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    Clinical Trial Results:
    monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of Abemaciclib plus Trastuzumab with or without Fulvestrant to Standard-of-Care Chemotherapy of Physician?s Choice plus Trastuzumab in Women with HR+, HER2+ Locally Advanced or Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2015-003400-24
    Trial protocol
    		 ES   GR   BE   GB   DE   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    24 Apr 2020
    First version publication date
    24 Apr 2020
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    I3Y-MC-JPBZ
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02675231
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 15804
    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
    Interim
    Date of interim/final analysis
    08 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Apr 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the effectiveness of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus physicians choice standard of care chemotherapy in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+) locally advanced or metastatic breast cancer after prior exposure to at least two HER2-directed therapies for advanced disease.
    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
    23 May 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 19
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 30
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 7
    Worldwide total number of subjects
    237
    EEA total number of subjects
    111
    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)
    185
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In the Subject disposition, participants who completed were those who died due to any cause or were alive and on study at conclusion but off treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Arm description
    		 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abemaciclib
    Investigational medicinal product code
    Other name
    LY2835219
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.

    Arm title
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Arm description
    		 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Abemaciclib
    Investigational medicinal product code
    Other name
    LY2835219
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg abemaciclib given orally Q12H of a 21-day cycle.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Arm title
    		 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Arm description
    		 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician’s choice administered according to product label.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Investigational medicinal product name
    Standard of Care Single Agent Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard-of-care single-agent chemotherapy of physician’s choice administered according to product label

    Number of subjects in period 1
    		150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Started
    79
    79
    79
    Received at Least One Dose of Drug
    78
    77
    72
    Completed
    53
    43
    53
    Not completed
    26
    36
    26
         On study treatment/follow up
    23
    31
    23
         Consent withdrawn by subject
    1
    3
    1
         Lost to follow-up
    2
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Reporting group description
    		 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.

    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Reporting group description
    		 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Reporting group title
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Reporting group description
    		 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician’s choice administered according to product label.

    Reporting group values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy Total
    Number of subjects
    		 79 79 79 237
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.34 ( 10.25 ) 54.99 ( 11.08 ) 56.77 ( 12.37 ) -
    Gender categorical
    Units: Subjects
        Female
    		 79 79 79 237
        Male
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 14 11 12 37
        Not Hispanic or Latino
    		 58 52 56 166
        Unknown or Not Reported
    		 7 16 11 34
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1 2
        Asian
    		 15 10 10 35
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 3 2 4 9
        White
    		 55 53 55 163
        More than one race
    		 0 0 1 1
        Unknown or Not Reported
    		 6 13 8 27
    Region of Enrollment
    Units: Subjects
        Argentina
    		 9 7 3 19
        United States
    		 20 8 17 45
        United Kingdom
    		 9 9 10 28
        Spain
    		 6 8 3 17
        Greece
    		 1 1 2 4
        Canada
    		 2 4 4 10
        South Korea
    		 11 9 10 30
        Belgium
    		 5 7 7 19
        Brazil
    		 3 1 4 8
        Italy
    		 2 5 2 9
        Mexico
    		 2 1 3 6
        Australia
    		 2 4 2 8
        France
    		 6 13 8 27
        Germany
    		 1 2 4 7

    End points

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    End points reporting groups
    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Reporting group description
    		 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.

    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Reporting group description
    		 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Reporting group title
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Reporting group description
    		 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician’s choice administered according to product label.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS time was measured from the date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death from any cause. Progressive Disease (PD) was at least a 20% increase in sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of first dose, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. Analysis Population Description (APD) included all enrolled participants.
    End point type
    Primary
    End point timeframe
    Baseline to Progressive Disease or Death from Any Cause (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79 [1]
    79 [2]
    79 [3]
    Units: Months
        median (confidence interval 95%)
    8.3 (5.9 to 12.6)
    5.7 (4.2 to 7.2)
    5.7 (5.4 to 6.9)
    Notes
    [1] - Censored participants: =23
    [2] - Censored participants: =18
    [3] - Censored participants: =27
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0506 [5]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.
    [5] - This is statistically significant at the pre-specified 2-sided alpha of 0·2
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.7695
    Method
    		 Logrank
    Confidence interval
    Notes
    [6] - PFS analysis was planned after approximately 165 PFS events occurred in the enrolled population, yielding greater than or equal to (≥) 80% power assuming a Hazard ration (HR) of 0·667 at an experiment-wise 2-sided alpha level of 0·2.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS defined as the time from first dose date to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.
    End point type
    Secondary
    End point timeframe
    Baseline to Death from Any Cause (Estimated up to 48 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79 [7]
    79 [8]
    79 [9]
    Units: Months
        number (not applicable)
    99999
    99999
    99999
    Notes
    [7] - Results will be reported after last patient visit (LPV). 99999=NA
    [8] - Results will be reported after LPV. 99999=NA
    [9] - Results will be reported after LPV. 99999=NA
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)

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    End point title
    		 Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Response Rate (ORR)
    End point description
    ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. APD included all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Objective Disease Progression (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79
    79
    79
    Units: Percentage of participants
        number (confidence interval 95%)
    32.9 (22.5 to 43.3)
    13.9 (6.3 to 21.6)
    13.9 (6.3 to 21.6)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    DoR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date. APD included all enrolled participants who received at least one dose of study drug and achieved CR or PR. 99999=NA because for 8 mg/kg Trastuzumab + Standard of Care Chemotherapy, the median and upper limit of the 95% CI was not calculated due to the high censoring rate.
    End point type
    Secondary
    End point timeframe
    Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    26 [10]
    11 [11]
    11 [12]
    Units: Months
        median (confidence interval 95%)
    12.5 (6.5 to 23.5)
    9.5 (2.8 to 22.7)
    99999 (4.1 to 99999)
    Notes
    [10] - Censored participants: =12
    [11] - Censored participants: =3
    [12] - Censored participants: =11 99999 = NA.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)

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    End point title
    		 Percentage of Participants with a Best Overall Response of CR, PR, or Stable Disease (SD): Disease Control Rate (DCR)
    End point description
    Disease Control Rate (DCR) was the percentage of participants with a best overall response of CR, PR, or Stable Disease (SD) as per Response using RECIST v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. APD included all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Baseline to Objective Disease Progression (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79
    79
    79
    Units: Percentage of participants
        number (confidence interval 95%)
    78.5 (69.4 to 87.5)
    74.7 (65.1 to 84.3)
    67.1 (56.7 to 77.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Best Overall Response of CR, PR, or SD with Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR)

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    End point title
    		 Percentage of Participants with Best Overall Response of CR, PR, or SD with Duration of SD for at Least 6 Months: Clinical Benefit Rate (CBR)
    End point description
    Clinical benefit rate defined as percentage of participants with best overall response of CR, PR, or SD with a duration of at least 6 months. CR, PR, or SD were defined using RECIST, v1.1 criteria. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. Percentage of participants = (participants with CR+PR+SD with a duration of at least 6 months /number of participants enrolled) *100. APD included all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Date of CR, PR or SD to 6 Months Post CR, PR or SD (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79
    79
    79
    Units: Percentage of participants
        number (confidence interval 95%)
    58.2 (47.4 to 69.1)
    45.6 (34.6 to 56.6)
    38.0 (27.3 to 48.7)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf)

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    End point title
    		 Change from Baseline in Pain and Symptom Burden Assessment on the Modified Brief Pain Inventory-Short Form (mBPI-sf)
    End point description
    The mBPI-sf is an 11-item instrument used as a multiple-item measure of cancer pain intensity. In addition to pain intensity (4 items), the mBPI-sf is designed for participants to record the presence of pain in general, pain relief, and pain interference with function (general activity, mood, ability to walk, ability to perform normal work, relations with others, sleep, enjoyment of life). Responses for the mBPI-sf items are captured through the use of 11-point numeric rating scales anchored at 0 (no pain or does not interfere) and 10 (pain as bad as you can imagine or completely interferes). The mBPI-sf recall period is 24 hours and typical completion time for this instrument is less than 5 minutes. Mean Interference Score data is reported here. Least square (LS) Mean value was controlled for Treatment, visit, Treatment*Visit and baseline. APD included all enrolled participants.
    End point type
    Secondary
    End point timeframe
    Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    79
    79
    79
    Units: units on a scale
        least squares mean (standard error)
    0 ( 0.18 )
    0.20 ( 0.18 )
    0.31 ( 0.19 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.232 [13]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [13] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.

    Secondary: Change from Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)

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    End point title
    		 Change from Baseline in Symptom Burden on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)
    End point description
    EORTC QLQ-C30 v3.0 was a self-administered questionnaire with multidimensional scales that measures 5 functional domains (physical, role, cognitive, emotional, and social), global health status, and symptom scales of fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties. A linear transformation is applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For functional domains and global health status, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms. LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline. APD included all randomized participants who received at least one dose of study drug with baseline and post-baseline EORTC QLQ-C30 data for each EORTC QLQ-C30 items.
    End point type
    Secondary
    End point timeframe
    Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    72
    72
    69
    Units: units on a scale
    least squares mean (standard error)
        Global health status
    -2.9 ( 1.6 )
    -5.9 ( 1.7 )
    -1.9 ( 1.8 )
        Functional scale: Physical functioning
    -1.0 ( 1.6 )
    -4.4 ( 1.6 )
    -4.5 ( 1.7 )
        Functional scale: Role functioning
    -2.7 ( 2.2 )
    -5.0 ( 2.3 )
    -8.2 ( 2.4 )
        Functional scale: Emotional functioning
    2.4 ( 1.7 )
    -0.4 ( 1.8 )
    1.1 ( 1.8 )
        Functional scale: Cognitive functioning
    -1.8 ( 1.4 )
    -1.1 ( 1.5 )
    -1.6 ( 1.6 )
        Functional scale: Social functioning
    -0.9 ( 1.9 )
    -0.9 ( 1.9 )
    -2.4 ( 2.0 )
        Symptom scale: Fatigue
    1.8 ( 1.9 )
    7.0 ( 2.0 )
    4.7 ( 2.1 )
        Symptom scale: Nausea and vomiting
    6.3 ( 1.4 )
    5.6 ( 1.4 )
    2.2 ( 1.5 )
        Symptom scale: Pain
    -2.5 ( 2.1 )
    3.1 ( 2.1 )
    4.3 ( 2.2 )
        Symptom scale: Dyspnoea
    0.7 ( 1.9 )
    2.9 ( 2.0 )
    3.7 ( 2.1 )
        Symptom scale: Insomnia
    -4.4 ( 2.1 )
    -1.6 ( 2.2 )
    2.0 ( 2.3 )
        Symptom scale: Appetite loss
    6.3 ( 2.3 )
    5.5 ( 2.4 )
    2.4 ( 2.5 )
        Symptom scale: Constipation
    -6.3 ( 1.9 )
    -10.5 ( 1.9 )
    -3.4 ( 2.0 )
        Symptom scale: Diarrhoea
    21.5 ( 2.2 )
    25.3 ( 2.3 )
    2.2 ( 2.4 )
        Symptom scale: Financial difficulties
    0.8 ( 2.0 )
    -1.9 ( 2.1 )
    -3.2 ( 2.2 )
    Statistical analysis title
    		 Statistical Analysis 1: Global health status
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.689 [14]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [14] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 2: Functional scale: Physical
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.141 [15]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [15] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 3: Functional scale: Role
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.095 [16]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [16] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical analysis 4:Functional scale: Emotional
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.591 [17]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [17] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 5: Functional scale:Cognitive
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.935 [18]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [18] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical analysis 6: Functional scale: Social
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.578 [19]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [19] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 7: Symptom scale: Fatigue
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.308 [20]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [20] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 8 : Symptom: Nausea, vomiting
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043 [21]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [21] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 9: Symptom scale: Pain
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026 [22]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [22] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 10: Symptom scale: Dyspnoea
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.276 [23]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [23] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 11: Symptom scale: Insomnia
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041 [24]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [24] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 12: Symptom: Appetite loss
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.262 [25]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [25] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 13:Symptom scale:Constipation
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.285
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [26] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 14: Symptom scale: Diarrhoea
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [27]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [27] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 15: Symptom scale: Financial
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18 [28]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [28] - p-values are from Type 3 sums of squares mixed models repeated measures model (MMRM): Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.

    Secondary: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

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    End point title
    		 Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score
    End point description
    The EQ-5D-5L is a standardized instrument for use as a measure of self-reported health status. Participants completed the 5-level (no problem, slight problem, moderate problem, severe problem, and inability or extreme problem), 5-dimension (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) questionnaire concerning their current health state. Five dimensions of health status are each assessed with 5 response options and scored as a composite index which were anchored on a scale of 0 to 1 with a higher score representing better health status.LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline. APD included all enrolled participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L data.
    End point type
    Secondary
    End point timeframe
    Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    72
    72
    68
    Units: units on a scale
        least squares mean (standard error)
    0.01 ( 0.02 )
    -0.01 ( 0.02 )
    -0.04 ( 0.02 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033 [29]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [29] - p-values are from Type 3 sums of squares mixed models repeated measures model: Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.275 [30]
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [30] - p-values are from Type 3 sums of squares mixed models repeated measures model: Change from baseline = Treatment + Visit + Treatment*Visit + Baseline.

    Secondary: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS)

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    End point title
    		 Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Visual Analogue Scale (VAS)
    End point description
    European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) is a standardized measure of health status of the participant. The EQ-5D-5L is assessed using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. A higher score indicates better health state. LS Mean value was controlled for Treatment, visit, Treatment*Visit and baseline. APD included all enrolled participants who received at least one dose of study drug with baseline and post-baseline EQ-5D 5L VAS data.
    End point type
    Secondary
    End point timeframe
    Baseline, 30 Days After Treatment Discontinuation (Up To 36 Months)
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects analysed
    72
    71
    70
    Units: millimeter (mm)
        least squares mean (standard error)
    0.61 ( 1.4 )
    -1.64 ( 1.4 )
    -0.61 ( 1.5 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant v 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.546
    Method
    		 MMRM Model
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy v 150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.62
    Method
    		 MMRM Model
    Confidence interval
    Notes
    [31] - EQ 5D-5L Visual Analog Scale Score

    Secondary: Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and its Metabolites (M2 and M20)

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    End point title
    		 Pharmacokinetics (PK): Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and its Metabolites (M2 and M20) [32]
    End point description
    Minimum Steady State Concentration (Cmin,ss) of Abemaciclib and Its Metabolites (M2 and M20) was evaluated. M2 and M20 are 2 major active metabolites of abemaciclib.
    End point type
    Secondary
    End point timeframe
    Cycle(C)1 Day(D)1,C1D15, C2D1, C2D8, C3D1,C3D15, C4D1, C5D1:pre-dose; C1D1, C2D1, C3D1, C4D1, C5D1:post-dose
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No inferential statistics were planned or conducted for this endpoint.
    End point values
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Number of subjects analysed
    77
    71
    Units: nanogram/milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Abemaciclib
    134 ( 77 )
    155 ( 53 )
        M2
    72.0 ( 120 )
    96.5 ( 120 )
        M20
    136 ( 120 )
    181 ( 130 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up To 36 Months
    Adverse event reporting additional description
    All enrolled participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant
    Reporting group description
    		 150 mg abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8mg/kg trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter.

    Reporting group title
    150 mg Abemaciclib + 8 mg/kg Trastuzumab
    Reporting group description
    		 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle.

    Reporting group title
    8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Reporting group description
    		 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician's choice administered according to product label.

    Serious adverse events
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 78 (26.92%)
    15 / 77 (19.48%)
    11 / 72 (15.28%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    drug hypersensitivity
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    vaginal haemorrhage
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    epistaxis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    interstitial lung disease
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumothorax
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    neutrophil count decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    white blood cell count decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    femur fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hip fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    radiation pneumonitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    cardio-respiratory arrest
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    pericardial effusion
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    cerebral haemorrhage
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ascites
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 77 (2.60%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    faecaloma
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct stone
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cholangitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary retention
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract obstruction
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    musculoskeletal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    osteonecrosis of jaw
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    cellulitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    fungal infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis viral
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    herpes zoster
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    influenza
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lung infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    lymphangitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    otitis media
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 77 (1.30%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    soft tissue infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 77 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant 150 mg Abemaciclib + 8 mg/kg Trastuzumab 8 mg/kg Trastuzumab + Standard of Care Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 78 (97.44%)
    75 / 77 (97.40%)
    68 / 72 (94.44%)
    Vascular disorders
    hot flush
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 77 (3.90%)
    2 / 72 (2.78%)
         occurrences all number
    7
    4
    2
    hypertension
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 77 (5.19%)
    2 / 72 (2.78%)
         occurrences all number
    4
    7
    3
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    11 / 78 (14.10%)
    12 / 77 (15.58%)
    7 / 72 (9.72%)
         occurrences all number
    17
    16
    14
    fatigue
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    33 / 78 (42.31%)
    29 / 77 (37.66%)
    26 / 72 (36.11%)
         occurrences all number
    58
    52
    30
    influenza like illness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 78 (2.56%)
    6 / 77 (7.79%)
    0 / 72 (0.00%)
         occurrences all number
    2
    12
    0
    mucosal inflammation
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 77 (3.90%)
    4 / 72 (5.56%)
         occurrences all number
    1
    4
    6
    non-cardiac chest pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 77 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    6
    0
    1
    oedema peripheral
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 77 (7.79%)
    7 / 72 (9.72%)
         occurrences all number
    6
    9
    9
    pyrexia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    11 / 78 (14.10%)
    4 / 77 (5.19%)
    10 / 72 (13.89%)
         occurrences all number
    15
    7
    16
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    18 / 78 (23.08%)
    11 / 77 (14.29%)
    8 / 72 (11.11%)
         occurrences all number
    25
    14
    12
    dyspnoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    14 / 78 (17.95%)
    7 / 77 (9.09%)
    12 / 72 (16.67%)
         occurrences all number
    21
    9
    14
    epistaxis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    7 / 77 (9.09%)
    5 / 72 (6.94%)
         occurrences all number
    8
    11
    5
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 77 (3.90%)
    4 / 72 (5.56%)
         occurrences all number
    2
    3
    4
    insomnia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 77 (7.79%)
    5 / 72 (6.94%)
         occurrences all number
    5
    12
    5
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    6 / 77 (7.79%)
    8 / 72 (11.11%)
         occurrences all number
    12
    12
    20
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    9 / 78 (11.54%)
    7 / 77 (9.09%)
    8 / 72 (11.11%)
         occurrences all number
    13
    12
    24
    blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 77 (1.30%)
    2 / 72 (2.78%)
         occurrences all number
    11
    1
    4
    blood bilirubin increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 77 (2.60%)
    4 / 72 (5.56%)
         occurrences all number
    6
    3
    8
    blood creatinine increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    10 / 78 (12.82%)
    11 / 77 (14.29%)
    0 / 72 (0.00%)
         occurrences all number
    14
    16
    0
    lymphocyte count decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 77 (5.19%)
    4 / 72 (5.56%)
         occurrences all number
    2
    5
    26
    neutrophil count decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    24 / 78 (30.77%)
    19 / 77 (24.68%)
    13 / 72 (18.06%)
         occurrences all number
    65
    73
    61
    platelet count decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    19 / 78 (24.36%)
    16 / 77 (20.78%)
    5 / 72 (6.94%)
         occurrences all number
    58
    42
    36
    weight decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    5 / 77 (6.49%)
    1 / 72 (1.39%)
         occurrences all number
    7
    5
    1
    white blood cell count decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    12 / 78 (15.38%)
    7 / 77 (9.09%)
    8 / 72 (11.11%)
         occurrences all number
    32
    26
    46
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    8 / 77 (10.39%)
    2 / 72 (2.78%)
         occurrences all number
    6
    10
    2
    dysgeusia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 77 (5.19%)
    2 / 72 (2.78%)
         occurrences all number
    4
    4
    2
    headache
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    12 / 78 (15.38%)
    10 / 77 (12.99%)
    13 / 72 (18.06%)
         occurrences all number
    17
    14
    15
    neuropathy peripheral
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 77 (0.00%)
    4 / 72 (5.56%)
         occurrences all number
    3
    0
    4
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 77 (6.49%)
    9 / 72 (12.50%)
         occurrences all number
    2
    6
    15
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    27 / 78 (34.62%)
    20 / 77 (25.97%)
    16 / 72 (22.22%)
         occurrences all number
    85
    43
    42
    leukopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 77 (2.60%)
    3 / 72 (4.17%)
         occurrences all number
    16
    2
    24
    neutropenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    17 / 78 (21.79%)
    9 / 77 (11.69%)
    15 / 72 (20.83%)
         occurrences all number
    54
    28
    51
    thrombocytopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 78 (3.85%)
    8 / 77 (10.39%)
    0 / 72 (0.00%)
         occurrences all number
    6
    13
    0
    Eye disorders
    lacrimation increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 77 (5.19%)
    2 / 72 (2.78%)
         occurrences all number
    12
    6
    2
    vision blurred
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 77 (3.90%)
    1 / 72 (1.39%)
         occurrences all number
    4
    3
    1
    Gastrointestinal disorders
    abdominal distension
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 77 (3.90%)
    0 / 72 (0.00%)
         occurrences all number
    5
    3
    0
    abdominal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    16 / 78 (20.51%)
    13 / 77 (16.88%)
    12 / 72 (16.67%)
         occurrences all number
    21
    14
    14
    abdominal pain upper
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    10 / 78 (12.82%)
    3 / 77 (3.90%)
    4 / 72 (5.56%)
         occurrences all number
    12
    7
    4
    constipation
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    9 / 78 (11.54%)
    8 / 77 (10.39%)
    14 / 72 (19.44%)
         occurrences all number
    11
    10
    18
    diarrhoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    61 / 78 (78.21%)
    60 / 77 (77.92%)
    18 / 72 (25.00%)
         occurrences all number
    191
    179
    40
    dry mouth
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 77 (5.19%)
    4 / 72 (5.56%)
         occurrences all number
    5
    5
    6
    dyspepsia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    8 / 78 (10.26%)
    6 / 77 (7.79%)
    5 / 72 (6.94%)
         occurrences all number
    15
    9
    5
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 77 (1.30%)
    1 / 72 (1.39%)
         occurrences all number
    5
    1
    1
    nausea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    36 / 78 (46.15%)
    32 / 77 (41.56%)
    25 / 72 (34.72%)
         occurrences all number
    58
    47
    36
    stomatitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 78 (3.85%)
    7 / 77 (9.09%)
    8 / 72 (11.11%)
         occurrences all number
    6
    10
    17
    vomiting
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    20 / 78 (25.64%)
    22 / 77 (28.57%)
    11 / 72 (15.28%)
         occurrences all number
    31
    29
    13
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    7 / 77 (9.09%)
    8 / 72 (11.11%)
         occurrences all number
    6
    8
    10
    dry skin
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    4 / 77 (5.19%)
    4 / 72 (5.56%)
         occurrences all number
    5
    4
    4
    nail disorder
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 78 (2.56%)
    4 / 77 (5.19%)
    1 / 72 (1.39%)
         occurrences all number
    3
    4
    2
    onychoclasis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 77 (1.30%)
    0 / 72 (0.00%)
         occurrences all number
    4
    1
    0
    palmar-plantar erythrodysaesthesia syndrome
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 77 (1.30%)
    12 / 72 (16.67%)
         occurrences all number
    0
    2
    19
    pruritus
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    11 / 78 (14.10%)
    9 / 77 (11.69%)
    3 / 72 (4.17%)
         occurrences all number
    18
    10
    3
    rash
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    8 / 77 (10.39%)
    6 / 72 (8.33%)
         occurrences all number
    7
    12
    8
    rash maculo-papular
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    6 / 77 (7.79%)
    2 / 72 (2.78%)
         occurrences all number
    6
    9
    4
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    10 / 78 (12.82%)
    8 / 77 (10.39%)
    8 / 72 (11.11%)
         occurrences all number
    13
    9
    9
    back pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    11 / 77 (14.29%)
    5 / 72 (6.94%)
         occurrences all number
    6
    12
    7
    bone pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 77 (3.90%)
    7 / 72 (9.72%)
         occurrences all number
    1
    3
    7
    musculoskeletal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 77 (6.49%)
    3 / 72 (4.17%)
         occurrences all number
    2
    7
    3
    myalgia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    7 / 78 (8.97%)
    7 / 77 (9.09%)
    10 / 72 (13.89%)
         occurrences all number
    9
    7
    12
    pain in extremity
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    5 / 77 (6.49%)
    8 / 72 (11.11%)
         occurrences all number
    2
    7
    9
    Infections and infestations
    gastroenteritis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 77 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    5
    0
    3
    influenza
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    5 / 77 (6.49%)
    2 / 72 (2.78%)
         occurrences all number
    6
    6
    2
    nasopharyngitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 77 (3.90%)
    2 / 72 (2.78%)
         occurrences all number
    5
    3
    2
    rhinitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 77 (2.60%)
    1 / 72 (1.39%)
         occurrences all number
    4
    2
    1
    upper respiratory tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    8 / 78 (10.26%)
    2 / 77 (2.60%)
    8 / 72 (11.11%)
         occurrences all number
    15
    2
    12
    urinary tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    8 / 77 (10.39%)
    5 / 72 (6.94%)
         occurrences all number
    9
    21
    8
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    16 / 78 (20.51%)
    16 / 77 (20.78%)
    13 / 72 (18.06%)
         occurrences all number
    27
    24
    15
    dehydration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 77 (2.60%)
    4 / 72 (5.56%)
         occurrences all number
    4
    2
    4
    hyperglycaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 77 (1.30%)
    4 / 72 (5.56%)
         occurrences all number
    1
    3
    9
    hyperkalaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 77 (3.90%)
    1 / 72 (1.39%)
         occurrences all number
    6
    3
    1
    hypokalaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 78 (7.69%)
    7 / 77 (9.09%)
    4 / 72 (5.56%)
         occurrences all number
    16
    15
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2015
    - Added the safety lead-in portion for Arm A due to no data around the triplet combination
    23 Jan 2019
    - Updated the safety language regarding hepatic monitoring, assessment of renal function, and venous thromboembolic events (VTEs) for ongoing patients and align with the updated label of abemaciclib.
    10 Feb 2020
    - Added dose modification table for interstitial lung disease (ILD)/pneumonitis and updated guidance for management of ILD/pneumonitis.

    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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