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    Clinical Trial Results:
    A phase II randomised study evaluating the biological and clinical effects of the combination of palbociclib with letrozole as neoadjuvant therapy in post-menopausal women with ER+ primary breast cancer

    Summary
    EudraCT number
    		 2014-000887-16
    Trial protocol
    		 GB  
    Global end of trial date
    03 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Mar 2021
    First version publication date
    03 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ICR-CTSU/2014/10044
    Additional study identifiers
    ISRCTN number
    		 ISRCTN31243262
    US NCT number
    		 NCT01889680
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 sponsor Indentification Number: CCR4133, CRUK reference number: CRUK/13/031
    Sponsors
    Sponsor organisation name
    Institute of Cancer Research
    Sponsor organisation address
    123 Old Brompton Road, Lo, United Kingdom, SW7 3RP
    Public contact
    Michelle Frost, The Institute of Cancer Research, 44 2034376605, pallet-icrctsu@icr.ac.uk
    Scientific contact
    Michelle Frost, The Institute of Cancer Research, 44 2034376605, pallet-icrctsu@icr.ac.uk
    Sponsor organisation name
    Royal Marsden NHS Foundation Trust
    Sponsor organisation address
    Fulham Road, London, United Kingdom, SW3 6JJ
    Public contact
    Michelle Frost, Institute of Cancer Research, 44 2034376605, pallet-icrctsu@icr.ac.uk
    Scientific contact
    Michelle Frost, Institute of Cancer Research, 44 2034376605, pallet-icrctsu@icr.ac.uk
    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
    03 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    PALLET has co-primary objectives: 1) To compare the changes in the proliferation (cell division) marker Ki67 after 14 weeks treatment with letrozole with or without palbociclib. 2) To compare clinical response (i.e. whether the tumour has responded to treatment) after 14 weeks treatment with letrozole with or without palbociclib.
    Protection of trial subjects
    Patients were provided with full verbal and written informed consent that included the purpose of the trial, the procedures and treatments involved along with potential risks and side effects. A patient information and consent form were provided and patients were given sufficient time to consider participation. Full details of the trial treatments and their safety profile were provided in the patient information sheet. Patients had the opportunity to discuss any concerns they had in relation to trial treatment prior to consent and throughout their involvement in the trial. The collection of core needle biopsies were a mandatory aspect of trial participation and used for the assessment of the co-primary endpoint. The reason for sample collection were clearly described in the patient information sheet as were the potential risks associated with biopsy collection. Every effort was made to minimise discomfort during the biopsy procedure.
    Background therapy
    		 Letrozole: the rationale for the PALLET trial was to assess the effectiveness of the addition of palbociclib, a CDK4/6 inhibitor, when added to letrozole for the neoadjuvant treatment of patients with ER+/HER2- early invasive breast cancer
    Evidence for comparator
    		 Palbociclib is an orally active potent and highly selective reversible inhibitor of CDK4 and CDK6. Preclinical evidence that palbociclib is highly active in ER+ cell lines and encouraging early safety and PK results led to a randomised phase II study evaluating the efficacy and safety of letrozole in combination with palbociclib when compared with letrozole alone in the first-line treatment of postmenopausal patients with ER+/HER2- advanced breast cancer (NCT00721409). A phase II dose of 125mg QD on a schedule of 21/7 (i.e. 21 days continuous treatment followed by 7 days off treatment) was used in combination with letrozole 2.5mg QD continuously. Later patients in the study were prospectively selected taking into account tumour CCND1 amplification and/or p16 loss. 165 patients were enrolled and the study demonstrated an improved clinical benefit rate (CR+PR+SD) of 59% v 36% and a prolongation of PFS from 7.5 to 26.1 months (HR 0.37 95%CI: 0.21, 0.63 P<0.001). The randomised phase II PALOMA-1 trial (palbociclib in combination with letrozole vs. letrozole alone as first-line treatment of ER+/HER2- advanced breast cancer) reported a median PFS of 10.2 months (95% CI 5.7–12.6) for the letrozole group compared to 20.2 months (13.8–27.5) for the palbociclib + letrozole group (HR 0.488, 95% CI 0.319–0.748; one-sided p=0·0004). A recent phase III trial of 521 patients with advanced HR+/HER2-breast cancer that had relapsed or progressed during prior endocrine therapy assessed the efficacy of palbociclib in combination with fulvestrant (NCT01942135, PALOMA-3). The trial reported median PFS of 9.2 months (95% CI, 7.5 to not estimable) with palbociclib–fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo–fulvestrant (HR for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001).
    Actual start date of recruitment
    01 Nov 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
    United States: 141
    Country: Number of subjects enrolled
    United Kingdom: 166
    Worldwide total number of subjects
    307
    EEA total number of subjects
    0
    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)
    155
    From 65 to 84 years
    147
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 306 patients were recruited between 27 February 2015 and 8 March 2018. 166 patients were randomised in the UK and 141 patients were randomised in North America.

    Pre-assignment
    Screening details
    		 Potentially eligible patients screened for PALLET included all postmenopausal women with ER+/HER2- invasive early breast cancer who were suitable for neoadjuvant endocrine therapy. The most common reasons for non-entry to PALLET were tumour size <2cm, patient pre or perimenopausal, patient declined trial or chose surgery over neoadjuvant therapy.

    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
    		 Group A: letrozole alone
    Arm description
    		 Group A: letrozole from baseline to week 14
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    L02BG04
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg/day

    Arm title
    		 Group B: letrozole for 2 weeks then letrozole + palbociclib
    Arm description
    		 Group B: letrozole from baseline to week 2 followed by letrozole plus palbociclib to week 14
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    L02BG04
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg/day

    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
    125mg daily on a schedule of 3 weeks on, 1 week off (3/1)

    Arm title
    		 Group C: palbociclib for 2 weeks then palbociclib + letrozole
    Arm description
    		 Group C: palbociclib from baseline to week 2 followed by palbociclib plus letrozole to week 14
    Arm type
    		 Experimental

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    L02BG04
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg/day

    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
    125mg/day

    Arm title
    		 Group D: letrozole plus palbociclib
    Arm description
    		 Group D: letrozole plus palbociclib from baseline to week 14
    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
    125mg/day

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    L02BG04
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg/day

    Number of subjects in period 1
    		Group A: letrozole alone Group B: letrozole for 2 weeks then letrozole + palbociclib Group C: palbociclib for 2 weeks then palbociclib + letrozole Group D: letrozole plus palbociclib
    Started
    103
    68
    69
    67
    Completed
    88
    55
    57
    62
    Not completed
    15
    13
    12
    5
         Consent withdrawn by subject
    3
    1
    2
    3
         Disease progression
    2
    -
    1
    -
         Adverse event, non-fatal
    -
    2
    2
    -
         Surgery delayed
    2
    -
    -
    -
         Death
    -
    2
    1
    -
         Lost to follow-up
    5
    5
    5
    2
         Missing data
    3
    3
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A: letrozole alone
    Reporting group description
    		 Group A: letrozole from baseline to week 14

    Reporting group title
    Group B: letrozole for 2 weeks then letrozole + palbociclib
    Reporting group description
    		 Group B: letrozole from baseline to week 2 followed by letrozole plus palbociclib to week 14

    Reporting group title
    Group C: palbociclib for 2 weeks then palbociclib + letrozole
    Reporting group description
    		 Group C: palbociclib from baseline to week 2 followed by palbociclib plus letrozole to week 14

    Reporting group title
    Group D: letrozole plus palbociclib
    Reporting group description
    		 Group D: letrozole plus palbociclib from baseline to week 14

    Reporting group values
    		 Group A: letrozole alone Group B: letrozole for 2 weeks then letrozole + palbociclib Group C: palbociclib for 2 weeks then palbociclib + letrozole Group D: letrozole plus palbociclib Total
    Number of subjects
    		 103 68 69 67 307
    Age categorical
    Units: Subjects
        40-49 years
    		 0 0 1 0 1
        50-59 years
    		 32 15 19 22 88
        60-69 years
    		 34 31 29 30 124
        70-79 years
    		 30 14 17 12 73
        80 or more years
    		 7 8 3 3 21
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 65.8 (59.4 to 72.0) 66.3 (60.4 to 72.5) 63.5 (59.3 to 70.5) 63.8 (58.5 to 69.1) -
    Gender categorical
    Units: Subjects
        Female
    		 103 68 69 67 307
        Male
    		 0 0 0 0 0
    Tumour grade
    Units: Subjects
        Low
    		 13 6 4 9 32
        Intermediate
    		 70 54 52 51 227
        High
    		 19 7 13 7 46
        Not known
    		 1 1 0 0 2
    Histological type
    Units: Subjects
        Ductal
    		 74 49 46 45 214
        Lobular
    		 24 14 19 18 75
        Mixed ductal and lobular
    		 4 1 4 2 11
        Mucinous
    		 1 4 0 2 7
    PgR status
    Units: Subjects
        Positive
    		 74 47 41 53 215
        Negative
    		 15 10 15 7 47
        Not done
    		 14 11 13 7 45
    Surgical intent at baseline
    Type of breast surgery planned at baseline
    Units: Subjects
        Partial mastectomy/lumpectomy
    		 61 45 40 39 185
        Total or modified radical mastectomy
    		 39 20 25 24 108
        Missing data
    		 3 3 4 4 14
    Subject analysis sets

    Subject analysis set title
    Groups B, C and D combined: letrozole with palbociclib
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients treated with letrozole with palbociclib, i.e. in groups B+C+D (Arms 2,3,4) were pooled and compared to those treated with letrozole alone (Group 1/Arm 1)

    Subject analysis sets values
    		 Groups B, C and D combined: letrozole with palbociclib
    Number of subjects
    204
    Age categorical
    Units: Subjects
        40-49 years
    1
        50-59 years
    56
        60-69 years
    90
        70-79 years
    43
        80 or more years
    14
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
        Male
    Tumour grade
    Units: Subjects
        Low
        Intermediate
        High
        Not known
    Histological type
    Units: Subjects
        Ductal
        Lobular
        Mixed ductal and lobular
        Mucinous
    PgR status
    Units: Subjects
        Positive
        Negative
        Not done
    Surgical intent at baseline
    Type of breast surgery planned at baseline
    Units: Subjects
        Partial mastectomy/lumpectomy
        Total or modified radical mastectomy
        Missing data

    End points

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    End points reporting groups
    Reporting group title
    Group A: letrozole alone
    Reporting group description
    		 Group A: letrozole from baseline to week 14

    Reporting group title
    Group B: letrozole for 2 weeks then letrozole + palbociclib
    Reporting group description
    		 Group B: letrozole from baseline to week 2 followed by letrozole plus palbociclib to week 14

    Reporting group title
    Group C: palbociclib for 2 weeks then palbociclib + letrozole
    Reporting group description
    		 Group C: palbociclib from baseline to week 2 followed by palbociclib plus letrozole to week 14

    Reporting group title
    Group D: letrozole plus palbociclib
    Reporting group description
    		 Group D: letrozole plus palbociclib from baseline to week 14

    Subject analysis set title
    Groups B, C and D combined: letrozole with palbociclib
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients treated with letrozole with palbociclib, i.e. in groups B+C+D (Arms 2,3,4) were pooled and compared to those treated with letrozole alone (Group 1/Arm 1)

    Primary: Clinical response as measured by ultrasound according to ECOG criteria after 14 weeks treatment with letrozole with or without palbociclib

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    End point title
    		 Clinical response as measured by ultrasound according to ECOG criteria after 14 weeks treatment with letrozole with or without palbociclib
    End point description
    End point type
    Primary
    End point timeframe
    Assessed after 14 weeks of treatmet with letrozole with or without palbociclib
    End point values
    		 Group A: letrozole alone Group B: letrozole for 2 weeks then letrozole + palbociclib Group C: palbociclib for 2 weeks then palbociclib + letrozole Group D: letrozole plus palbociclib Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    93
    63
    61
    62
    186
    Units: Number
        Complete response
    2
    1
    2
    1
    4
        Partial response
    44
    30
    33
    34
    97
        Stable disease
    42
    30
    25
    23
    78
        Progressive disease
    5
    2
    1
    4
    7
    Statistical analysis title
    		 Comparison of clinical response
    Statistical analysis description
    A Mann-Whitney test was used to determined if there was evidence of a difference in clinical response between Group A (letrozole alone) and Groups B+C+D (letrozole with palbociclib)
    Comparison groups
    Group A: letrozole alone v Groups B, C and D combined: letrozole with palbociclib
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.21
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: Change in Ki67 (% positive tumour cells) from baseline to after 14 weeks treatment with letrozole with or without palbociclib

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    End point title
    		 Change in Ki67 (% positive tumour cells) from baseline to after 14 weeks treatment with letrozole with or without palbociclib
    End point description
    Change in the proliferation marker Ki67 (% positive tumour cells) as tested by IHC from baseline to after 14 weeks treatment with letrozole with or without palbociclib . Paired Ki67 data from baseline and end of treatment at 14 weeks were available for 190 (61.9%) patients. Where pathological complete response was indicated due to no invasive tumour cells present in the surgical specimen and where Ki67 data at week 14 was missing, a value of 0 was imputed.
    End point type
    Primary
    End point timeframe
    Change from baseline to 14 weeks of treatment
    End point values
    		 Group A: letrozole alone Group B: letrozole for 2 weeks then letrozole + palbociclib Group C: palbociclib for 2 weeks then palbociclib + letrozole Group D: letrozole plus palbociclib Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    65
    40
    47
    38
    125
    Units: Log-fold change in Ki67
        median (inter-quartile range (Q1-Q3))
    -2.2 (-3.4 to -1.0)
    -4.1 (-5.1 to -2.7)
    -4.0 (-5.1 to -3.0)
    -3.9 (-5.0 to -2.9)
    -4.1 (-5.0 to -2.8)
    Statistical analysis title
    		 Comparison of log-fold change in Ki67
    Statistical analysis description
    Comparison of log-fold change in Ki67 between Group A and Groups B + C + D
    Comparison groups
    Group A: letrozole alone v Groups B, C and D combined: letrozole with palbociclib
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Effect of of randomised treatment on Ki67 after 2 weeks

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    End point title
    		 Effect of of randomised treatment on Ki67 after 2 weeks
    End point description
    Effect of of randomised treatment on Ki67 after 2 weeks
    End point type
    Secondary
    End point timeframe
    From baseline to 2 weeks
    End point values
    		 Group A: letrozole alone Group B: letrozole for 2 weeks then letrozole + palbociclib Group C: palbociclib for 2 weeks then palbociclib + letrozole Group D: letrozole plus palbociclib Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    61
    39
    44
    32
    115
    Units: Log fold change in Ki67
    median (inter-quartile range (Q1-Q3))
        From baseline to week 2
    -1.3 (-2.9 to -0.6)
    -1.3 (-2.5 to -0.8)
    -3.1 (-4.1 to -1.5)
    -3.9 (-4.7 to -2.7)
    -2.8 (-4.1 to -1.2)
    No statistical analyses for this end point

    Secondary: Added effect of additional randomised treatment from weeks 2-14

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    End point title
    		 Added effect of additional randomised treatment from weeks 2-14
    End point description
    Added effect of additional randomised treatment from weeks 2-14
    End point type
    Secondary
    End point timeframe
    From week 2 to week 14
    End point values
    		 Group A: letrozole alone Group B: letrozole for 2 weeks then letrozole + palbociclib Group C: palbociclib for 2 weeks then palbociclib + letrozole Group D: letrozole plus palbociclib Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    61
    39
    44
    32
    115
    Units: Log-fold change in Ki67
    median (inter-quartile range (Q1-Q3))
        From week 2 to week 14
    -0.1 (-1.1 to 0.4)
    -2.1 (-3.5 to -1.3)
    -0.4 (-2.1 to 0.0)
    0.0 (-0.1 to 0.9)
    -1.0 (-2.2 to 0.0)
    No statistical analyses for this end point

    Secondary: Pathologic complete response rates after letrozole with or without 14 weeks palbociclib

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    End point title
    		 Pathologic complete response rates after letrozole with or without 14 weeks palbociclib [1]
    End point description
    Pathologic complete response in the breast (pCR breast) is defined as no histologic evidence of invasive tumour cells in the surgical breast specimen. Pathologic complete response in breast and axillary lymph nodes as well as non-axillary sentinel node (pCR breast & nodes) is defined as no histologic evidence of invasive tumour cells in the surgical breast specimen, axillary nodes or sentinel nodes identified after neoadjuvant treatment.
    End point type
    Secondary
    End point timeframe
    14 weeks from baseline
    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: This endpoint assessed the effect of addition of palbociclib on change at 14 weeks so arms B, C, D were combined for this end-point analysis as all patients in these arms were on palbociclib at week 14.
    End point values
    		 Group A: letrozole alone Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    91
    187
    Units: Number
        pCR breast
    1
    7
        pCR breast & nodes
    0
    2
    Statistical analysis title
    		 Comparison of pathologic complete response
    Statistical analysis description
    Fisher's exact test to compare rates of pathologic complete response between letrozole alone group (Group A) and letrozole plus palbociclib groups (Groups B+C+D)
    Comparison groups
    Group A: letrozole alone v Groups B, C and D combined: letrozole with palbociclib
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.28 [2]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - pCR breast comparison: p=0.28 pCR breast & nodes comparison: p=1.00

    Secondary: PEPI score after letrozole with or without 14 weeks palbociclib

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    End point title
    		 PEPI score after letrozole with or without 14 weeks palbociclib [3]
    End point description
    A preoperative endocrine prognostic index (PEPI) for relapse-free survival (PFS) and breast cancer-specific survival (BCSS) was modelled using surgical staging parameters after neoadjuvant treatment (histological grade, pathological tumour size, node status, treatment response), estrogen receptor status, and levels of the proliferation marker Ki67 as described by Ellis MJ et al, J Natl Cancer Inst 2008;100:1380-1388. PEPI risk scores were calculated for RFS and BCSS.
    End point type
    Secondary
    End point timeframe
    14 weeks from baseline
    Notes
    [3] - 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: This endpoint assessed the effect of addition of palbociclib on change at 14 weeks so arms B, C, D were combined for this end-point analysis as all patients in these arms were on palbociclib at week 14.
    End point values
    		 Group A: letrozole alone Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    65
    129
    Units: Risk score
    arithmetic mean (standard deviation)
        PEPI Risk score for relapse-free survival
    3.7 ( 2.3 )
    3.6 ( 2.3 )
        PEPI risk score - breast cancer specific survival
    3.9 ( 2.5 )
    3.6 ( 2.3 )
    No statistical analyses for this end point

    Secondary: Changes between surgical intent at baseline and surgical intent at 14 weeks

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    End point title
    		 Changes between surgical intent at baseline and surgical intent at 14 weeks [4]
    End point description
    Changes between surgical intent at baseline and surgical intent after 14 weeks after treatment with letrozole with or without palbociclib.
    End point type
    Secondary
    End point timeframe
    At end of treatment at 14 weeks from baseline
    Notes
    [4] - 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: This endpoint assessed the effect of addition of palbociclib on change at 14 weeks so arms B, C, D were combined for this end-point analysis as all patients in these arms were on palbociclib at week 14.
    End point values
    		 Group A: letrozole alone Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    93
    177
    Units: Percentage
        Change to breast conservation
    14
    25
        Breast conservation intended after treatment
    62
    118
    Statistical analysis title
    		 Change in surgical intent at end of treatment
    Statistical analysis description
    Comparison of change in surgical intent from baseline to end of treatment.
    Comparison groups
    Group A: letrozole alone v Groups B, C and D combined: letrozole with palbociclib
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.86 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Change to breast conservation comparison: p=0.86 Breast conservation intended at end of treatment comparison: p=1.00

    Secondary: Changes between surgical intent at baseline and actual surgery received

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    End point title
    		 Changes between surgical intent at baseline and actual surgery received [6]
    End point description
    Changes between surgical intent at baseline and actual surgery received after treatment with letrozole with or without palbociclib.
    End point type
    Secondary
    End point timeframe
    At surgery
    Notes
    [6] - 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: This endpoint assessed the effect of addition of palbociclib on change at 14 weeks so arms B, C, D were combined for this end-point analysis as all patients in these arms were on palbociclib at week 14.
    End point values
    		 Group A: letrozole alone Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    90
    178
    Units: Percentage
        Change to breast conservation
    16
    25
        Breast conservation intended at end of treatment
    63
    123
    Statistical analysis title
    		 Change in surgical intent and surgery received
    Statistical analysis description
    Comparison of change from surgical intent to surgery received by treatment group
    Comparison groups
    Group A: letrozole alone v Groups B, C and D combined: letrozole with palbociclib
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.47 [7]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - Change to breast conservation comparison: p=0.47 Breast conservation intended at end of treatment comparison: p=1.00

    Secondary: Assessment of safety and tolerability

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    End point title
    		 Assessment of safety and tolerability [8]
    End point description
    Summary of worst grade event reported per patient
    End point type
    Secondary
    End point timeframe
    From day 1 to 30 days after the last dose of trial treatment
    Notes
    [8] - 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: This endpoint assessed the effect of addition of palbociclib on change at 14 weeks so arms B, C, D were combined for this end-point analysis as all patients in these arms were on palbociclib at week 14.
    End point values
    		 Group A: letrozole alone Groups B, C and D combined: letrozole with palbociclib
    Number of subjects analysed
    100
    201
    Units: Number
        Any grade
    91
    199
        Grade 3 or more
    17
    100
    Statistical analysis title
    		 Comparison of worst adverse event grade reported
    Statistical analysis description
    A Mann-Whitney test was used to determine if there was a difference in worst AE grade between Group A (letrozole only) and Groups B+C+D (letrozole plus palbociclib). Mann Whitney two-sided.
    Comparison groups
    Group A: letrozole alone v Groups B, C and D combined: letrozole with palbociclib
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From day 1 of trial treatment to 30 days after the last administration of trial treatment
    Adverse event reporting additional description
    Any toxicity, sign or symptom that occurred after commencement of study treatment and within 30 days of the last administration of study treatment, which was not unequivocally due to progression of disease.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.9
    Reporting groups
    Reporting group title
    Group A: letrozole alone
    Reporting group description
    		 Group A: letrozole from baseline to week 14

    Reporting group title
    Group B: letrozole for 2 weeks then letrozole + palbociclib
    Reporting group description
    		 Group B: letrozole from baseline to week 2 followed by letrozole plus palbociclib to week 14

    Reporting group title
    Group C: palbociclib for 2 weeks then palbociclib + letrozole
    Reporting group description
    		 Group C: palbociclib from baseline to week 2 followed by palbociclib plus letrozole to week 14

    Reporting group title
    Group D: letrozole plus palbociclib
    Reporting group description
    		 Group D: letrozole plus palbociclib from baseline to week 14

    Serious adverse events
    		 Group A: letrozole alone Group B: letrozole for 2 weeks then letrozole + palbociclib Group C: palbociclib for 2 weeks then palbociclib + letrozole Group D: letrozole plus palbociclib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 66 (4.55%)
    4 / 69 (5.80%)
    1 / 66 (1.52%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
    Additional description: Minor head injury following a fall
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    0 / 69 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
    Additional description: Enterocolitis with C-difficile infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Neutropenic sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 66 (1.52%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A: letrozole alone Group B: letrozole for 2 weeks then letrozole + palbociclib Group C: palbociclib for 2 weeks then palbociclib + letrozole Group D: letrozole plus palbociclib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    91 / 100 (91.00%)
    65 / 66 (98.48%)
    69 / 69 (100.00%)
    65 / 66 (98.48%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    40 / 100 (40.00%)
    19 / 66 (28.79%)
    13 / 69 (18.84%)
    22 / 66 (33.33%)
         occurrences all number
    51
    26
    17
    23
    Hypertension
         subjects affected / exposed
    11 / 100 (11.00%)
    5 / 66 (7.58%)
    3 / 69 (4.35%)
    7 / 66 (10.61%)
         occurrences all number
    12
    13
    3
    9
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 66 (3.03%)
    1 / 69 (1.45%)
    3 / 66 (4.55%)
         occurrences all number
    2
    2
    1
    3
    Fatigue
         subjects affected / exposed
    41 / 100 (41.00%)
    37 / 66 (56.06%)
    42 / 69 (60.87%)
    38 / 66 (57.58%)
         occurrences all number
    46
    43
    53
    52
    Mucosal inflammation
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 66 (4.55%)
    0 / 69 (0.00%)
    4 / 66 (6.06%)
         occurrences all number
    0
    4
    0
    5
    Pain
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 66 (0.00%)
    4 / 69 (5.80%)
    3 / 66 (4.55%)
         occurrences all number
    5
    0
    5
    4
    Pyrexia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    3 / 69 (4.35%)
    3 / 66 (4.55%)
         occurrences all number
    0
    0
    3
    3
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    12 / 100 (12.00%)
    6 / 66 (9.09%)
    5 / 69 (7.25%)
    9 / 66 (13.64%)
         occurrences all number
    12
    7
    7
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 100 (3.00%)
    5 / 66 (7.58%)
    8 / 69 (11.59%)
    8 / 66 (12.12%)
         occurrences all number
    4
    5
    10
    9
    Dyspnoea
         subjects affected / exposed
    4 / 100 (4.00%)
    3 / 66 (4.55%)
    4 / 69 (5.80%)
    7 / 66 (10.61%)
         occurrences all number
    4
    3
    4
    11
    Epistaxis
         subjects affected / exposed
    2 / 100 (2.00%)
    8 / 66 (12.12%)
    4 / 69 (5.80%)
    8 / 66 (12.12%)
         occurrences all number
    3
    8
    4
    11
    Oropharyngeal pain
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 66 (1.52%)
    5 / 69 (7.25%)
    4 / 66 (6.06%)
         occurrences all number
    2
    1
    7
    4
    Productive cough
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    5 / 69 (7.25%)
    0 / 66 (0.00%)
         occurrences all number
    1
    0
    6
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    2 / 69 (2.90%)
    4 / 66 (6.06%)
         occurrences all number
    0
    0
    2
    5
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    2 / 69 (2.90%)
    4 / 66 (6.06%)
         occurrences all number
    0
    0
    2
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 66 (1.52%)
    1 / 69 (1.45%)
    3 / 66 (4.55%)
         occurrences all number
    4
    1
    1
    4
    Depression
         subjects affected / exposed
    10 / 100 (10.00%)
    2 / 66 (3.03%)
    3 / 69 (4.35%)
    4 / 66 (6.06%)
         occurrences all number
    10
    4
    3
    4
    Insomnia
         subjects affected / exposed
    7 / 100 (7.00%)
    4 / 66 (6.06%)
    5 / 69 (7.25%)
    7 / 66 (10.61%)
         occurrences all number
    7
    4
    9
    7
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 100 (7.00%)
    5 / 66 (7.58%)
    11 / 69 (15.94%)
    7 / 66 (10.61%)
         occurrences all number
    8
    13
    19
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 100 (3.00%)
    4 / 66 (6.06%)
    8 / 69 (11.59%)
    3 / 66 (4.55%)
         occurrences all number
    3
    6
    8
    5
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 100 (6.00%)
    0 / 66 (0.00%)
    5 / 69 (7.25%)
    2 / 66 (3.03%)
         occurrences all number
    8
    0
    8
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 100 (0.00%)
    4 / 66 (6.06%)
    4 / 69 (5.80%)
    2 / 66 (3.03%)
         occurrences all number
    0
    17
    4
    2
    Neutrophil count decreased
         subjects affected / exposed
    2 / 100 (2.00%)
    39 / 66 (59.09%)
    38 / 69 (55.07%)
    33 / 66 (50.00%)
         occurrences all number
    4
    103
    125
    94
    Platelet count decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    5 / 66 (7.58%)
    18 / 69 (26.09%)
    8 / 66 (12.12%)
         occurrences all number
    0
    16
    28
    20
    White blood cell count decreased
         subjects affected / exposed
    1 / 100 (1.00%)
    12 / 66 (18.18%)
    17 / 69 (24.64%)
    20 / 66 (30.30%)
         occurrences all number
    1
    21
    67
    53
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    7 / 100 (7.00%)
    5 / 66 (7.58%)
    3 / 69 (4.35%)
    1 / 66 (1.52%)
         occurrences all number
    7
    5
    4
    1
    Fall
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 66 (1.52%)
    5 / 69 (7.25%)
    0 / 66 (0.00%)
         occurrences all number
    4
    1
    5
    0
    Procedural pain
         subjects affected / exposed
    5 / 100 (5.00%)
    4 / 66 (6.06%)
    3 / 69 (4.35%)
    2 / 66 (3.03%)
         occurrences all number
    5
    5
    3
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 100 (8.00%)
    6 / 66 (9.09%)
    9 / 69 (13.04%)
    9 / 66 (13.64%)
         occurrences all number
    9
    9
    10
    12
    Dysgeusia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 66 (1.52%)
    3 / 69 (4.35%)
    5 / 66 (7.58%)
         occurrences all number
    1
    1
    3
    6
    Headache
         subjects affected / exposed
    21 / 100 (21.00%)
    12 / 66 (18.18%)
    7 / 69 (10.14%)
    19 / 66 (28.79%)
         occurrences all number
    23
    15
    8
    34
    Hypoaesthesia
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 66 (0.00%)
    0 / 69 (0.00%)
    3 / 66 (4.55%)
         occurrences all number
    3
    0
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 100 (3.00%)
    7 / 66 (10.61%)
    6 / 69 (8.70%)
    7 / 66 (10.61%)
         occurrences all number
    5
    13
    13
    10
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 66 (0.00%)
    6 / 69 (8.70%)
    1 / 66 (1.52%)
         occurrences all number
    2
    0
    6
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 100 (10.00%)
    10 / 66 (15.15%)
    7 / 69 (10.14%)
    9 / 66 (13.64%)
         occurrences all number
    11
    10
    8
    12
    Diarrhoea
         subjects affected / exposed
    14 / 100 (14.00%)
    9 / 66 (13.64%)
    11 / 69 (15.94%)
    13 / 66 (19.70%)
         occurrences all number
    18
    10
    15
    16
    Dry mouth
         subjects affected / exposed
    4 / 100 (4.00%)
    2 / 66 (3.03%)
    4 / 69 (5.80%)
    1 / 66 (1.52%)
         occurrences all number
    4
    2
    4
    1
    Dyspepsia
         subjects affected / exposed
    7 / 100 (7.00%)
    6 / 66 (9.09%)
    6 / 69 (8.70%)
    7 / 66 (10.61%)
         occurrences all number
    8
    7
    8
    7
    Flatulence
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 66 (1.52%)
    0 / 69 (0.00%)
    3 / 66 (4.55%)
         occurrences all number
    1
    1
    0
    3
    Mouth ulceration
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 66 (4.55%)
    4 / 69 (5.80%)
    1 / 66 (1.52%)
         occurrences all number
    1
    4
    4
    1
    Nausea
         subjects affected / exposed
    18 / 100 (18.00%)
    16 / 66 (24.24%)
    17 / 69 (24.64%)
    17 / 66 (25.76%)
         occurrences all number
    23
    20
    26
    26
    Oral pain
         subjects affected / exposed
    1 / 100 (1.00%)
    5 / 66 (7.58%)
    4 / 69 (5.80%)
    3 / 66 (4.55%)
         occurrences all number
    1
    8
    4
    3
    Stomatitis
         subjects affected / exposed
    0 / 100 (0.00%)
    5 / 66 (7.58%)
    8 / 69 (11.59%)
    7 / 66 (10.61%)
         occurrences all number
    0
    5
    14
    9
    Vomiting
         subjects affected / exposed
    4 / 100 (4.00%)
    4 / 66 (6.06%)
    7 / 69 (10.14%)
    3 / 66 (4.55%)
         occurrences all number
    4
    5
    8
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 100 (3.00%)
    6 / 66 (9.09%)
    8 / 69 (11.59%)
    12 / 66 (18.18%)
         occurrences all number
    3
    6
    8
    14
    Dry skin
         subjects affected / exposed
    4 / 100 (4.00%)
    4 / 66 (6.06%)
    4 / 69 (5.80%)
    6 / 66 (9.09%)
         occurrences all number
    4
    4
    4
    7
    Pruritus
         subjects affected / exposed
    2 / 100 (2.00%)
    5 / 66 (7.58%)
    5 / 69 (7.25%)
    7 / 66 (10.61%)
         occurrences all number
    2
    6
    5
    8
    Rash
         subjects affected / exposed
    2 / 100 (2.00%)
    4 / 66 (6.06%)
    4 / 69 (5.80%)
    4 / 66 (6.06%)
         occurrences all number
    2
    5
    4
    4
    Rash maculo-papular
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 66 (3.03%)
    4 / 69 (5.80%)
    3 / 66 (4.55%)
         occurrences all number
    3
    2
    4
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    26 / 100 (26.00%)
    12 / 66 (18.18%)
    14 / 69 (20.29%)
    13 / 66 (19.70%)
         occurrences all number
    28
    14
    17
    19
    Back pain
         subjects affected / exposed
    8 / 100 (8.00%)
    5 / 66 (7.58%)
    5 / 69 (7.25%)
    4 / 66 (6.06%)
         occurrences all number
    8
    5
    6
    5
    Muscular weakness
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    3 / 66 (4.55%)
         occurrences all number
    1
    0
    1
    6
    Musculoskeletal pain
         subjects affected / exposed
    2 / 100 (2.00%)
    4 / 66 (6.06%)
    2 / 69 (2.90%)
    1 / 66 (1.52%)
         occurrences all number
    2
    5
    3
    1
    Myalgia
         subjects affected / exposed
    11 / 100 (11.00%)
    0 / 66 (0.00%)
    3 / 69 (4.35%)
    5 / 66 (7.58%)
         occurrences all number
    12
    0
    3
    5
    Osteoporosis
         subjects affected / exposed
    2 / 100 (2.00%)
    4 / 66 (6.06%)
    3 / 69 (4.35%)
    1 / 66 (1.52%)
         occurrences all number
    2
    4
    3
    1
    Pain in extre
         subjects affected / exposed
    9 / 100 (9.00%)
    4 / 66 (6.06%)
    3 / 69 (4.35%)
    2 / 66 (3.03%)
         occurrences all number
    11
    4
    3
    3
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 66 (1.52%)
    2 / 69 (2.90%)
    4 / 66 (6.06%)
         occurrences all number
    1
    2
    2
    4
    Oral herpes
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    6 / 69 (8.70%)
    1 / 66 (1.52%)
         occurrences all number
    1
    0
    8
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 100 (5.00%)
    5 / 66 (7.58%)
    7 / 69 (10.14%)
    3 / 66 (4.55%)
         occurrences all number
    6
    5
    7
    4
    Urinary tract infection
         subjects affected / exposed
    5 / 100 (5.00%)
    5 / 66 (7.58%)
    7 / 69 (10.14%)
    3 / 66 (4.55%)
         occurrences all number
    6
    5
    7
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 66 (1.52%)
    5 / 69 (7.25%)
    7 / 66 (10.61%)
         occurrences all number
    4
    1
    5
    9
    Hyperglycaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 66 (0.00%)
    1 / 69 (1.45%)
    6 / 66 (9.09%)
         occurrences all number
    2
    0
    1
    7
    Hypokalaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 66 (0.00%)
    4 / 69 (5.80%)
    1 / 66 (1.52%)
         occurrences all number
    0
    0
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Nov 2015
    Addition of secondary endpoint and associated secondary objective: Changes between surgical intent at baseline, surgical intent after 14 weeks and actual surgery received after treatment with letrozole with or without palbociclib. Background and trial rationale section of protocol updated to reflect new information following publication of data from a Phase III trial of palbociclib. Eligibility criteria updated in UK protocol for clarity and to ensure alignment with North American protocol. Minor revisions and clarification to screening assessment section. Prohibition of PPIs as a concomitant medication with palbociclib treatment removed.
    18 Mar 2016
    Update to palbociclib Investigator Brochure. No change to protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30523750
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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