Embolism
         subjects affected / exposed
    14 / 377 (3.71%)
    15 / 391 (3.84%)
    14 / 395 (3.54%)
    15 / 373 (4.02%)
         occurrences all number
    14
    15
    14
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    270 / 377 (71.62%)
    273 / 391 (69.82%)
    292 / 395 (73.92%)
    251 / 373 (67.29%)
         occurrences all number
    270
    273
    292
    251
    Decreased appetite
         subjects affected / exposed
    48 / 377 (12.73%)
    51 / 391 (13.04%)
    61 / 395 (15.44%)
    38 / 373 (10.19%)
         occurrences all number
    48
    51
    61
    38
    Pyrexia
         subjects affected / exposed
    66 / 377 (17.51%)
    54 / 391 (13.81%)
    76 / 395 (19.24%)
    44 / 373 (11.80%)
         occurrences all number
    66
    54
    76
    44
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    3 / 377 (0.80%)
    0 / 391 (0.00%)
    2 / 395 (0.51%)
    1 / 373 (0.27%)
         occurrences all number
    3
    0
    2
    1
    Hypersensitivity
         subjects affected / exposed
    10 / 377 (2.65%)
    15 / 391 (3.84%)
    13 / 395 (3.29%)
    12 / 373 (3.22%)
         occurrences all number
    10
    15
    13
    12
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    80 / 377 (21.22%)
    78 / 391 (19.95%)
    106 / 395 (26.84%)
    52 / 373 (13.94%)
         occurrences all number
    80
    78
    106
    52
    Dyspnoea
         subjects affected / exposed
    50 / 377 (13.26%)
    46 / 391 (11.76%)
    54 / 395 (13.67%)
    42 / 373 (11.26%)
         occurrences all number
    50
    46
    54
    42
    Pneumonitis
         subjects affected / exposed
    3 / 377 (0.80%)
    0 / 391 (0.00%)
    3 / 395 (0.76%)
    0 / 373 (0.00%)
         occurrences all number
    3
    0
    3
    0
    Cough
         subjects affected / exposed
    39 / 377 (10.34%)
    46 / 391 (11.76%)
    50 / 395 (12.66%)
    35 / 373 (9.38%)
         occurrences all number
    39
    46
    50
    35
    Pulmonary toxicity
         subjects affected / exposed
    2 / 377 (0.53%)
    8 / 391 (2.05%)
    5 / 395 (1.27%)
    5 / 373 (1.34%)
         occurrences all number
    2
    8
    5
    5
    Investigations
    Ejection fraction decreased
    Additional description: >= 10% decrease in LVEF from baseline and < 50%
         subjects affected / exposed
    2 / 377 (0.53%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    2 / 373 (0.54%)
         occurrences all number
    2
    1
    1
    2
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    10 / 377 (2.65%)
    7 / 391 (1.79%)
    10 / 395 (2.53%)
    7 / 373 (1.88%)
         occurrences all number
    10
    7
    10
    7
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 377 (0.00%)
    1 / 391 (0.26%)
    1 / 395 (0.25%)
    0 / 373 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    76 / 377 (20.16%)
    80 / 391 (20.46%)
    85 / 395 (21.52%)
    71 / 373 (19.03%)
         occurrences all number
    76
    80
    85
    71
    Peripheral sensory neuropathy
         subjects affected / exposed
    226 / 377 (59.95%)
    245 / 391 (62.66%)
    296 / 395 (74.94%)
    175 / 373 (46.92%)
         occurrences all number
    226
    245
    296
    175
    Cranial nerve disorder
         subjects affected / exposed
    1 / 377 (0.27%)
    4 / 391 (1.02%)
    5 / 395 (1.27%)
    0 / 373 (0.00%)
         occurrences all number
    1
    4
    5
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    357 / 377 (94.69%)
    379 / 391 (96.93%)
    382 / 395 (96.71%)
    354 / 373 (94.91%)
         occurrences all number
    357
    379
    382
    354
    Leukopenia
         subjects affected / exposed
    355 / 377 (94.16%)
    376 / 391 (96.16%)
    380 / 395 (96.20%)
    351 / 373 (94.10%)
         occurrences all number
    355
    376
    380
    351
    Neutropenia
         subjects affected / exposed
    339 / 377 (89.92%)
    354 / 391 (90.54%)
    361 / 395 (91.39%)
    332 / 373 (89.01%)
         occurrences all number
    339
    354
    361
    332
    Febrile neutropenia
         subjects affected / exposed
    17 / 377 (4.51%)
    32 / 391 (8.18%)
    26 / 395 (6.58%)
    23 / 373 (6.17%)
         occurrences all number
    17
    32
    26
    23
    Thrombocytopenia
         subjects affected / exposed
    197 / 377 (52.25%)
    210 / 391 (53.71%)
    200 / 395 (50.63%)
    207 / 373 (55.50%)
         occurrences all number
    197
    210
    200
    207
    Blood bilirubin increased
         subjects affected / exposed
    12 / 377 (3.18%)
    19 / 391 (4.86%)
    22 / 395 (5.57%)
    9 / 373 (2.41%)
         occurrences all number
    12
    19
    22
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    124 / 377 (32.89%)
    144 / 391 (36.83%)
    141 / 395 (35.70%)
    127 / 373 (34.05%)
         occurrences all number
    124
    144
    141
    127
    Aspartate aminotransferase increased
         subjects affected / exposed
    158 / 377 (41.91%)
    151 / 391 (38.62%)
    169 / 395 (42.78%)
    140 / 373 (37.53%)
         occurrences all number
    158
    151
    169
    140
    Alanine aminotransferase increased
         subjects affected / exposed
    234 / 377 (62.07%)
    233 / 391 (59.59%)
    256 / 395 (64.81%)
    211 / 373 (56.57%)
         occurrences all number
    234
    233
    256
    211
    Blood creatinine increased
         subjects affected / exposed
    40 / 377 (10.61%)
    54 / 391 (13.81%)
    45 / 395 (11.39%)
    49 / 373 (13.14%)
         occurrences all number
    40
    54
    45
    49
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    225 / 377 (59.68%)
    238 / 391 (60.87%)
    222 / 395 (56.20%)
    241 / 373 (64.61%)
         occurrences all number
    225
    238
    222
    241
    Vomiting
         subjects affected / exposed
    58 / 377 (15.38%)
    51 / 391 (13.04%)
    57 / 395 (14.43%)
    52 / 373 (13.94%)
         occurrences all number
    58
    51
    57
    52
    Diarrhoea
         subjects affected / exposed
    140 / 377 (37.14%)
    148 / 391 (37.85%)
    164 / 395 (41.52%)
    124 / 373 (33.24%)
         occurrences all number
    140
    148
    164
    124
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    327 / 377 (86.74%)
    337 / 391 (86.19%)
    345 / 395 (87.34%)
    319 / 373 (85.52%)
         occurrences all number
    327
    337
    345
    319
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    24 / 377 (6.37%)
    23 / 391 (5.88%)
    34 / 395 (8.61%)
    13 / 373 (3.49%)
         occurrences all number
    24
    23
    34
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    94 / 377 (24.93%)
    77 / 391 (19.69%)
    100 / 395 (25.32%)
    71 / 373 (19.03%)
         occurrences all number
    94
    77
    100
    71
    Myalgia
         subjects affected / exposed
    63 / 377 (16.71%)
    43 / 391 (11.00%)
    56 / 395 (14.18%)
    50 / 373 (13.40%)
         occurrences all number
    63
    43
    56
    50
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 377 (0.27%)
    0 / 391 (0.00%)
    0 / 395 (0.00%)
    1 / 373 (0.27%)
         occurrences all number
    1
    0
    0
    1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    10 / 377 (2.65%)
    4 / 391 (1.02%)
    12 / 395 (3.04%)
    2 / 373 (0.54%)
         occurrences all number
    10
    4
    12
    2
    Infection
    Additional description: other than pneumonia
         subjects affected / exposed
    159 / 377 (42.18%)
    157 / 391 (40.15%)
    167 / 395 (42.28%)
    149 / 373 (39.95%)
         occurrences all number
    159
    157
    167
    149
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    193 / 377 (51.19%)
    112 / 391 (28.64%)
    160 / 395 (40.51%)
    145 / 373 (38.87%)
         occurrences all number
    193
    112
    160
    145

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Mar 2017
    Amendment 1 comprised the inclusion of a trastuzumab biosimilar replacing Herceptin® (and thus opening the study for patients with HER2-positive tumor), minor adjustments to the protocol and deletion of the PET-CT substudy.
    18 Jun 2018
    Amendment 2 implemented the change of the co-ordinating investigator and adjustments in the informed consent form (ICF) required due to several updates to the reference document for the investigational medicinal product Denosumab.
    11 Apr 2019
    Amendment 3 contained a clarification of end of study and timeframe from end of therapy until surgery. Moreover, several reformulations and additions in ICF, especially for the marketing authorization of the trastuzumab biosimilar were included.

    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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