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    Clinical Trial Results:
    neoMONARCH: A Phase 2 Neoadjuvant Trial Comparing the Biological Effects of 2 Weeks of Abemaciclib (LY2835219) in Combination with Anastrozole to those of Abemaciclib Monotherapy and Anastrozole Monotherapy and Evaluating the Clinical Activity and Safety of a Subsequent 14 Weeks of Therapy with Abemaciclib in Combination with Anastrozole in Postmenopausal Women with Hormone Receptor Positive, HER2 Negative Breast Cancer

    Summary
    EudraCT number
    		 2014-005486-75
    Trial protocol
    		 ES   AT   DE   NL   BE   IT  
    Global end of trial date
    12 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Feb 2019
    First version publication date
    24 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I3Y-MC-JPBY
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02441946
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial ID: 15805
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon - Fri 9 AM - 5 PM EST , Eli Lilly and Company, 1 877-CTLilly,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-285-4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the biological activity of abemaciclib in combination with anastrozole, abemaciclib monotherapy, and anastrozole monotherapy by assessing the percentage change from the baseline value in Ki67 expression after 2 weeks of therapy.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Austria: 26
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    United States: 80
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    224
    EEA total number of subjects
    103
    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)
    117
    From 65 to 84 years
    103
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants who had progressive disease at the end of the study but off study drug were considered to have completed the study. Participants were randomized to anastrozole, or abemaciclib, and abemaciclib + anastrozole in cycle 1. All participants received abemaciclib + anastrozole post cycle 1.

    Period 1
    Period 1 title
    Cycle 1 Period 1 (2 Weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Abemaciclib + Anastrozole
    Arm description
    		 Participants were given 150 milligram (mg) of abemaciclib orally every 12 hours (Q12H) plus 1 mg of anastrozole orally once daily (QD) for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Abemaciclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were given 150 mg of abemaciclib orally Q12H.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg of anastrozole orally QD for 2 weeks.

    Arm title
    		 Abemaciclib
    Arm description
    		 Participants received 150 mg of abemaciclib orally Q12H for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abemaciclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 150 mg of abemaciclib orally Q12H for 2 weeks.

    Arm title
    		 Anastrozole
    Arm description
    		 Participants received 1 mg of anastrozole orally QD for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 1 mg of anastrozole orally QD for 2 weeks.

    Number of subjects in period 1
    		Abemaciclib + Anastrozole Abemaciclib Anastrozole
    Started
    74
    76
    74
    Received at least one dose of study drug
    74
    75
    74
    Completed
    72
    71
    74
    Not completed
    2
    5
    0
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    -
    3
    -
         Never Treated
    -
    1
    -
         Adverse event, non-fatal
    1
    1
    -
    Period 2
    Period 2 title
    Cycle 2 - 5 Period 2 (14 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    All 217 participants were treated with abemaciclib + anastrozole post cycle 1.

    Arms
    Arm title
    		 Abemaciclib + Anastrozole
    Arm description
    		 All participants received 150 mg of abemaciclib orally Q12H plus 1 mg of anastrozole orally QD for an additional 14 weeks. Total treatment duration was 16 weeks. Cycle 2 lasts 14 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Abemaciclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 150 mg of abemaciclib orally Q12H for 14 weeks.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg of anastrozole orally QD for 2 weeks

    Number of subjects in period 2
    		Abemaciclib + Anastrozole
    Started
    217
    Received at Least One Dose of Study Drug
    217
    Completed
    190
    Not completed
    27
         Consent withdrawn by subject
    9
         Physician Decision
    1
         Adverse event, non-fatal
    15
         Noncompliance with study drug
    1
         Protocol deviation
    1
    Period 3
    Period 3 title
    Extension Period (8 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Abemaciclib + Anastrozole
    Arm description
    		 150 mg of abemaciclib orally Q12H or 1 mg of anastrozole orally QD for 2 weeks. All participants received 150 mg of abemaciclib orally Q12H plus 1 mg of anastrozole orally QD for an additional 8 weeks, after completed the mandatory 16 weeks of study treatment. Total treatment duration was 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Abemaciclib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were given 150 mg of abemaciclib orally Q12H.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 1 mg of anastrozole orally QD for 8 weeks. All participants received 150 mg of abemaciclib orally Q12H plus 1 mg of anastrozole orally QD for an additional 8 weeks. Total treatment duration was 24 weeks.

    Number of subjects in period 3 [1]
    		Abemaciclib + Anastrozole
    Started
    42
    Completed
    40
    Not completed
    2
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: All participants who did not discontinue continued to the extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Abemaciclib + Anastrozole
    Reporting group description
    		 Participants were given 150 milligram (mg) of abemaciclib orally every 12 hours (Q12H) plus 1 mg of anastrozole orally once daily (QD) for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.

    Reporting group title
    Abemaciclib
    Reporting group description
    		 Participants received 150 mg of abemaciclib orally Q12H for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.

    Reporting group title
    Anastrozole
    Reporting group description
    		 Participants received 1 mg of anastrozole orally QD for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.

    Reporting group values
    		 Abemaciclib + Anastrozole Abemaciclib Anastrozole Total
    Number of subjects
    		 74 76 74 224
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.9 ( 8.4 ) 63.8 ( 7.9 ) 64.9 ( 8.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 74 76 74 224
        Male
    		 0 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 8 5 19
        Not Hispanic or Latino
    		 61 61 60 182
        Unknown or Not Reported
    		 7 7 9 23
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 12 16 16 44
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Black or African American
    		 5 1 2 8
        White
    		 55 57 55 167
        More than one race
    		 1 1 1 3
        Unknown or Not Reported
    		 1 0 0 1
    Region of Enrollment
    Units: Subjects
        Canada
    		 0 3 1 4
        Austria
    		 10 4 12 26
        Netherlands
    		 1 0 2 3
        Belgium
    		 5 2 4 11
        United States
    		 26 28 26 80
        Taiwan
    		 5 7 11 23
        Korea, Republic of Italy
    		 5 7 2 14
        Italy
    		 4 3 4 11
        Germany
    		 5 6 4 15
        Spain
    		 13 16 8 37
    Eastern Cooperative Oncology Group (ECOG)
    Units: Subjects
        0 (Fully Active)
    		 69 70 64 203
        1 (Restricted, able to do light sedentary work)
    		 5 5 10 20
        Unknown or Not Reported)
    		 0 1 0 1
    Ki67 at Baseline
    Tumor tissue collected through a core biopsy at baseline and at the end of cycle 1 was used to determine Ki67 expression. Ki67 expression is defined as the percent of cells staining positive by validated central assay.
    Units: Percent Cells Positive
        arithmetic mean (standard deviation)
    		 27.24 ( 13.56 ) 27.88 ( 12.13 ) 26.86 ( 12.32 ) -

    End points

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    End points reporting groups
    Reporting group title
    Abemaciclib + Anastrozole
    Reporting group description
    		 Participants were given 150 milligram (mg) of abemaciclib orally every 12 hours (Q12H) plus 1 mg of anastrozole orally once daily (QD) for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.

    Reporting group title
    Abemaciclib
    Reporting group description
    		 Participants received 150 mg of abemaciclib orally Q12H for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.

    Reporting group title
    Anastrozole
    Reporting group description
    		 Participants received 1 mg of anastrozole orally QD for 2 weeks. Total treatment duration was 16 weeks. Cycle 1 lasts 14 days.
    Reporting group title
    Abemaciclib + Anastrozole
    Reporting group description
    		 All participants received 150 mg of abemaciclib orally Q12H plus 1 mg of anastrozole orally QD for an additional 14 weeks. Total treatment duration was 16 weeks. Cycle 2 lasts 14 days.
    Reporting group title
    Abemaciclib + Anastrozole
    Reporting group description
    		 150 mg of abemaciclib orally Q12H or 1 mg of anastrozole orally QD for 2 weeks. All participants received 150 mg of abemaciclib orally Q12H plus 1 mg of anastrozole orally QD for an additional 8 weeks, after completed the mandatory 16 weeks of study treatment. Total treatment duration was 24 weeks.

    Subject analysis set title
    Abemaciclib + Anastrozole
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received combination treatment post cycle 1.

    Primary: Percent Change From Baseline to 2 Weeks in Ki67 Expression

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    End point title
    		 Percent Change From Baseline to 2 Weeks in Ki67 Expression
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, 2 Weeks
    End point values
    		 Abemaciclib + Anastrozole Abemaciclib Anastrozole
    Number of subjects analysed
    59 [1]
    52 [2]
    56 [3]
    Units: Percent Change
        geometric mean (confidence interval 95%)
    -93 (-95 to -90)
    -91 (-93 to -87)
    -63 (-73 to -49)
    Notes
    [1] - Geometric mean and confidence interval are percentages.
    [2] - Participants with a valid baseline Ki67 of at least 5% and valid Ki67 at 2-weeks.
    [3] - Participants with a valid baseline Ki67 of at least 5% and valid Ki67 at 2-weeks.
    Statistical analysis title
    		 Statistical Analysis Percent Change Ki67 (1)
    Comparison groups
    Abemaciclib + Anastrozole v Anastrozole
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 1-sided
    Parameter type
    		 Ratio of Geometric Means
    Point estimate
    0.19
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.28
    Statistical analysis title
    		 Statistical Analysis Percent Change Ki67 (2)
    Comparison groups
    Abemaciclib v Anastrozole
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 1-sided
    Parameter type
    		 Ratio of Geometric Mean
    Point estimate
    0.25
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.38

    Secondary: Percentage of Participants With Pathologic Complete Response (pCR)

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    End point title
    		 Percentage of Participants With Pathologic Complete Response (pCR)
    End point description
    pCR is defined as absence of invasive cancer in the breast and sampled regional lymph nodes.
    End point type
    Secondary
    End point timeframe
    16 Weeks
    End point values
    		 Abemaciclib + Anastrozole
    Number of subjects analysed
    190 [4]
    Units: Percentage of Participants
        number (not applicable)
    3.7
    Notes
    [4] - All participants who received combination treatment and underwent surgery after the end of treatment
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complete Response (CR) or Partial Response (PR): Clinical Objective Response

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    End point title
    		 Percentage of Participants With Complete Response (CR) or Partial Response (PR): Clinical Objective Response
    End point description
    The best overall response rate (ORR) is the percentage of participants with a best OR of CR or PR, according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1. ORR is recorded from the start of the study treatment until the earliest of objective progression or start of new anticancer therapy. A responder depends on target and non-target disease and the appearance of new lesions. CR is defined as the disappearance of all nontarget lesions. PR is at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. All lymph nodes are non-pathological or normal in size (<10mm short axis). Progressive disease (PD) is a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, a relative increase of 20%, the sum must also demonstrate an absolute increase of 5 mm. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
    End point type
    Secondary
    End point timeframe
    From Start of Treatment up to 16 Weeks
    End point values
    		 Abemaciclib + Anastrozole
    Number of subjects analysed
    224 [5]
    Units: Percentage of Participants
        number (not applicable)
    53.6
    Notes
    [5] - All participants who were randomized at study entry.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complete Radiologic Response or Partial Radiological Response: Radiological Response

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    End point title
    		 Percentage of Participants With Complete Radiologic Response or Partial Radiological Response: Radiological Response
    End point description
    Radiological response is the percentage of participants with CR, PR according to RECIST v.1.1. A responder is defined as any participant who exhibits a CR or PR. CR is the disappearance of all target lesions. PR is a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. PD is 20% increase in the sum of diameters of target lesions taking as reference the smallest sum and the appearance of 1 or more new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as PD.
    End point type
    Secondary
    End point timeframe
    From Start of Treatment Up to 16 Weeks
    End point values
    		 Abemaciclib + Anastrozole
    Number of subjects analysed
    224 [6]
    Units: Percentage of Participants
        number (not applicable)
    46.4
    Notes
    [6] - All participants who were randomized at study entry.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 2 in EORTC QLQ-C30

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    End point title
    		 Change from Baseline to Week 2 in EORTC QLQ-C30
    End point description
    The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire is a self-reported general cancer instrument consisting of 30 items covered by 1 of 3 dimensions: global health status/quality of life (2 items), functional scales (15 total items addressing either physical, role, emotional, cognitive, or social functioning), and symptom scales (13 total items addressing either fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, or financial impact) EORTC QLQ-C30 data were scored on a scale ranging from 0 to 100 as described by Aaronson and colleagues (1993). A higher score represents a higher level of response. A lower score represents a lower level of response. Thus a high score for a functional scale or global health status represents a high level of functioning or health status. On the other hand, a high score for a symptom scale/item represents a high level of symptomatology.
    End point type
    Secondary
    End point timeframe
    Baseline, 2 Weeks
    End point values
    		 Abemaciclib + Anastrozole Abemaciclib Anastrozole
    Number of subjects analysed
    62 [7]
    66 [8]
    69 [9]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Global Health Status
    -9.5 ( 17.9 )
    -7.6 ( 18.1 )
    -2.3 ( 13.4 )
        Physical Functioning
    -3.2 ( 10.2 )
    -5.5 ( 12.6 )
    -0.3 ( 7.5 )
        Role Functioning
    -11.3 ( 23.7 )
    -11.4 ( 24.0 )
    -2.2 ( 17.4 )
        Emotional
    5.4 ( 17.1 )
    3.5 ( 21.4 )
    1.3 ( 14.0 )
        Cognitive
    0.5 ( 12.4 )
    -2.0 ( 15.6 )
    -1.4 ( 11.0 )
        Social Functioning
    -8.3 ( 18.8 )
    -3.5 ( 16.7 )
    -0.7 ( 12.6 )
        Fatigue
    13.6 ( 23.2 )
    13.9 ( 22.6 )
    4.0 ( 12.8 )
        Nausea/Vomiting
    11.8 ( 17.7 )
    9.6 ( 12.4 )
    2.7 ( 7.4 )
        Pain
    4.8 ( 19.9 )
    3.5 ( 19.3 )
    2.9 ( 16.7 )
        Dyspnea
    1.1 ( 19.1 )
    0.5 ( 19.8 )
    -1.0 ( 12.7 )
        Insomnia
    -1.1 ( 19.1 )
    0.5 ( 29.5 )
    -1.9 ( 22.1 )
        Appetite Loss
    16.9 ( 28.3 )
    16.9 ( 27.5 )
    1.9 ( 15.0 )
        Constipation
    22.4 ( 31.5 )
    16.9 ( 31.2 )
    1.9 ( 15.0 )
        Diarrhea
    18.3 ( 29.4 )
    27.8 ( 25.9 )
    0.0 ( 15.1 )
        Financial Impact
    -2.8 ( 19.7 )
    2.0 ( 18.4 )
    0.0 ( 11.4 )
    Notes
    [7] - n=61 for appetite loss and n=61 for constipation and n=60 for financial impact.
    [8] - n=60 for constipation.
    [9] - All participants who had evaluable EORTC QLQ-30 data.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Apparent Clearance of Abemaciclib and Anastrozole

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    End point title
    		 Pharmacokinetics (PK): Apparent Clearance of Abemaciclib and Anastrozole
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle(C)1, Day(D)1: 2 to 4 Hours (Hrs) Postdose; C1D14 (+2 Days) -4 Hours, Predose, 3 Hrs Postdose; C3D1-C5D28: Predose, 3+/- 0.5 Hrs Postdose
    End point values
    		 Abemaciclib + Anastrozole Abemaciclib Anastrozole
    Number of subjects analysed
    74 [10]
    75 [11]
    74 [12]
    Units: Liters/Hour
        geometric mean (geometric coefficient of variation)
    24.0 ( 32 )
    19.1 ( 55 )
    24.4 ( 61 )
    Notes
    [10] - geometric coefficient of variation is a percentage.
    [11] - geometric coefficient of variation is a percentage.
    [12] - geometric coefficient of variation is a percentage.
    No statistical analyses for this end point

    Secondary: PK: Apparent Volume of Distribution of Abemaciclib and Anastrozole

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    End point title
    		 PK: Apparent Volume of Distribution of Abemaciclib and Anastrozole
    End point description
    End point type
    Secondary
    End point timeframe
    C1D1: 2 to 4 Hrs Postdose; C1D14 (+2 Days) -4 Hrs, Predose, 3 Hrs Postdose; C3D1-C5D28: Predose, 3+/- 0.5 Hrs Postdose
    End point values
    		 Abemaciclib + Anastrozole Abemaciclib Anastrozole
    Number of subjects analysed
    74 [13]
    75 [14]
    74 [15]
    Units: Liters
        geometric mean (geometric coefficient of variation)
    941 ( 53 )
    720 ( 58 )
    758 ( 49 )
    Notes
    [13] - geometric coefficient of variation is a percentage.
    [14] - geometric coefficient of variation is a percentage.
    [15] - geometric coefficient of variation is a percentage.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 Weeks
    Adverse event reporting additional description
    I3Y-MC-JPBY
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Abemaciclib + Anastrozole 1 mg Cycle1
    Reporting group description
    		 -

    Reporting group title
    Anastrozole Cycle1
    Reporting group description
    		 -

    Reporting group title
    Abemaciclib Cycle1
    Reporting group description
    		 -

    Reporting group title
    Abemaciclib + Anastrozole Post Cycle1 and Beyond
    Reporting group description
    		 -

    Serious adverse events
    		 Abemaciclib + Anastrozole 1 mg Cycle1 Anastrozole Cycle1 Abemaciclib Cycle1 Abemaciclib + Anastrozole Post Cycle1 and Beyond
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    16 / 217 (7.37%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    0 / 217 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    blood creatinine increased
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    fracture
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    3 / 217 (1.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    acute coronary syndrome
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         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
    angina pectoris
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    seizure
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    neutropenia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         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
    abdominal pain
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pancreatitis
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    hypoxia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    skin ulcer
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    chronic kidney disease
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         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
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         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
    Infections and infestations
    mastitis
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    0 / 217 (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
    dehydration
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         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
    hypokalaemia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 75 (0.00%)
    1 / 217 (0.46%)
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Abemaciclib + Anastrozole 1 mg Cycle1 Anastrozole Cycle1 Abemaciclib Cycle1 Abemaciclib + Anastrozole Post Cycle1 and Beyond
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 74 (83.78%)
    17 / 74 (22.97%)
    58 / 75 (77.33%)
    189 / 217 (87.10%)
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    26 / 217 (11.98%)
         occurrences all number
    4
    0
    1
    27
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    22 / 217 (10.14%)
         occurrences all number
    3
    0
    1
    23
    blood creatinine increased
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    14 / 217 (6.45%)
         occurrences all number
    2
    0
    1
    15
    weight decreased
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    2 / 75 (2.67%)
    15 / 217 (6.91%)
         occurrences all number
    0
    0
    2
    17
    Vascular disorders
    hot flush
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    3 / 74 (4.05%)
    5 / 74 (6.76%)
    2 / 75 (2.67%)
    19 / 217 (8.76%)
         occurrences all number
    3
    5
    2
    20
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 74 (1.35%)
    5 / 75 (6.67%)
    8 / 217 (3.69%)
         occurrences all number
    1
    1
    5
    10
    dysgeusia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 74 (0.00%)
    5 / 75 (6.67%)
    17 / 217 (7.83%)
         occurrences all number
    4
    0
    5
    18
    headache
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 74 (0.00%)
    5 / 75 (6.67%)
    16 / 217 (7.37%)
         occurrences all number
    3
    0
    5
    17
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    3 / 75 (4.00%)
    27 / 217 (12.44%)
         occurrences all number
    0
    0
    3
    31
    leukopenia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    3 / 75 (4.00%)
    19 / 217 (8.76%)
         occurrences all number
    1
    0
    3
    22
    neutropenia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    45 / 217 (20.74%)
         occurrences all number
    2
    0
    1
    58
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    19 / 74 (25.68%)
    3 / 74 (4.05%)
    17 / 75 (22.67%)
    62 / 217 (28.57%)
         occurrences all number
    20
    4
    18
    70
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    13 / 74 (17.57%)
    2 / 74 (2.70%)
    7 / 75 (9.33%)
    30 / 217 (13.82%)
         occurrences all number
    15
    2
    7
    34
    constipation
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    27 / 74 (36.49%)
    5 / 74 (6.76%)
    26 / 75 (34.67%)
    50 / 217 (23.04%)
         occurrences all number
    27
    5
    30
    62
    diarrhoea
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    31 / 74 (41.89%)
    2 / 74 (2.70%)
    29 / 75 (38.67%)
    101 / 217 (46.54%)
         occurrences all number
    34
    2
    33
    162
    dry mouth
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    5 / 75 (6.67%)
    7 / 217 (3.23%)
         occurrences all number
    1
    0
    5
    8
    dyspepsia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    6 / 74 (8.11%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    7 / 217 (3.23%)
         occurrences all number
    6
    0
    1
    7
    nausea
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    19 / 74 (25.68%)
    2 / 74 (2.70%)
    15 / 75 (20.00%)
    67 / 217 (30.88%)
         occurrences all number
    19
    2
    15
    75
    stomatitis
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    19 / 217 (8.76%)
         occurrences all number
    2
    0
    1
    21
    vomiting
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    25 / 217 (11.52%)
         occurrences all number
    6
    0
    1
    32
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 75 (1.33%)
    12 / 217 (5.53%)
         occurrences all number
    0
    0
    1
    12
    pruritus
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 74 (1.35%)
    1 / 75 (1.33%)
    20 / 217 (9.22%)
         occurrences all number
    2
    1
    1
    21
    rash
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    2 / 75 (2.67%)
    22 / 217 (10.14%)
         occurrences all number
    0
    0
    2
    24
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 19.1
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 74 (0.00%)
    13 / 75 (17.33%)
    33 / 217 (15.21%)
         occurrences all number
    5
    0
    13
    36

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2015
    Amendment (a): updated the dosing guidance and clarify that blood cell growth factors are only to be used in a manner consistent with American Society of Clinical Oncology (ASCO) guidelines. Additional modifications duration of neoadjuvant therapy reference, clarified inclusion criterion lymph nodes and exclusion criterion loperamide hypersensitivity, extended treatment for patients experiencing clinical benefit, clarified cautions when coadministering cytochrome P450s, updated tumor measurement information and cycle 5 biopsy window, and clarified guidelines for ultrasound use, included information on biopsy after treatment discontinuation due to AE and added interim analyses.

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

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