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    Clinical Trial Results:
    Phase III study of Palbociclib (PD-0332991) in combination with Exemestane versus chemotherapy (capecitabine) in Hormonal Receptor (HR) positive/HER2 negative Metastatic Breast Cancer (MBC) patients with Resistance to non-steroidal Aromatase inhibitors The PEARL study

    Summary
    EudraCT number
    		 2013-003170-27
    Trial protocol
    		 ES   AT   HU   LV   IE  
    Global end of trial date
    11 Jan 2021

    Results information
    Results version number
    		 v1
    This version publication date
    18 Apr 2022
    First version publication date
    18 Apr 2022
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GEICAM/2013-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02028507
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GEICAM (FUNDACIÓN GRUPO ESPAÑOL DE INVESTIGACIÓN EN CÁNCER DE MAMA)
    Sponsor organisation address
    Avenida de los Pirineos 7, San Sebastián de los Reyes / Madrid, Spain, 28703
    Public contact
    Clinical Operations Department, GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama), 34 916592870, geicam@geicam.org
    Scientific contact
    Clinical Operations Department, GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama), +34 916592870, geicam@geicam.org
    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
    30 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that palbociclib in combination with exemestane is superior to capecitabine in prolonging Progression-Free Survival (PFS) in postmenopausal women with HR positive/HER2 negative MBC whose disease was resistant to non-steroidal aromatase inhibitors.
    Protection of trial subjects
    Not applicable. It was not necessary to applied extra measures for protection of the subjects out of the good clinical practice environment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2014
    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
    Austria: 15
    Country: Number of subjects enrolled
    Spain: 488
    Country: Number of subjects enrolled
    Hungary: 59
    Country: Number of subjects enrolled
    Israel: 39
    Worldwide total number of subjects
    601
    EEA total number of subjects
    562
    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)
    391
    From 65 to 84 years
    205
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 92 patients were screening failure. A total of 601 patients were included in this study from March 2014 to July 2018. Cohort 1 included 296 patients (153 on palbociclib plus exemestane and 143 on capecitabine) and cohort 2 included 305 patients (149 on palbociclib plus fulvestrant and 156 on capecitabine).

    Pre-assignment
    Screening details
    		 92 patients were screening failure. A total of 601 patients were included in this study from March 2014 to July 2018. Cohort 1 included 296 patients (153 on palbociclib plus exemestane and 143 on capecitabine) and cohort 2 included 305 patients (149 on palbociclib plus fulvestrant and 156 on capecitabine).

    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
    		 Cohort 1: Arm A: Palbociclib Plus Exemestane
    Arm description
    		 Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Exemestane 25 mg orally once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Ibrance
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Palbociclib will be administered at a dose of 125mg PO daily on Day 1 to Day 21 following a 1 week of rest period, given as 4 weeks cycles.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Aromasil
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane will be administered at a dose of 25 mg PO daily (continuously).

    Arm title
    		 Cohort 1: Arm B: Capecitabine
    Arm description
    		 Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine will be administered at a dose of 1,250mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age. Capecitabine Dose will be calculated for each patient in mg/m2, it is recommeded to calculate the dose according to the Protocol Attachment 4. The real Body Surface Area (BSA) of the patient determined in the baseline visit will be the reference BSA throughout the study. The BSA and the capecitabine dose will be recalculated in the event that patients experience body weight variations greater than 10% during the treatment period.

    Arm title
    		 Cohort 2: Palbociclib Plus Fulvestrant
    Arm description
    		 Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    Other name
    Ibrance
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Palbociclib will be administered at a dose of 125mg PO daily on Day 1 to Day 21 following a 1 week of rest period, given as 4 weeks cycles.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Faslodex
    Pharmaceutical forms
    Emulsion for injection/infusion in pre-filled syringe
    Routes of administration
    Concentrate for solution for infusion
    Dosage and administration details
    Fulvestrant will be administered at a dose of 500mg, as two 5ml intramuscular injections (one in each buttock), on days 1 and 15 (±3 days) of Cycle 1, and then on Day 1 of each subsequent 28 days Cycle (± 3 days). Time windows extended to ±7 days after 24 weeks.

    Arm title
    		 Cohort 2: Arm B: Capecitabine
    Arm description
    		 Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine will be administered at a dose of 1,250mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age. Capecitabine Dose will be calculated for each patient in mg/m2, it is recommeded to calculate the dose according to the Protocol Attachment 4. The real Body Surface Area (BSA) of the patient determined in the baseline visit will be the reference BSA throughout the study. The BSA and the capecitabine dose will be recalculated in the event that patients experience body weight variations greater than 10% during the treatment period.

    Number of subjects in period 1
    		Cohort 1: Arm A: Palbociclib Plus Exemestane Cohort 1: Arm B: Capecitabine Cohort 2: Palbociclib Plus Fulvestrant Cohort 2: Arm B: Capecitabine
    Started
    153
    143
    149
    156
    Completed
    0
    0
    0
    0
    Not completed
    153
    143
    149
    156
         Consent withdrawn by subject
    6
    8
    5
    9
         Physician decision
    -
    4
    -
    -
         Enzyme defect
    -
    -
    -
    1
         Adverse event, non-fatal
    8
    25
    3
    16
         Death
    1
    -
    1
    3
         Progressive Disease
    122
    90
    102
    89
         Second Invasive Primary Malignancy
    1
    -
    -
    1
         Patient Required Therapy/ Procedure Not Permitted
    -
    1
    -
    1
         Randomized But Not Treated
    3
    6
    -
    4
         Ongoing at date of cut-off 30-May-2019
    10
    5
    37
    28
         Protocol deviation
    2
    4
    1
    3
         Patient was not able to take whole dose of capecit
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Arm A: Palbociclib Plus Exemestane
    Reporting group description
    		 Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Exemestane 25 mg orally once daily

    Reporting group title
    Cohort 1: Arm B: Capecitabine
    Reporting group description
    		 Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age.

    Reporting group title
    Cohort 2: Palbociclib Plus Fulvestrant
    Reporting group description
    		 Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.

    Reporting group title
    Cohort 2: Arm B: Capecitabine
    Reporting group description
    		 Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age

    Reporting group values
    		 Cohort 1: Arm A: Palbociclib Plus Exemestane Cohort 1: Arm B: Capecitabine Cohort 2: Palbociclib Plus Fulvestrant Cohort 2: Arm B: Capecitabine Total
    Number of subjects
    		 153 143 149 156 601
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 97 98 93 103 391
        From 65-84 years
    		 55 44 54 52 205
        85 years and over
    		 1 1 2 1 5
    Age continuous
    Units: years
        median (full range (min-max))
    		 60 (31 to 89) 60 (38 to 87) 62 (38 to 86) 60 (33 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 153 143 149 156 601
        Male
    		 0 0 0 0 0
    Race/Ethnicity
    Units: Subjects
        Hispanic Or Latino
    		 20 21 16 18 75
        Not Hispanic Or Latino
    		 128 118 129 136 511
        Unknown
    		 5 4 4 2 15
    Region of Enrollment
    Units: Subjects
        Austria
    		 5 1 4 5 15
        Hungary
    		 10 8 22 19 59
        Israel
    		 7 6 12 14 39
        Spain
    		 131 128 111 118 488
    Eastern Cooperative Oncology Group (ECOG) status
    Measure Description: ECOG score runs from 0 to 5, with 0 denoting perfect health and 5 death. 0. - Asymptomatic 1. - Symptomatic but completely ambulatory 2. - Symptomatic, <50% in bed during the day 3. - Symptomatic, >50% in bed, but not bedbound 4. - Bedbound 5. - Death
    Units: Subjects
        ECOG 0
    		 85 84 90 93 352
        ECOG 1
    		 68 59 59 63 249
    Visceral disease
    Units: Subjects
        Yes
    		 103 94 97 102 396
        No
    		 50 48 52 54 204
        Not available
    		 0 1 0 0 1
    Hormone receptor status
    Estrogen receptor (ER) Progesterone receptor (PR)
    Units: Subjects
        ER positive and PR positive
    		 114 103 114 118 449
        ER positive and PR negative
    		 36 38 33 33 140
        ER negative and PR positive/ ER positive and PR NA
    		 2 2 2 5 11
        Triple negative
    		 1 0 0 0 1
    ESR1 mutational status
    Units: Subjects
        Wild-type
    		 104 89 102 98 393
        Mutant
    		 41 37 38 48 164
        Not available
    		 8 17 9 10 44
    Sensitivity to prior endocrine therapy
    Units: Subjects
        Yes
    		 107 104 119 122 452
        No
    		 46 39 30 34 149
    Number of prior lines of endocrine therapy for metastatic breast cancer
    Units: Subjects
        1 prior line
    		 82 70 85 90 327
        2 prior line
    		 35 34 12 9 90
        3 prior line
    		 3 4 1 1 9
        Maintenance after chemotherapy
    		 3 4 12 12 31
        Combination
    		 0 0 1 0 1
        No prior endocrine therapy for MBC
    		 30 31 38 44 143
    Prior chemotherapy for metastatic breast cancer
    Units: Subjects
        Yes
    		 48 41 41 41 171
        No
    		 105 102 108 115 430
    Line at study entry
    Units: Subjects
        1st line
    		 27 31 38 43 139
        2nd line
    		 63 50 76 79 268
        ≥3rd line
    		 63 62 35 34 194
    Status at initial diagnosis
    Units: Subjects
        M0: Cancer not spread to other parts of the body
    		 127 109 115 120 471
        M1: Cancer has spread to other parts of the body
    		 26 34 34 36 130
    Histopathology type
    Units: Subjects
        Breast Invasive Ductal Carcinoma
    		 122 117 117 125 481
        Breast Invasive Lobular Carcinoma
    		 23 24 24 20 91
        Other
    		 3 1 4 8 16
        Not Available/ Not Done
    		 5 1 4 3 13
    Histologic grade
    Cancer cells are given a Grade (G) when they are removed from the breast and checked under a microscope. The G is based on how much the cancer cells look like normal cells. G1 or well differentiated (score 3, 4, or 5): cells are slower-growing, and look more like normal breast tissue. G2 or moderately differentiated (score 6, 7): cells are growing at a speed of and look like cells somewhere between G1 and 3. G3 or poorly differentiated (score 8, 9): cells look very different from normal and will probably grow and spread faster.
    Units: Subjects
        G1, Well Differentiated
    		 17 15 13 14 59
        G2, Moderately Differentiated
    		 68 57 70 72 267
        G3, Poorly Differentiated
    		 36 37 38 40 151
        GX, Unknown
    		 23 23 19 19 84
        Not Available/ Not Done
    		 9 11 9 11 40

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Arm A: Palbociclib Plus Exemestane
    Reporting group description
    		 Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Exemestane 25 mg orally once daily

    Reporting group title
    Cohort 1: Arm B: Capecitabine
    Reporting group description
    		 Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age.

    Reporting group title
    Cohort 2: Palbociclib Plus Fulvestrant
    Reporting group description
    		 Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.

    Reporting group title
    Cohort 2: Arm B: Capecitabine
    Reporting group description
    		 Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age

    Subject analysis set title
    Exemestane or Fulvestrant + Palbo ESR1 wild type population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The ESR1 wild type population will include all patients who are randomized, with study drug/medication assignment designated according to initial randomization and whose tumor had estrogen receptor (ESR1) mutational status as wild type at study entry. ESR1 wild type population include patients with ESR1 mutational status as wild type at study entry. • Exemestane or Fulvestrant plus Palbociclib ESR1 wild type population: Cohort 1 (n=153) of which ESR1 wild type (n=104) and cohort 2 (n=149) of which ESR1 wild type (n=102). Total ESR1 wild type 206 • Capecitabine ESR1 wild type population: Cohort 1 (n=143) of which ESR1 wild type (n=89) and cohort 2 (n=156) of which ESR1 wild type (n=98). Total ESR1 wild type 187

    Subject analysis set title
    Capecitabine ESR1 Wild Type Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The ESR1 wild type population will include all patients who are randomized, with study drug/medication assignment designated according to initial randomization and whose tumor had estrogen receptor (ESR1) mutational status as wild type at study entry. ESR1 wild type population include patients with ESR1 mutational status as wild type at study entry. • Exemestane or Fulvestrant plus Palbociclib ESR1 wild type population: Cohort 1 (n=153) of which ESR1 wild type (n=104) and cohort 2 (n=149) of which ESR1 wild type (n=102). Total ESR1 wild type 206 • Capecitabine ESR1 wild type population: Cohort 1 (n=143) of which ESR1 wild type (n=89) and cohort 2 (n=156) of which ESR1 wild type (n=98). Total ESR1 wild type 187

    Subject analysis set title
    Cohort 1 and 2: (Exemestane or Fulvestrant) Plus Palbociclib
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    • Cohort 1: Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Exemestane 25 mg orally once daily. • Cohort 2: Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle.

    Subject analysis set title
    Cohort 1 and 2: Capecitabine
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age.

    Subject analysis set title
    Cohort 1 & 2: (Exemestane or Fulvestrant) + Palbo & Cape
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    QoL population: a subset of enrolled patients with available QoL questionnaires (the baseline and at least one more). - Cohort 1: Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Exemestane 25 mg orally once daily. Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles. Capecitabine must be administered at a dose of 1,000 mg/m2 twice daily for 2 weeks followed by a 1 week of rest period, given as 3 weeks cycles, in patients over 70 years of age. - Cohort 2: Palbociclib 125 mg orally once daily on Day 1 to Day 21 followed by 7 days off treatment on every 28 days cycles in combination with Fulvestrant 500 mg on Days 1 and 15 of Cycle 1, and Day 1 of each subsequent 28 days Cycle. Capecitabine, 1,250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, given as 3 weeks cycles.

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS) [1]
    End point description
    The primary efficacy variable is PFS based on the investigator’s assessment. PFS is defined as the time from randomization to the first documented progressive disease based on the investigator’s assessment, using RECIST version 1.1, or death from any cause, whichever occurs first. Estrogen Receptor 1 (ESR1) mutational status will be determined in circulating free DNA (cDNA) obtained from. Disease assessments will be performed at baseline and every 8 weeks (± 7 days) from the start of treatment and every 12 weeks (±7 days) after 120 weeks of treatment baseline plasma samples and will be prospectively determined before the interims or final analyses. ESR1 mutational status will be blinded to the patients, investigators and study team.
    End point type
    Primary
    End point timeframe
    Through study treatment, and average of 8 months
    Notes
    [1] - 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: Primary objectives are to demonstrate that the combination of palbociclib-fulvestrant is superior to capecitabine in prolonging PFS and to demostrate that palbociclib in combination with endocrine therapy (exemestane or fulvestrant) is superior to capecitabine in prolonging PFS in wild type patients.
    End point values
    		 Cohort 2: Palbociclib Plus Fulvestrant Cohort 2: Arm B: Capecitabine Exemestane or Fulvestrant + Palbo ESR1 wild type population Capecitabine ESR1 Wild Type Population
    Number of subjects analysed
    149
    156
    206
    187
    Units: months
        median (confidence interval 95%)
    7.5 (5.7 to 10.9)
    10 (6.3 to 12.9)
    8 (6.5 to 10.9)
    10.6 (7.4 to 13)
    Statistical analysis title
    		 Progression-Free survival analysis Cohort 2
    Comparison groups
    Cohort 2: Palbociclib Plus Fulvestrant v Cohort 2: Arm B: Capecitabine
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.597
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.44
    Statistical analysis title
    		 Progression-Free survival analysis Wild type
    Comparison groups
    Exemestane or Fulvestrant + Palbo ESR1 wild type population v Capecitabine ESR1 Wild Type Population
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.421
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.36

    Secondary: Overall Survival (OS) ESR1 Wild Type

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    End point title
    		 Overall Survival (OS) ESR1 Wild Type
    End point description
    OS is defined as the time from the date of randomization to the date of death from any cause.
    End point type
    Secondary
    End point timeframe
    From randomization until death (up to approximately 34 months)
    End point values
    		 Exemestane or Fulvestrant + Palbo ESR1 wild type population Capecitabine ESR1 Wild Type Population
    Number of subjects analysed
    206
    187
    Units: months
        median (confidence interval 95%)
    33.7 (27.6 to 45.1)
    32 (28 to 46.9)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) ESR1 Wild Type

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    End point title
    		 Objective Response Rate (ORR) ESR1 Wild Type
    End point description
    Complete Response (CR) plus Partial Response (PR) based on the investigator’s assessment according to the RECIST version 1.1 in patients randomized with measurable disease. Tumor assessment will be performed at baseline, the same method of measurement used at baseline will be used for further evaluations, that will be conducted every 8 weeks (±7days). The best response across treatment will be recorded. OR is defined as the complete plus partial responses out of the patients who had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Through study treatment, and average of 8 months
    End point values
    		 Exemestane or Fulvestrant + Palbo ESR1 wild type population Capecitabine ESR1 Wild Type Population
    Number of subjects analysed
    206
    187
    Units: participants
    47
    55
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) ESR1 Wild Type

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    End point title
    		 Clinical Benefit Rate (CBR) ESR1 Wild Type
    End point description
    CB is defined as complete response (CR), partial response (PR), or stable disease (SD) based on the investigator´s assessment lasting more than 24 weeks according to the RECIST version 1.1 in all randomized patients (ITT population). Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.
    End point type
    Secondary
    End point timeframe
    Through study treatment, and average of 8 months
    End point values
    		 Exemestane or Fulvestrant + Palbo ESR1 wild type population Capecitabine ESR1 Wild Type Population
    Number of subjects analysed
    206
    187
    Units: participants
    157
    154
    No statistical analyses for this end point

    Secondary: Response Duration (RD) ESR1 Wild Type

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    End point title
    		 Response Duration (RD) ESR1 Wild Type
    End point description
    Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
    End point type
    Secondary
    End point timeframe
    Through study treatment, and average of 8 months
    End point values
    		 Exemestane or Fulvestrant + Palbo ESR1 wild type population Capecitabine ESR1 Wild Type Population
    Number of subjects analysed
    47
    55
    Units: months
        median (confidence interval 95%)
    9.7 (8.7 to 21.7)
    11.2 (7.2 to 17.3)
    No statistical analyses for this end point

    Secondary: Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores

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    End point title
    		 Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scale Scores
    End point description
    The EORTC QLQ C30 is a 30 item questionnaire composed of 5 multi item functional subscales (physical, role, cognitive emotional, and social functioning), 3 multi item symptom scales (fatigue, nausea/vomiting, pain), a global health/quality of life (QOL) subscale, and 6 items cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation, financial impact of cancer). The questionnaire employs 28 4 point Likert scales with responses from “not at all” to “very much” and 2 7 point Likert scales for global health and overall QOL. For functional and global QOL scales, higher scores represent a better level of functioning and are converted to a 0 to 100 scale. For symptom oriented scales, a higher score represents more severe symptoms. Patients completed EORTC QLQ-C30 (v3.0) at baseline, at every two cycles for the first seven cycles, then at every three cycles until the end of treatment, and once again at the visit after treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 and 2: (Exemestane or Fulvestrant) Plus Palbociclib Cohort 1 and 2: Capecitabine
    Number of subjects analysed
    268
    269
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Global health status / QoL
    3.28 (1.06 to 5.49)
    1.97 (-0.33 to 4.29)
        Physical functioning
    -1.73 (-3.94 to 0.48)
    -2.94 (-5.07 to -0.81)
        Role functioning
    -1.09 (-4.45 to 2.27)
    -4.97 (-7.82 to -2.12)
        Emotional functioning
    6.78 (3.67 to 9.88)
    8.67 (6.04 to 11.29)
        Cognitive functioning
    -2.18 (-4.91 to 0.54)
    -2.42 (-4.66 to -0.18)
        Social functioning
    -0.67 (-3.43 to 2.07)
    -3.01 (-5.45 to -0.56)
    No statistical analyses for this end point

    Secondary: Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores

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    End point title
    		 Change From Baseline Between Treatment Comparison in EORTC QLQ-C30 Symptom Scale Scores
    End point description
    The EORTC QLQ C30 is a 30 item questionnaire composed of 5 multi item functional subscales (physical, role, cognitive emotional, and social functioning), 3 multi item symptom scales (fatigue, nausea/vomiting, pain), a global health/quality of life (QOL) subscale, and 6 items cancer related symptoms (dyspnea, sleep disturbance, appetite, diarrhea, constipation, financial impact of cancer). The questionnaire employs 28 4 point Likert scales with responses from “not at all” to “very much” and 2 7 point Likert scales for global health and overall QOL. For functional and global QOL scales, higher scores represent a better level of functioning and are converted to a 0 to 100 scale. For symptom oriented scales, a higher score represents more severe symptoms. Patients completed EORTC QLQ-C30 (v3.0) at baseline, at every two cycles for the first seven cycles, then at every three cycles until the end of treatment, and once again at the visit after treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 and 2: (Exemestane or Fulvestrant) Plus Palbociclib Cohort 1 and 2: Capecitabine
    Number of subjects analysed
    268
    269
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Fatigue
    3.85 (0.82 to 6.88)
    5.79 (3.14 to 8.43)
        Nausea and vomiting
    1.65 (-0.02 to 3.33)
    1.45 (-0.07 to 2.98)
        Pain
    -1.79 (-4.86 to 1.27)
    -1.9 (-4.7 to 0.91)
        Dyspnoea
    2.73 (-0.64 to 6.11)
    -0.05 (-2.44 to 2.34)
        Insomnia
    -3.04 (-6.63 to 0.54)
    -5.94 (-8.92 to -2.97)
        Appetite loss
    2.99 (-0.3 to 6.3)
    1.04 (-1.57 to 3.65)
        Constipation
    3.91 (0.56 to 7.27)
    -1.45 (-4.10 to 1.19)
        Diarrhoea
    3.67 (1.06 to 6.29)
    6.73 (4.61 to 8.85)
        Financial difficulties
    -1.31 (-4.74 to 2.10)
    1.73 (-1.11 to 4.59)
    No statistical analyses for this end point

    Secondary: Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores

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    End point title
    		 Change From Baseline Between Treatment Comparison in European Organization for Research and Treatment of Cancer Breast Cancer Module (EORTC QLQ BR23) Functional Scale Scores
    End point description
    Patient reported outcomes of health related quality of life will be assessed using the breast modules (QLQ-BR23) instruments The EORTC QLQ BR23 is a 23 item breast cancer specific companion module to the EORTC QLQ C30 and consists of two functional scales (body image and sexuality); 3 symptom subscales (arm/hand, breast, and systemic side effects) and single items covering sexual enjoyment, distress at hair loss, and future perspective. Patients completed BC-specific EORTC QLQ-BR23 (v1.0) at baseline, at every two cycles for the first seven cycles, then at every three cycles until the end of treatment, and once again at the visit after treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 and 2: (Exemestane or Fulvestrant) Plus Palbociclib Cohort 1 and 2: Capecitabine
    Number of subjects analysed
    268
    269
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Body image
    -1.83 (-4.73 to 1.06)
    0.14 (-2.16 to 2.44)
        Sexual functioning
    2.94 (0.56 to 5.31)
    1.72 (-0.37 to 3.81)
        Sexual enjoyment
    -6.32 (-11.86 to -0.78)
    -4.32 (-9.25 to 0.6)
        Future perspective
    13.8 (9.61 to 17.99)
    15.22 (11.66 to 18.78)
    No statistical analyses for this end point

    Secondary: Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores

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    End point title
    		 Change From Baseline Between Treatment Comparison in EORTC QLQ BR23 Symptom Scale Scores
    End point description
    Patient reported outcomes of health related quality of life will be assessed using the breast modules (QLQ-BR23) instruments The EORTC QLQ BR23 is a 23 item breast cancer specific companion module to the EORTC QLQ C30 and consists of two functional scales (body image and sexuality); 3 symptom subscales (arm/hand, breast, and systemic side effects) and single items covering sexual enjoyment, distress at hair loss, and future perspective. Patients completed BC-specific EORTC QLQ-BR23 (v1.0) at baseline, at every two cycles for the first seven cycles, then at every three cycles until the end of treatment, and once again at the visit after treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 and 2: (Exemestane or Fulvestrant) Plus Palbociclib Cohort 1 and 2: Capecitabine
    Number of subjects analysed
    268
    269
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Systemic therapy side effects
    5.61 (3.29 to 7.94)
    4.49 (2.88 to 6.10)
        Breast symptoms
    -0.42 (-2.31 to 1.46)
    -2.0 (-3.46 to -0.53)
        Arm symptoms
    -2.26 (-4.44 to -0.08)
    -2.09 (-4.02 to -0.15)
        Upset by hair loss
    8.35 (2.25 to 14.45)
    -1.96 (-7.53 to 3.6)
    No statistical analyses for this end point

    Secondary: Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index Scores

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    End point title
    		 Change From Baseline Between Treatment Comparison in EuroQoL 5D (EQ-5D) Health Index Scores
    End point description
    EQ 5D (version 3L) is a 6 item instrument which assess health status in terms of a single index value. It consists of 5 descriptors of current health state (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression); a patient is asked to rate each state on a 3 level scale (1=no problem, 2=some problem, and 3=extreme problem) with higher levels indicating greater severity/impairment. It also includes a visual analogue scale, EQ VAS, which records patient’s self-rated health on a scale from 0 (worst imaginable) to 100 (best imaginable). Published weights are available that allow for the creation of a single summary score. Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction and 1 as perfect health. EQ 5D questionnaires were completed at baseline, at every two cycles for the first seven cycles, then at every three cycles until the end of treatment, and once again at the visit after treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 and 2: (Exemestane or Fulvestrant) Plus Palbociclib Cohort 1 and 2: Capecitabine
    Number of subjects analysed
    268
    269
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    0.72 (0.69 to 0.74)
    0.71 (0.69 to 0.73)
    No statistical analyses for this end point

    Secondary: Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale

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    End point title
    		 Change From Baseline Between Treatment Comparison in EQ-5D Visual Analog Scale (VAS) Scores Scale
    End point description
    The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 and 2: (Exemestane or Fulvestrant) Plus Palbociclib Cohort 1 and 2: Capecitabine
    Number of subjects analysed
    268
    269
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    67.1 (65.3 to 69)
    66.6 (64.9 to 68.2)
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale

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    End point title
    		 Time to Deterioration (TTD) in EORTC QLQ-C30 Functional Scale
    End point description
    Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration for each EORTC QLQ-C30 subscales, the global health status/QOL score, and for each QLQ-BR23 score [(date of first detection of deterioration – date of randomization + 1). Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for EORTC QLQ-C30 symptom scores and QLQ-BR23 score and as a change from baseline ≤ -MID for EORTC QLQ-C30 functional scales, global health status/QOL score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 & 2: (Exemestane or Fulvestrant) + Palbo & Cape
    Number of subjects analysed
    537
    Units: Hazard ratio
    number (confidence interval 95%)
        Physical functioning
    0.62 (0.5 to 0.7)
        Role functioning
    0.63 (0.51 to 0.79)
        Emotional functioning
    0.97 (0.76 to 1.25)
        Cognitive functioning
    0.7 (0.54 to 0.89)
        Social functioning
    0.62 (0.49 to 0.78)
        Global health status/quality of life
    0.7 (0.55 to 0.89)
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale

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    End point title
    		 Time to Deterioration (TTD) in EORTC QLQ-C30 Symptom Scale
    End point description
    Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration for each EORTC QLQ-C30 subscales, the global health status/QOL score, and for each QLQ-BR23 score [(date of first detection of deterioration – date of randomization + 1). Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for EORTC QLQ-C30 symptom scores and QLQ-BR23 score and as a change from baseline ≤ -MID for EORTC QLQ-C30 functional scales, global health status/QOL score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 & 2: (Exemestane or Fulvestrant) + Palbo & Cape
    Number of subjects analysed
    537
    Units: Hazard ratio
    number (confidence interval 95%)
        Fatigue
    0.7 (0.57 to 0.86)
        Nausea and vomiting
    0.58 (0.45 to 0.76)
        Pain
    0.78 (0.62 to 0.99)
        Dyspnea
    1.08 (0.81 to 1.44)
        Insomnia
    0.84 (0.64 to 1.1)
        Appetite loss
    0.71 (0.54 to 0.92)
        Constipation
    1.08 (0.83 to 1.41)
        Diarrhea
    0.42 (0.32 to 0.55)
        Financial difficulties
    0.78 (0.56 to 1.07)
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale

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    End point title
    		 Time to Deterioration (TTD) in EORTC QLQ-BR23 Functional Scale
    End point description
    Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration for each EORTC QLQ-C30 subscales, the global health status/QOL score, and for each QLQ-BR23 score [(date of first detection of deterioration – date of randomization + 1). Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for EORTC QLQ-C30 symptom scores and QLQ-BR23 score and as a change from baseline ≤ -MID for EORTC QLQ-C30 functional scales, global health status/QOL score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 & 2: (Exemestane or Fulvestrant) + Palbo & Cape
    Number of subjects analysed
    537
    Units: Hazard ratio
    number (confidence interval 95%)
        Body image
    0.95 (0.74 to 1.21)
        Sexual functioning
    0.8 (0.54 to 1.18)
        Sexual enjoyment
    1.53 (0.91 to 2.55)
        Future perspective
    1.01 (0.74 to 1.39)
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale

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    End point title
    		 Time to Deterioration (TTD) in EORTC QLQ-BR23 Symptom Scale
    End point description
    Time to deterioration is defined as the time from the date of randomization to the date of first detection of deterioration for each EORTC QLQ-C30 subscales, the global health status/QOL score, and for each QLQ-BR23 score [(date of first detection of deterioration – date of randomization + 1). Deterioration is defined as a change from baseline ≥ minimally important difference (MID) for EORTC QLQ-C30 symptom scores and QLQ-BR23 score and as a change from baseline ≤ -MID for EORTC QLQ-C30 functional scales, global health status/QOL score. Patients without deterioration have been censored at their last quality of life assessment. For patients with no post-baseline assessment time to deterioration have been censored at Day 1
    End point type
    Secondary
    End point timeframe
    Baseline, cycles 3, 5, 7, then at every three cycles until the end of treatment, and at the visit after treatment
    End point values
    		 Cohort 1 & 2: (Exemestane or Fulvestrant) + Palbo & Cape
    Number of subjects analysed
    537
    Units: Hazard ratio
    number (confidence interval 95%)
        Upset by hair loss
    1.33 (0.83 to 2.15)
        Systemic side-effects
    0.79 (0.64 to 0.98)
        Breast symptoms
    0.93 (0.71 to 1.21)
        Arm symptoms
    0.84 (0.66 to 1.09)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Through study treatment, an average of 8 months
    Adverse event reporting additional description
    AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Cohort 1: Palbociclib Plus Exemestane
    Reporting group description
    		 -

    Reporting group title
    Cohort 2: Palbociclib Plus Fulvestrant
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 and 2: Capecitabine
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort 1: Palbociclib Plus Exemestane Cohort 2: Palbociclib Plus Fulvestrant Cohort 1 and 2: Capecitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 150 (26.67%)
    31 / 149 (20.81%)
    104 / 289 (35.99%)
         number of deaths (all causes)
    85
    43
    116
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    5 / 150 (3.33%)
    3 / 149 (2.01%)
    3 / 289 (1.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    0 / 3
    Malignant melanoma
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    2 / 289 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 149 (0.67%)
    3 / 289 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    2 / 289 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Mastitis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophorectomy bilateral
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 150 (2.00%)
    1 / 149 (0.67%)
    6 / 289 (2.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    6 / 289 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hypokalaemia
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 149 (0.67%)
    2 / 289 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    2 / 289 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haematoma
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 149 (0.00%)
    3 / 289 (1.04%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    3 / 289 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Diarrhoea
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 149 (0.67%)
    17 / 289 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    18 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Diverticulitis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    2 / 289 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 149 (0.67%)
    4 / 289 (1.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    2 / 289 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    2 / 289 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 150 (0.67%)
    2 / 149 (1.34%)
    1 / 289 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 150 (1.33%)
    1 / 149 (0.67%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 150 (1.33%)
    2 / 149 (1.34%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 149 (0.00%)
    0 / 289 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Palbociclib Plus Exemestane Cohort 2: Palbociclib Plus Fulvestrant Cohort 1 and 2: Capecitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    149 / 150 (99.33%)
    149 / 149 (100.00%)
    283 / 289 (97.92%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    52 / 150 (34.67%)
    58 / 149 (38.93%)
    114 / 289 (39.45%)
         occurrences all number
    123
    145
    299
    Hot flashes
         subjects affected / exposed
    15 / 150 (10.00%)
    10 / 149 (6.71%)
    2 / 289 (0.69%)
         occurrences all number
    16
    16
    2
    Thromboembolic event
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    17 / 289 (5.88%)
         occurrences all number
    0
    0
    19
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    84 / 150 (56.00%)
    80 / 149 (53.69%)
    170 / 289 (58.82%)
         occurrences all number
    143
    168
    414
    Hypothermia
         subjects affected / exposed
    28 / 150 (18.67%)
    22 / 149 (14.77%)
    46 / 289 (15.92%)
         occurrences all number
    47
    72
    86
    Fever
         subjects affected / exposed
    15 / 150 (10.00%)
    12 / 149 (8.05%)
    30 / 289 (10.38%)
         occurrences all number
    22
    16
    37
    Flu like symptoms
         subjects affected / exposed
    15 / 150 (10.00%)
    16 / 149 (10.74%)
    22 / 289 (7.61%)
         occurrences all number
    21
    18
    29
    Pain
         subjects affected / exposed
    15 / 150 (10.00%)
    10 / 149 (6.71%)
    18 / 289 (6.23%)
         occurrences all number
    19
    10
    22
    Edema limbs
         subjects affected / exposed
    10 / 150 (6.67%)
    9 / 149 (6.04%)
    13 / 289 (4.50%)
         occurrences all number
    12
    11
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 150 (14.00%)
    17 / 149 (11.41%)
    26 / 289 (9.00%)
         occurrences all number
    32
    19
    35
    Dyspnea
         subjects affected / exposed
    8 / 150 (5.33%)
    16 / 149 (10.74%)
    24 / 289 (8.30%)
         occurrences all number
    9
    17
    34
    Epistaxis
         subjects affected / exposed
    9 / 150 (6.00%)
    3 / 149 (2.01%)
    12 / 289 (4.15%)
         occurrences all number
    10
    3
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 150 (9.33%)
    8 / 149 (5.37%)
    23 / 289 (7.96%)
         occurrences all number
    16
    8
    25
    Anxiety
         subjects affected / exposed
    13 / 150 (8.67%)
    8 / 149 (5.37%)
    15 / 289 (5.19%)
         occurrences all number
    18
    10
    20
    Investigations
    Weight loss
         subjects affected / exposed
    31 / 150 (20.67%)
    38 / 149 (25.50%)
    79 / 289 (27.34%)
         occurrences all number
    52
    65
    145
    Weight gain
         subjects affected / exposed
    33 / 150 (22.00%)
    28 / 149 (18.79%)
    78 / 289 (26.99%)
         occurrences all number
    70
    61
    161
    White blood cell decreased
         subjects affected / exposed
    146 / 150 (97.33%)
    141 / 149 (94.63%)
    129 / 289 (44.64%)
         occurrences all number
    2001
    1951
    772
    Neutrophil count decreased
         subjects affected / exposed
    142 / 150 (94.67%)
    140 / 149 (93.96%)
    102 / 289 (35.29%)
         occurrences all number
    1899
    1878
    692
    Aspartate aminotransferase increased
         subjects affected / exposed
    65 / 150 (43.33%)
    84 / 149 (56.38%)
    174 / 289 (60.21%)
         occurrences all number
    210
    281
    820
    Alkaline phosphatase increased
         subjects affected / exposed
    45 / 150 (30.00%)
    65 / 149 (43.62%)
    185 / 289 (64.01%)
         occurrences all number
    190
    391
    1359
    Alanine aminotransferase increased
         subjects affected / exposed
    54 / 150 (36.00%)
    58 / 149 (38.93%)
    140 / 289 (48.44%)
         occurrences all number
    15
    166
    580
    Platelet count decreased
         subjects affected / exposed
    72 / 150 (48.00%)
    80 / 149 (53.69%)
    87 / 289 (30.10%)
         occurrences all number
    427
    466
    415
    Creatinine increased
         subjects affected / exposed
    37 / 150 (24.67%)
    42 / 149 (28.19%)
    57 / 289 (19.72%)
         occurrences all number
    162
    245
    345
    Blood bilirubin increased
         subjects affected / exposed
    10 / 150 (6.67%)
    14 / 149 (9.40%)
    84 / 289 (29.07%)
         occurrences all number
    38
    33
    497
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 150 (16.67%)
    29 / 149 (19.46%)
    39 / 289 (13.49%)
         occurrences all number
    35
    45
    70
    Dizziness
         subjects affected / exposed
    12 / 150 (8.00%)
    12 / 149 (8.05%)
    42 / 289 (14.53%)
         occurrences all number
    17
    12
    58
    Dysgeusia
         subjects affected / exposed
    9 / 150 (6.00%)
    7 / 149 (4.70%)
    29 / 289 (10.03%)
         occurrences all number
    10
    7
    33
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    112 / 150 (74.67%)
    123 / 149 (82.55%)
    178 / 289 (61.59%)
         occurrences all number
    1149
    1355
    1289
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    17 / 150 (11.33%)
    12 / 149 (8.05%)
    59 / 289 (20.42%)
         occurrences all number
    30
    19
    84
    Watering eyes
         subjects affected / exposed
    8 / 150 (5.33%)
    5 / 149 (3.36%)
    22 / 289 (7.61%)
         occurrences all number
    11
    7
    30
    Dry eye
         subjects affected / exposed
    5 / 150 (3.33%)
    4 / 149 (2.68%)
    20 / 289 (6.92%)
         occurrences all number
    8
    6
    22
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    30 / 150 (20.00%)
    31 / 149 (20.81%)
    161 / 289 (55.71%)
         occurrences all number
    58
    62
    416
    Nausea
         subjects affected / exposed
    35 / 150 (23.33%)
    39 / 149 (26.17%)
    112 / 289 (38.75%)
         occurrences all number
    53
    62
    186
    Mucositis oral
         subjects affected / exposed
    39 / 150 (26.00%)
    24 / 149 (16.11%)
    85 / 289 (29.41%)
         occurrences all number
    82
    50
    133
    Vomiting
         subjects affected / exposed
    27 / 150 (18.00%)
    23 / 149 (15.44%)
    85 / 289 (29.41%)
         occurrences all number
    49
    30
    130
    Constipation
         subjects affected / exposed
    23 / 150 (15.33%)
    17 / 149 (11.41%)
    42 / 289 (14.53%)
         occurrences all number
    27
    19
    56
    Abdominal pain
         subjects affected / exposed
    19 / 150 (12.67%)
    6 / 149 (4.03%)
    44 / 289 (15.22%)
         occurrences all number
    22
    8
    74
    Dyspepsia
         subjects affected / exposed
    18 / 150 (12.00%)
    11 / 149 (7.38%)
    32 / 289 (11.07%)
         occurrences all number
    21
    18
    38
    Dry mouth
         subjects affected / exposed
    8 / 150 (5.33%)
    7 / 149 (4.70%)
    23 / 289 (7.96%)
         occurrences all number
    14
    9
    28
    Gastrointestinal pain
         subjects affected / exposed
    8 / 150 (5.33%)
    7 / 149 (4.70%)
    19 / 289 (6.57%)
         occurrences all number
    12
    8
    28
    Sore throat
         subjects affected / exposed
    8 / 150 (5.33%)
    4 / 149 (2.68%)
    7 / 289 (2.42%)
         occurrences all number
    10
    5
    7
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    8 / 150 (5.33%)
    2 / 149 (1.34%)
    211 / 289 (73.01%)
         occurrences all number
    13
    2
    939
    Pruritus
         subjects affected / exposed
    23 / 150 (15.33%)
    12 / 149 (8.05%)
    25 / 289 (8.65%)
         occurrences all number
    31
    25
    30
    Alopecia
         subjects affected / exposed
    15 / 150 (10.00%)
    21 / 149 (14.09%)
    11 / 289 (3.81%)
         occurrences all number
    16
    29
    11
    Dry skin
         subjects affected / exposed
    9 / 150 (6.00%)
    8 / 149 (5.37%)
    20 / 289 (6.92%)
         occurrences all number
    11
    8
    25
    Nail disorder
         subjects affected / exposed
    4 / 150 (2.67%)
    3 / 149 (2.01%)
    24 / 289 (8.30%)
         occurrences all number
    4
    4
    54
    Rash and other skin disorders
         subjects affected / exposed
    8 / 150 (5.33%)
    5 / 149 (3.36%)
    5 / 289 (1.73%)
         occurrences all number
    13
    8
    8
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    16 / 289 (5.54%)
         occurrences all number
    0
    0
    21
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    25 / 150 (16.67%)
    31 / 149 (20.81%)
    51 / 289 (17.65%)
         occurrences all number
    32
    46
    69
    Arthralgia
         subjects affected / exposed
    31 / 150 (20.67%)
    22 / 149 (14.77%)
    34 / 289 (11.76%)
         occurrences all number
    49
    30
    44
    Bone pain
         subjects affected / exposed
    18 / 150 (12.00%)
    13 / 149 (8.72%)
    28 / 289 (9.69%)
         occurrences all number
    27
    14
    37
    Pain in extremity
         subjects affected / exposed
    12 / 150 (8.00%)
    15 / 149 (10.07%)
    29 / 289 (10.03%)
         occurrences all number
    22
    17
    38
    Myalgia
         subjects affected / exposed
    12 / 150 (8.00%)
    7 / 149 (4.70%)
    12 / 289 (4.15%)
         occurrences all number
    15
    10
    13
    Infections and infestations
    Upper respiratory infection
         subjects affected / exposed
    28 / 150 (18.67%)
    20 / 149 (13.42%)
    41 / 289 (14.19%)
         occurrences all number
    44
    25
    52
    Chills
         subjects affected / exposed
    10 / 150 (6.67%)
    14 / 149 (9.40%)
    17 / 289 (5.88%)
         occurrences all number
    13
    15
    19
    Urinary tract infection
         subjects affected / exposed
    10 / 150 (6.67%)
    7 / 149 (4.70%)
    10 / 289 (3.46%)
         occurrences all number
    11
    8
    13
    Paronychia
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 149 (0.00%)
    17 / 289 (5.88%)
         occurrences all number
    0
    0
    39
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    23 / 150 (15.33%)
    19 / 149 (12.75%)
    68 / 289 (23.53%)
         occurrences all number
    34
    27
    86
    Obesity
         subjects affected / exposed
    14 / 150 (9.33%)
    16 / 149 (10.74%)
    28 / 289 (9.69%)
         occurrences all number
    24
    22
    43
    Hyperglycemia
         subjects affected / exposed
    71 / 150 (47.33%)
    81 / 149 (54.36%)
    158 / 289 (54.67%)
         occurrences all number
    575
    522
    1092
    Hyperkalemia
         subjects affected / exposed
    29 / 150 (19.33%)
    29 / 149 (19.46%)
    55 / 289 (19.03%)
         occurrences all number
    68
    62
    117
    Hypercalcemia
         subjects affected / exposed
    22 / 150 (14.67%)
    27 / 149 (18.12%)
    59 / 289 (20.42%)
         occurrences all number
    38
    86
    229
    Hypocalcemia
         subjects affected / exposed
    20 / 150 (13.33%)
    30 / 149 (20.13%)
    52 / 289 (17.99%)
         occurrences all number
    49
    101
    187
    Hypomagnesemia
         subjects affected / exposed
    25 / 150 (16.67%)
    28 / 149 (18.79%)
    43 / 289 (14.88%)
         occurrences all number
    88
    160
    181
    Hyponatremia
         subjects affected / exposed
    15 / 150 (10.00%)
    26 / 149 (17.45%)
    49 / 289 (16.96%)
         occurrences all number
    19
    125
    95
    Hypokalemia
         subjects affected / exposed
    17 / 150 (11.33%)
    14 / 149 (9.40%)
    49 / 289 (16.96%)
         occurrences all number
    57
    20
    176
    Hypoalbuminemia
         subjects affected / exposed
    8 / 150 (5.33%)
    29 / 149 (19.46%)
    40 / 289 (13.84%)
         occurrences all number
    13
    97
    146
    Hypernatremia
         subjects affected / exposed
    20 / 150 (13.33%)
    14 / 149 (9.40%)
    34 / 289 (11.76%)
         occurrences all number
    39
    34
    92
    Hypermagnesemia
         subjects affected / exposed
    7 / 150 (4.67%)
    14 / 149 (9.40%)
    33 / 289 (11.42%)
         occurrences all number
    28
    20
    85
    Hypoglycemia
         subjects affected / exposed
    11 / 150 (7.33%)
    10 / 149 (6.71%)
    20 / 289 (6.92%)
         occurrences all number
    29
    14
    50

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2013
    Update on the number of plasma samples needed for exploratory analyses
    19 Feb 2014
    Modify the eligibility criteria. New instructions about palbociclib administration and change information about the prohibited concomitant medication
    02 Mar 2014
    Clarify the eligiblity criteria and the stratification factors.
    09 Mar 2016
    The design of the study is modified to include a new Cohort in order to provide the opportunity to confirm the clinical benefit of PAL in combination with ET in relation to ESR1 mutational status. The study objectives, the eligibility criteria and the sample size were changed according to the new study design.
    12 Jul 2017
    Modify the eligibility criteria. Add the collection of the new biological samples. Clarify the dose modification of capecitabine in case of non-haematologic toxicities. Update the list of “List of Drugs Known to Predispose to Torsade de Pointes”.
    24 Aug 2018
    Clarify palbociclib and capecitabine dose modifications. Modify the mandatory assessments. Modify the eligibility criteria.
    05 Nov 2019
    Include the guidance for the clinical management of Interstitial Lung Disease (ILD)/ pneumonitis according to palbociclib IB v Jun2019

    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.
    1. capecitabine outcome was better than initially anticipated 2. open-label study design may lead to biased interpretations 3. subtype classification for exploratory objective was carried out in 70% of patients in the primary tumour

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33385521
    http://www.ncbi.nlm.nih.gov/pubmed/34425406
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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