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    Clinical Trial Results:
    A Randomized, Multicenter, Double Blind Phase 3 Study of PD 0332991 (Oral CDK 4/6 Inhibitor) Plus Letrozole Versus Placebo Plus Letrozole for the Treatment of Postmenopausal Women With ER (+), HER2 (-) Breast Cancer Who Have Not Received Any Prior Systemic Anti Cancer Treatment for Advanced Disease

    Summary
    EudraCT number
    2012-004601-27
    Trial protocol
    DE   BE   IE   FR   GB   ES   HU   IT   PL  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Dec 2016
    First version publication date
    16 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A5481008
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01740427
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    26 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the combination of palbociclib with letrozole is superior to placebo plus letrozole in prolonging progression-free survival (PFS) in postmenopausal women with ER-positive/HER2-negative ABC who have not received any prior systemic anti cancer therapies for their advanced/metastatic disease.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines . In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of study participants.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Feb 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    46 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Belgium: 28
    Country: Number of subjects enrolled
    Canada: 70
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Ireland: 22
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Japan: 46
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 24
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Spain: 57
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Ukraine: 39
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 197
    Worldwide total number of subjects
    666
    EEA total number of subjects
    208
    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)
    404
    From 65 to 84 years
    262
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Between 28 February 2013 and 29 July 2014, 666 women were randomized at 186 sites in 17 countries.

    Pre-assignment
    Screening details
    The study consisted of a screening visit within 28 days before randomization, an active treatment phase, divided in cycles of 28 days each, and a post-treatment follow-up period during which survival and new anti-cancer therapy information was collected every 6 months (±7 days) from the last dose of study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Palbociclib plus Letrozole
    Arm description
    Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Palbociclib
    Investigational medicinal product code
    PD-0332991
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Palbociclib was supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of palbociclib free base

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg, orally once daily

    Arm title
    Placebo plus Letrozole
    Arm description
    Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.
    Arm type
    Control

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was supplied as capsules containing 75 mg, 100 mg, or 125 mg equivalents of placebo free base

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg, orally once daily

    Number of subjects in period 1
    Palbociclib plus Letrozole Placebo plus Letrozole
    Started
    444
    222
    Completed
    0
    0
    Not completed
    444
    222
         Global deterioration of health status
    16
    9
         Protocol deviation
    5
    3
         Ongoing at date of cutoff (26 Feb 2016)
    205
    61
         Adverse event, serious fatal
    6
    2
         Objective progression or relapse
    172
    125
         Adverse event, non-fatal
    20
    9
         Study terminated by Sponsor
    1
    -
         Other reasons
    6
    4
         Subject refused continued treatment
    12
    9
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Palbociclib plus Letrozole
    Reporting group description
    Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Reporting group title
    Placebo plus Letrozole
    Reporting group description
    Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Reporting group values
    Palbociclib plus Letrozole Placebo plus Letrozole Total
    Number of subjects
    444 222 666
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    263 141 404
        From 65-84 years
    181 81 262
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    61.7 ± 10.6 60.6 ± 11.2 -
    Gender, Male/Female
    Units: participants
        Female
    444 222 666
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Palbociclib plus Letrozole
    Reporting group description
    Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Reporting group title
    Placebo plus Letrozole
    Reporting group description
    Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Subject analysis set title
    Palbociclib plus Letrozole
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD or 21 days of every-28-day cycle, followed by 7 days off treatment.

    Subject analysis set title
    Placebo plus Letrozole
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle,followed by 7 days off treatment.

    Primary: Progression-Free Survival (PFS) as assessed by the Investigator.

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    End point title
    Progression-Free Survival (PFS) as assessed by the Investigator.
    End point description
    PFS is defined as the time from the date of randomization to the date of the first documentation of objective tumor progression as per RECIST v.1.1 or death due to any cause in the absence of documented PD, whichever occurs first. If tumor progression data include more than 1 date, the first date will be used. PFS (in months) will be calculated as (first event date − randomization date +1)/30.4.
    End point type
    Primary
    End point timeframe
    From randomization date to date of first documentation of progression OR death (up to approximately 2.5 years)
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Months
        median (confidence interval 95%)
    24.8 (22.1 to 99999)
    14.5 (12.9 to 17.1)
    Statistical analysis title
    Statistical Analysis for PFS
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.000001 [1]
    Method
    Stratified Log Rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.576
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.463
         upper limit
    0.718
    Notes
    [1] - 1-sided p-value from the stratified log-rank test.

    Secondary: Objective Response as assessed by the Investigator

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    End point title
    Objective Response as assessed by the Investigator
    End point description
    Objective Response (OR) is defined as the overall complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Objective Response Rate (ORR) is defined as the proportion of participants with CR or PR relative to all randomized patients and randomized patients with measurable disease at baseline. Patients who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR.
    End point type
    Secondary
    End point timeframe
    From randomization until end of treatment (up to approximately 2.5 years)
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Percentage of participants
        number (confidence interval 95%)
    46.4 (41.7 to 51.2)
    38.3 (31.9 to 45)
    Statistical analysis title
    Statistical Analysis for OR
    Statistical analysis description
    Stratified analysis: Stratified by disease site (visceral vs non-visceral) per randomization.
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0224 [2]
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.428
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.008
         upper limit
    2.03
    Notes
    [2] - 1-sided p-value is from exact test.

    Secondary: Objective Response: Patients with measurable disease at baseline as assessed by the Investigator

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    End point title
    Objective Response: Patients with measurable disease at baseline as assessed by the Investigator
    End point description
    Objective Response (OR) is defined as the overall complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Objective Response Rate (ORR) is defined as the proportion of participants with CR or PR relative to all randomized patients and randomized patients with measurable disease at baseline. Patients who do not have on-study radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or who died, progressed, or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR.
    End point type
    Secondary
    End point timeframe
    From randomization until end of treatment (up to approximately 2.5 years)
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    338
    171
    Units: Percentage of participants
        number (confidence interval 95%)
    60.7 (55.2 to 65.9)
    49.1 (41.4 to 56.9)
    Statistical analysis title
    Statistical Analysis for OR
    Statistical analysis description
    Stratified analysis: Stratified by disease site (visceral vs non-visceral) per randomization.
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    509
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.009 [3]
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.594
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    2.347
    Notes
    [3] - 1-sided p-value is from exact test.

    Secondary: Duration of Response (DR)

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    End point title
    Duration of Response (DR)
    End point description
    DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first. If tumor progression data included more than 1 date, the first date will be used. DR was calculated as [the date response ended (i.e. date of PD or death) – first CR or PR date + 1)]/30.4. DR would only be calculated for the subgroup of patients with an objective tumor response.
    End point type
    Secondary
    End point timeframe
    From randomization until end of treatment (up to approximately 2.5 years)
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    206
    85
    Units: Months
        median (confidence interval 95%)
    20.1 (19.3 to 28)
    16.7 (13.8 to 22.5)
    No statistical analyses for this end point

    Secondary: Disease Control (DC)/Clinical Benefit Response (CBR)

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    End point title
    Disease Control (DC)/Clinical Benefit Response (CBR)
    End point description
    DC is defined as the overall CR, PR, or stable disease (SD) ≥24 weeks according to the RECIST version 1.1; Appendix 1. Disease Control Rate (DCR) is defined as the proportion of participants with CR, PR, or SD ≥24 weeks relative to all randomized participants. Designation of best response of SD ≥24 weeks required the criteria to be met at least 24 weeks after randomization. Participants who do not have on-study radiographic tumor reevaluation, who received anti-tumor treatment other than the study medication prior to reaching a CR or PR, a best response of SD≥24 weeks, or who died, progressed, or dropped out for any reason prior to achieving reaching a CR or PR and a best response of SD ≥24 weeks was counted as non-responders in the assessment of DCR.
    End point type
    Secondary
    End point timeframe
    From randomization until end of treatment (up to approximately 2.5 years)
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Percentage of participants
        number (confidence interval 95%)
    85.8 (82.2 to 88.9)
    71.2 (64.7 to 77)
    Statistical analysis title
    Statistical Analysis for DC/CBR
    Statistical analysis description
    Stratified analysis: Stratified by disease site (visceral, non-visceral) per randomization.
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.451
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.619
         upper limit
    3.722
    Notes
    [4] - 1-sided p-value is from exact test.

    Secondary: Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1, CDKN2A), proteins (eg, Ki67, pRb), and RNA expression (eg, cdk4, cdk6): Protein biomarker analyses by using immunohistochemistry are presented

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    End point title
    Tumor tissue biomarkers, including genes (eg, copy numbers of CCND1, CDKN2A), proteins (eg, Ki67, pRb), and RNA expression (eg, cdk4, cdk6): Protein biomarker analyses by using immunohistochemistry are presented
    End point description
    PFS survival by biomarker status by Investigator assessment. Positive is defined as H-Score ≥1 and negative as H-Score <1. H-Score is calculated as the sum of the % of cells at each level of staining intensity (0, 1+, 2+, and 3+) multiplied by the staining intensity value: H-Score = (% at 0)*0 + (% at 1+)*1 + (% at 2+)*2 + (% at 3+)*3. H-Score values range from 0 to 300. ER stands for estrogen receptor and Rb stands for retinoblastoma susceptibility gene product.
    End point type
    Secondary
    End point timeframe
    From randomization until end of treatment (up to approximately 24 Months)
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Months
    median (confidence interval 95%)
        ER Positive (N= 338, 166)
    24.9 (22.2 to 99999)
    16.3 (12.9 to 19.1)
        ER Negative (N= 40, 22)
    15.6 (8.3 to 22)
    5.4 (2.7 to 11.1)
        Rb Positive (N= 345, 167)
    24.2 (21.4 to 25.7)
    13.7 (11 to 16.5)
        Rb Negative (N= 29, 22)
    99999 (11.4 to 99999)
    18.5 (2.9 to 99999)
        Cyclin D1 Positive (N= 370, 179)
    24.8 (21.5 to 27.6)
    13.8 (11.3 to 16.8)
        Cyclin D1 Negative (N= 5, 10)
    11.1 (2.2 to 23.9)
    8.1 (0.4 to 99999)
        p16 Positive (N= 305, 161)
    24.8 (21.5 to 99999)
    13.8 (11.1 to 16.8)
        p16 Negative (N= 59, 25)
    16.8 (11.1 to 24.9)
    13.8 (8.1 to 99999)
        p16 H-Score<175 (N= 341, 177)
    23.7 (19.6 to 25.7)
    13.8 (11.2 to 16.8)
        p16 H-Score≥175 (N= 23, 9)
    24.2 (11.1 to 99999)
    5.6 (1.5 to 19.1)
        Ki67 ≤20% (N= 216, 102)
    27.6 (24.2 to 99999)
    16.8 (13.7 to 22)
        Ki67 >20% (N= 152, 83)
    17.5 (13.8 to 22)
    8.4 (5.6 to 13.6)
    Statistical analysis title
    Statistical analysis for ER positive
    Statistical analysis description
    Statistical analysis for ER positive
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.571
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.443
         upper limit
    0.737
    Statistical analysis title
    Statistical analysis for ER Negative
    Statistical analysis description
    Statistical analysis for ER Negative
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.405
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.218
         upper limit
    0.751
    Statistical analysis title
    Statistical analysis for Rb Positive
    Statistical analysis description
    Statistical analysis for Rb Positive
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.531
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.416
         upper limit
    0.68
    Statistical analysis title
    Statistical analysis for Rb Negative
    Statistical analysis description
    Statistical analysis for Rb Negative
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3237
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.675
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.308
         upper limit
    1.481
    Statistical analysis title
    Statistical analysis for Cyclin D1 Positive
    Statistical analysis description
    Statistical analysis for Cyclin D1 Positive
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.555
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.437
         upper limit
    0.705
    Statistical analysis title
    Statistical analysis for Cyclin D1 Negative
    Statistical analysis description
    Statistical analysis for Cyclin D1 Negative
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9964
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.997
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.287
         upper limit
    3.461
    Statistical analysis title
    Statistical analysis for p16 Positive
    Statistical analysis description
    Statistical analysis for p16 Positive
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.518
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.67
    Statistical analysis title
    Statistical analysis for p16 Negative
    Statistical analysis description
    Statistical analysis for p16 Negative
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3221
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.731
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.392
         upper limit
    1.364
    Statistical analysis title
    Statistical analysis for p16 HScore<175
    Statistical analysis description
    Statistical analysis for p16 HScore<175
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.581
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.455
         upper limit
    0.742
    Statistical analysis title
    Statistical analysis for p16 HScore≥175
    Statistical analysis description
    Statistical analysis for p16 HScore≥175
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0022
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.255
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.65
    Statistical analysis title
    Statistical analysis for Ki67 ≤20%
    Statistical analysis description
    Statistical analysis for Ki67 ≤20%
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.379
         upper limit
    0.742
    Statistical analysis title
    Statistical analysis for Ki67 >20%
    Statistical analysis description
    Statistical analysis for Ki67 >20%
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    Unstratified log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.569
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.409
         upper limit
    0.791

    Secondary: Corrected QT interval (QTc) time-matched change from baseline on Cycle 1 Day 14

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    End point title
    Corrected QT interval (QTc) time-matched change from baseline on Cycle 1 Day 14
    End point description
    Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and sent to a central laboratory for blinded manual adjudication. The average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR), by Bazette's formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Time-matched change from baseline values were reported for QTc analysis population.
    End point type
    Secondary
    End point timeframe
    Time-matched triplicate ECGs were collected at 0 (predose), 2, 4, 6 and 8 hours on Day 0 and on Cycle1 Day14
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    76
    47
    Units: msec
    least squares mean (confidence interval 90%)
        QTcS at 0 hour
    0.8 (-1.67 to 3.26)
    2.95 (-0.19 to 6.1)
        QTcS at 2 hour
    3.32 (0.79 to 5.85)
    1.65 (-1.48 to 4.78)
        QTcS at 4 hour
    2.76 (0.23 to 5.3)
    1.74 (-1.39 to 4.87)
        QTcS at 6 hour
    4.49 (1.96 to 7.02)
    0.72 (-2.41 to 3.85)
        QTcS at 8 hour
    0.94 (-1.6 to 3.48)
    3.14 (0.01 to 6.27)
        QTcF at 0 hour
    1.1 (-1.39 to 3.58)
    3.06 (-0.11 to 6.23)
        QTcF at 2 hour
    3.68 (1.12 to 6.23)
    1.73 (-1.43 to 4.88)
        QTcF at 4 hour
    2.86 (0.31 to 5.41)
    1.54 (-1.62 to 4.7)
        QTcF at 6 hour
    4.57 (2.01 to 7.12)
    0.71 (-2.44 to 3.87)
        QTcF at 8 hour
    1.21 (-1.36 to 3.77)
    2.84 (-0.31 to 6)
        QTcB at 0 hour
    -0.11 (-2.83 to 2.61)
    2.78 (-0.69 to 6.25)
        QTcB at 2 hour
    1.46 (-1.34 to 4.25)
    0.83 (-2.63 to 4.28)
        QTcB at 4 hour
    2.58 (-0.22 to 5.38)
    2.47 (-0.98 to 5.92)
        QTcB at 6 hour
    4.03 (1.24 to 6.83)
    0.53 (-2.92 to 3.99)
        QTcB at 8 hour
    -0.17 (-2.98 to 2.64)
    4.14 (0.69 to 7.59)
    No statistical analyses for this end point

    Secondary: Corrected QT interval (QTc)

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    End point title
    Corrected QT interval (QTc)
    End point description
    Triplicate 12-lead ECG measurements (each recording separated by approximately 2 minutes) were performed and sent to a central laboratory for blinded manual adjudication. The average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) was adjusted for RR interval using QT and RR from each ECG by Fridericia's formula (QTcF = QT divided by cube root of RR), by Bazette's formula (QTcB = QT divided by square root of RR) and corrected QT interval according to study-specific criteria (QTcS). Percentage of participants with post-baseline maximum absolute values and maximum increase from baseline were summarized for the safety analysis population.
    End point type
    Secondary
    End point timeframe
    For safety monitoring triplicate ECGs were obtained at 0 hour (pre-dose) on Day 1 of Cycle 1, Day 14 of Cycles 1 and Cycle 2, then on Day 1 of Cycles 4, 7, and 10. ECGs beyond Cycle 10 were performed as clinically indicated
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    441
    220
    Units: Percentage of participants
    number (not applicable)
        Maximum QTcS <450 msec
    80.5
    85.9
        Maximum QTcS 450-<480 msec
    17.9
    11.8
        Maximum QTcS 480-<500 msec
    1.1
    2.3
        Maximum QTcS ≥500 msec
    0.5
    0
        Maximum QTcF <450 msec
    85.9
    89.5
        Maximum QTcF 450-<480 msec
    12.2
    9.5
        Maximum QTcF 480-<500 msec
    1.6
    0.9
        Maximum QTcF ≥500 msec
    0.2
    0
        Maximum QTcB <450 msec
    64.9
    69.1
        Maximum QTcB 450-<480 msec
    32.2
    27.3
        Maximum QTcB 480-<500 msec
    2.3
    3.2
        Maximum QTcB ≥500 msec
    0.7
    0.5
        Maximum QTcS Change <30 msec
    92.7
    94.5
        Maximum QTcS 30≤Change <60 msec
    6.6
    5.5
        Maximum QTcS Change≥60 msec
    0.7
    0
        Maximum QTcF Change <30 msec
    91.6
    93.6
        Maximum QTcF 30≤Change <60 msec
    7.9
    6.4
        Maximum QTcF Change≥60 msec
    0.5
    0
        Maximum QTcB Change <30 msec
    88.9
    91.4
        Maximum QTcB 30≤Change <60 msec
    10.2
    8.2
        Maximum QTcB Change≥60 msec
    0.9
    0.5
    No statistical analyses for this end point

    Secondary: Observed Plasma Trough Concentration (Ctrough) at Steady-State

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    End point title
    Observed Plasma Trough Concentration (Ctrough) at Steady-State [5]
    End point description
    Summary of Plasma Palbociclib Within-Patient Mean Steady-State Trough Concentrations.
    End point type
    Secondary
    End point timeframe
    Day 14 of cycles 1 and 2
    Notes
    [5] - 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: No descriptive statistic was available for the reporting arm placebo plus letrozole for the Secondary Endpoint: Observed Plasma Trough Concentration (Ctrough) at Steady-State.
    End point values
    Palbociclib plus Letrozole
    Number of subjects analysed
    423
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 14 (N= 395)
    70.1 ± 59
        Cycle 2 Day 14 (N= 401)
    64.2 ± 82
    No statistical analyses for this end point

    Secondary: Change from Baseline Between Treatment Comparison in Euro Quality of Life (EQ-5D) Index

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    End point title
    Change from Baseline Between Treatment Comparison in Euro Quality of Life (EQ-5D) Index
    End point description
    The EuroQol EQ-5D is a brief self-administered health status instrument consisting of two parts. In the first part participants were asked to describe their health state on 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having 3 levels of function (1=no problem, 2=some problem, and 3=extreme problem). The scores on the 5 dimensions were summarized to create a single summary score, because the questions may be answered differently in different countries / regions due to different local customs and social perspectives. The summary score is called the summary index or the health utility value. The second part of EuroQoL EQ-5D is a visual analogue scale (VAS) in which the participants rate their overall health status using values from 0 (worst imaginable) to 100 (best imaginable). A positive change indicates improvement from baseline and a negative change indicates deterioration.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 2.5 years
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    437
    218
    Units: Units on a scale
        arithmetic mean (confidence interval 95%)
    0.014 (0 to 0.03)
    -0.01 (-0.03 to 0.01)
    Statistical analysis title
    Statistical Analysis for EQ-5D
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    655
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0925
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.051

    Secondary: Change from Baseline Between Treatment Comparison in Functional Assessment of Cancer therapy -Breast (FACT-B)

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    End point title
    Change from Baseline Between Treatment Comparison in Functional Assessment of Cancer therapy -Breast (FACT-B)
    End point description
    FACT is a modular approach to assess participant health-related quality of life using a ‘core’ set of questions (FACT-G) as well as a cancer site-specific module. The FACT-G is a 27-item compilation of general questions divided into 4 domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. The FACT-B consisted of the FACT-G (27-item) and a breast-specific module: a 10-item instrument designed to assess participant concerns relating to breast cancer. For all questions, participants were asked to respond to a five-level scale where 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much. FACT-B total score = Physical Well-Being + Social/Family Well-Being + Emotional Well-Being + Functional Well-Being + Breast Cancer Subscale.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 2.5 years
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    439
    218
    Units: Units on a scale
        arithmetic mean (confidence interval 95%)
    -0.106 (-1.42 to 1.21)
    0.219 (-1.68 to 2.12)
    Statistical analysis title
    Statistical Analysis for FACT-B
    Comparison groups
    Palbociclib plus Letrozole v Placebo plus Letrozole
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7822
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.325
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.63
         upper limit
    1.98

    Secondary: Percentage of participants with Treatment-Emergent Adverse Events (TEAEs; All Causalities)

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    End point title
    Percentage of participants with Treatment-Emergent Adverse Events (TEAEs; All Causalities)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is any untoward medical occurrence at any dose that results in death; is life-threatening; requires hospitalization; results in persistent or significant disability or in congenital anomaly/birth defect. Severity will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0.
    End point type
    Secondary
    End point timeframe
    From the participant randomization up to 28 days after last dose of study drug
    End point values
    Palbociclib plus Letrozole Placebo plus Letrozole
    Number of subjects analysed
    444
    222
    Units: Percentage of Participants
    number (not applicable)
        Participants with AEs
    98.9
    95.5
        Participants with SAEs
    19.6
    12.6
        Participants with Grade 3 or 4 AEs
    77.5
    25.2
        Participants with Grade 5 AEs
    2.3
    1.8
        Permanently discontinued study due to AEs
    2.5
    1.8
        Permanently disc. palbociclib/placebo due to AEs
    9.2
    5.4
        Permanently discontinued letrozole due to AEs
    6.1
    5
        Temporarily disc. palbociclib/placebo due to AEs
    74.8
    15.8
        Temporarily discontinued letrozole due to AEs
    17.3
    9.9
        With palbociclib/placebo dose reduction due to AEs
    36
    1.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of randomization up to 28 days after last dose of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo plus Letrozole
    Reporting group description
    Participants received letrozole 2.5 mg orally QD combined with placebo QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Reporting group title
    Palbociclib plus Letrozole
    Reporting group description
    Participants received letrozole 2.5 milligram (mg) orally QD (once daily) combined with palbociclib 125 mg QD for 21 days of every-28-day cycle, followed by 7 days off treatment.

    Serious adverse events
    Placebo plus Letrozole Palbociclib plus Letrozole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 222 (12.61%)
    87 / 444 (19.59%)
         number of deaths (all causes)
    6
    12
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 222 (0.45%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Device dislocation
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 222 (0.45%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Puncture site pain
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast haematoma
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis radiation
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 222 (0.45%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 222 (1.35%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tracheomalacia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 222 (0.00%)
    7 / 444 (1.58%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cauda equina syndrome
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 222 (0.90%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stag horn calculus
         subjects affected / exposed
    1 / 222 (0.45%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 222 (0.90%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 222 (0.90%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 222 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo plus Letrozole Palbociclib plus Letrozole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    206 / 222 (92.79%)
    433 / 444 (97.52%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    68 / 222 (30.63%)
    93 / 444 (20.95%)
         occurrences all number
    71
    112
    Hypertension
         subjects affected / exposed
    21 / 222 (9.46%)
    28 / 444 (6.31%)
         occurrences all number
    29
    55
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    26 / 222 (11.71%)
    75 / 444 (16.89%)
         occurrences all number
    42
    133
    Fatigue
         subjects affected / exposed
    61 / 222 (27.48%)
    166 / 444 (37.39%)
         occurrences all number
    84
    281
    Influenza like illness
         subjects affected / exposed
    10 / 222 (4.50%)
    25 / 444 (5.63%)
         occurrences all number
    10
    38
    Oedema peripheral
         subjects affected / exposed
    14 / 222 (6.31%)
    50 / 444 (11.26%)
         occurrences all number
    14
    63
    Mucosal inflammation
         subjects affected / exposed
    8 / 222 (3.60%)
    41 / 444 (9.23%)
         occurrences all number
    10
    78
    Pain
         subjects affected / exposed
    20 / 222 (9.01%)
    34 / 444 (7.66%)
         occurrences all number
    23
    41
    Pyrexia
         subjects affected / exposed
    19 / 222 (8.56%)
    53 / 444 (11.94%)
         occurrences all number
    22
    63
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    25 / 222 (11.26%)
    36 / 444 (8.11%)
         occurrences all number
    28
    42
    Depression
         subjects affected / exposed
    20 / 222 (9.01%)
    34 / 444 (7.66%)
         occurrences all number
    22
    39
    Insomnia
         subjects affected / exposed
    26 / 222 (11.71%)
    66 / 444 (14.86%)
         occurrences all number
    32
    80
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 222 (4.95%)
    35 / 444 (7.88%)
         occurrences all number
    13
    47
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 222 (4.05%)
    43 / 444 (9.68%)
         occurrences all number
    12
    90
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 222 (4.95%)
    42 / 444 (9.46%)
         occurrences all number
    19
    79
    Neutrophil count decreased
         subjects affected / exposed
    7 / 222 (3.15%)
    87 / 444 (19.59%)
         occurrences all number
    9
    644
    Platelet count decreased
         subjects affected / exposed
    1 / 222 (0.45%)
    27 / 444 (6.08%)
         occurrences all number
    2
    102
    Weight decreased
         subjects affected / exposed
    10 / 222 (4.50%)
    23 / 444 (5.18%)
         occurrences all number
    18
    44
    White blood cell count decreased
         subjects affected / exposed
    4 / 222 (1.80%)
    72 / 444 (16.22%)
         occurrences all number
    7
    397
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 222 (0.45%)
    106 / 444 (23.87%)
         occurrences all number
    1
    401
    Anaemia
         subjects affected / exposed
    20 / 222 (9.01%)
    103 / 444 (23.20%)
         occurrences all number
    40
    265
    Neutropenia
         subjects affected / exposed
    7 / 222 (3.15%)
    294 / 444 (66.22%)
         occurrences all number
    13
    2166
    Thrombocytopenia
         subjects affected / exposed
    2 / 222 (0.90%)
    44 / 444 (9.91%)
         occurrences all number
    3
    108
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    42 / 222 (18.92%)
    111 / 444 (25.00%)
         occurrences all number
    53
    163
    Dyspnoea
         subjects affected / exposed
    30 / 222 (13.51%)
    66 / 444 (14.86%)
         occurrences all number
    35
    80
    Epistaxis
         subjects affected / exposed
    14 / 222 (6.31%)
    41 / 444 (9.23%)
         occurrences all number
    24
    58
    Oropharyngeal pain
         subjects affected / exposed
    7 / 222 (3.15%)
    41 / 444 (9.23%)
         occurrences all number
    7
    49
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    33 / 222 (14.86%)
    63 / 444 (14.19%)
         occurrences all number
    38
    78
    Dysgeusia
         subjects affected / exposed
    11 / 222 (4.95%)
    45 / 444 (10.14%)
         occurrences all number
    14
    52
    Headache
         subjects affected / exposed
    58 / 222 (26.13%)
    95 / 444 (21.40%)
         occurrences all number
    94
    138
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    2 / 222 (0.90%)
    25 / 444 (5.63%)
         occurrences all number
    5
    28
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    12 / 222 (5.41%)
    18 / 444 (4.05%)
         occurrences all number
    14
    22
    Abdominal pain
         subjects affected / exposed
    12 / 222 (5.41%)
    50 / 444 (11.26%)
         occurrences all number
    19
    70
    Abdominal pain upper
         subjects affected / exposed
    17 / 222 (7.66%)
    26 / 444 (5.86%)
         occurrences all number
    27
    32
    Constipation
         subjects affected / exposed
    34 / 222 (15.32%)
    86 / 444 (19.37%)
         occurrences all number
    42
    110
    Diarrhoea
         subjects affected / exposed
    43 / 222 (19.37%)
    116 / 444 (26.13%)
         occurrences all number
    78
    269
    Dry mouth
         subjects affected / exposed
    11 / 222 (4.95%)
    25 / 444 (5.63%)
         occurrences all number
    17
    31
    Dyspepsia
         subjects affected / exposed
    27 / 222 (12.16%)
    41 / 444 (9.23%)
         occurrences all number
    33
    46
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 222 (3.15%)
    27 / 444 (6.08%)
         occurrences all number
    10
    30
    Nausea
         subjects affected / exposed
    57 / 222 (25.68%)
    156 / 444 (35.14%)
         occurrences all number
    104
    260
    Stomatitis
         subjects affected / exposed
    13 / 222 (5.86%)
    68 / 444 (15.32%)
         occurrences all number
    15
    120
    Vomiting
         subjects affected / exposed
    35 / 222 (15.77%)
    69 / 444 (15.54%)
         occurrences all number
    58
    123
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    35 / 222 (15.77%)
    146 / 444 (32.88%)
         occurrences all number
    36
    153
    Dry skin
         subjects affected / exposed
    13 / 222 (5.86%)
    55 / 444 (12.39%)
         occurrences all number
    13
    77
    Pruritus
         subjects affected / exposed
    8 / 222 (3.60%)
    39 / 444 (8.78%)
         occurrences all number
    14
    61
    Rash
         subjects affected / exposed
    22 / 222 (9.91%)
    61 / 444 (13.74%)
         occurrences all number
    26
    99
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    75 / 222 (33.78%)
    148 / 444 (33.33%)
         occurrences all number
    109
    222
    Back pain
         subjects affected / exposed
    48 / 222 (21.62%)
    96 / 444 (21.62%)
         occurrences all number
    70
    132
    Bone pain
         subjects affected / exposed
    22 / 222 (9.91%)
    38 / 444 (8.56%)
         occurrences all number
    26
    59
    Muscle spasms
         subjects affected / exposed
    12 / 222 (5.41%)
    37 / 444 (8.33%)
         occurrences all number
    18
    47
    Musculoskeletal chest pain
         subjects affected / exposed
    9 / 222 (4.05%)
    25 / 444 (5.63%)
         occurrences all number
    13
    38
    Musculoskeletal pain
         subjects affected / exposed
    16 / 222 (7.21%)
    37 / 444 (8.33%)
         occurrences all number
    19
    56
    Myalgia
         subjects affected / exposed
    20 / 222 (9.01%)
    53 / 444 (11.94%)
         occurrences all number
    27
    64
    Neck pain
         subjects affected / exposed
    10 / 222 (4.50%)
    23 / 444 (5.18%)
         occurrences all number
    13
    30
    Pain in extremity
         subjects affected / exposed
    39 / 222 (17.57%)
    68 / 444 (15.32%)
         occurrences all number
    56
    91
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    20 / 222 (9.01%)
    65 / 444 (14.64%)
         occurrences all number
    23
    91
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    22 / 222 (9.91%)
    62 / 444 (13.96%)
         occurrences all number
    31
    93
    Oral herpes
         subjects affected / exposed
    3 / 222 (1.35%)
    28 / 444 (6.31%)
         occurrences all number
    7
    47
    Sinusitis
         subjects affected / exposed
    7 / 222 (3.15%)
    23 / 444 (5.18%)
         occurrences all number
    11
    36
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 222 (11.26%)
    59 / 444 (13.29%)
         occurrences all number
    31
    82
    Urinary tract infection
         subjects affected / exposed
    17 / 222 (7.66%)
    52 / 444 (11.71%)
         occurrences all number
    34
    75

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2013
    Amendment 1: For France only: Clarification of inclusion criterion #10
    03 Jan 2014
    Amendment 2: Clarification of inclusion criterion #10 and 4; Clarification of exclusion criterion #1 and 17; Added preliminary results; Added recommendation to take palbociclib with a meal; Added prohibition to take proton-pump inhibitors; Added recommendation to use local antacids as well as H2-receptor antagonist; Editorial changes were done.
    21 Mar 2014
    Amendment 3: Added ophthalmic procedures; Included preliminary results from a preclinical ocular study with palbociclib in rats; Clarified that safety related assessments must continue if participants continue study treatment beyond RECIST-defined disease progression; Changes done to align with updated protocol template; Electrocardiogram: Definition of of “evaluable” patient revised; Ocular Safety Assessment and Adverse Event Reporting: were added; sample size was revised; Section 15.1 and Appendix 6 FACT-B: updated; Appendix 8 was added.
    18 Sep 2014
    Amendment 4: Added prospective monitoring of hemoglobin A1c; Ocular Preclinical Date: Updated section to report emergent data findings from the 27-week rat toxicity study; updated study design to reflect Sponsor’s decision to no longer require safety review by an internal oncology business unit safety data monitoring committee (IOBU-SDMC) for studies already monitored by an external data monitoring committee (E-DMC). Language related to cycle delay further defined to clearly state that any new cycle may only start if blinded study treatment can be resumed. Provided results from study A5481038 designed to investigate the effect of H2-receptor antagonists, proton pump inhibitors and local antacids; Editorial changes to differentiate between strong and moderate CYP3A inducers/inhibitors and to reflect current Sponsor protocol template.
    02 Dec 2014
    Amendment 5: Changed the interim analysis efficacy boundary from O’Brien-Fleming to Haybittle-Peto boundary to ensure that the study would only be stopped at the interim analysis if the primary analysis (PFS) results are statistically significant, and clinically meaningful and editorial changes to reflect current instructions for investigational product destruction at the end of the trial. Prohibited Medications: Strong/Moderate CYP3A inducers/inhibitors and proton-pump inhibitors are allowed for patients who permanently discontinue blinded therapy and continue on study with letrozole monotherapy only. Analysis of Primary Endpoint: Editorial change to clarify planned analyses.
    07 Apr 2015
    Amendment 6: Analysis Secondary Endpoints: Changes reflecting the collection of Patient Reported Outcome data during the post-progression follow-up period to assess potential impact of post-progression status on patient’s quality of life and editorial changes to reflect current Sponsor’s protocol template.
    15 Oct 2015
    Amendment 7 protocol language revise to reflect that collection of disease progression dates on subsequent anticancer therapy to better understand the potential influence of palbociclib response to subsequent anticancer therapies. Additional language was also added to clarify that the 7-day off treatment period in any given cycle should always be respected.

    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.
    For Overall Survival: The patients continue to be followed for survival and the final OS analysis will be performed when 390 deaths have been reported. OS should not be reported at this time because the OS data is still being followed.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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