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    Clinical Trial Results:
    A Phase 2 Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor Positive Breast Cancer

    Summary
    EudraCT number
    2014-004010-28
    Trial protocol
    AT   BE   FR   ES   IT  
    Global end of trial date
    08 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Dec 2020
    First version publication date
    10 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I3Y-MC-JPBO
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02308020
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Trial Number: 15450
    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
    08 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to evaluate the safety and effectiveness of the study drug known as abemaciclib in participants with hormone receptor positive breast cancer, non-small cell lung cancer (NSCLC), or melanoma that has spread to the brain.
    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
    20 Apr 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    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
    Canada: 3
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    United States: 71
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Spain: 7
    Worldwide total number of subjects
    162
    EEA total number of subjects
    73
    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)
    123
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    No Text Available

    Pre-assignment
    Screening details
    Completers include participants who died or discontinued study treatment due to progressive disease and is in follow up.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer
    Arm description
    Abemaciclib 200 milligram (mg) was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants with hormone receptor positive (HR+), hormone epidermal growth factor receptor 2 positive (HER2+) breast cancer receiving concurrent trastuzumab, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
    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
    Abemaciclib 200 milligram (mg) was administered orally once every 12 hours on days 1-21 of a 21-day cycle.

    Arm title
    Part B Abemaciclib: HR+, HER2- Breast Cancer
    Arm description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants may continue to receive treatment until discontinuation criteria are met.
    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
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle

    Arm title
    Part C Abemaciclib: Surgical Resection
    Arm description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+, HER2+ breast cancer, NSCLC, or melanoma with intracranial lesions for which surgical resection is clinically indicated receiving concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours for 5-14 days prior to surgical resection. Dosing may resume following wound healing on a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
    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
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle

    Arm title
    Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC)
    Arm description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants with NSCLC receiving concurrent gemcitabine or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
    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
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle

    Arm title
    Part E Abemaciclib: Melanoma
    Arm description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
    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
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle

    Arm title
    Part F Abemaciclib: HR+ Breast Cancer, NSCLC, or Melanoma
    Arm description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+ (either HER2+ or HER2-) breast cancer, NSCLC, or melanoma and leptomeningeal metastases received concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.
    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
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle

    Number of subjects in period 1
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part C Abemaciclib: Surgical Resection Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma Part F Abemaciclib: HR+ Breast Cancer, NSCLC, or Melanoma
    Started
    27
    58
    9
    28
    23
    17
    Received at least one dose of study drug
    27
    58
    9
    28
    23
    17
    Completed
    23
    38
    6
    24
    19
    12
    Not completed
    4
    20
    3
    4
    4
    5
         Consent withdrawn by subject
    3
    5
    3
    2
    1
    2
         Sponsor Decision
    -
    8
    -
    2
    2
    1
         Lost to follow-up
    1
    7
    -
    -
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer
    Reporting group description
    Abemaciclib 200 milligram (mg) was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants with hormone receptor positive (HR+), hormone epidermal growth factor receptor 2 positive (HER2+) breast cancer receiving concurrent trastuzumab, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part B Abemaciclib: HR+, HER2- Breast Cancer
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part C Abemaciclib: Surgical Resection
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+, HER2+ breast cancer, NSCLC, or melanoma with intracranial lesions for which surgical resection is clinically indicated receiving concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours for 5-14 days prior to surgical resection. Dosing may resume following wound healing on a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC)
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants with NSCLC receiving concurrent gemcitabine or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part E Abemaciclib: Melanoma
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part F Abemaciclib: HR+ Breast Cancer, NSCLC, or Melanoma
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+ (either HER2+ or HER2-) breast cancer, NSCLC, or melanoma and leptomeningeal metastases received concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part C Abemaciclib: Surgical Resection Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma Part F Abemaciclib: HR+ Breast Cancer, NSCLC, or Melanoma Total
    Number of subjects
    27 58 9 28 23 17 162
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.9 ± 10.9 54.1 ± 10.5 57.0 ± 17.9 58.4 ± 10.9 55.1 ± 14.4 50.1 ± 12.3 -
    Gender categorical
    Units: Subjects
        Female
    27 57 8 14 11 14 131
        Male
    0 1 1 14 12 3 31
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 3 0 0 1 1 5
        Not Hispanic or Latino
    21 42 8 20 20 14 125
        Unknown or Not Reported
    6 13 1 8 2 2 32
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0 0 0
        Asian
    1 3 1 0 0 0 5
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0 0
        Black or African American
    1 4 0 1 0 1 7
        White
    17 35 7 20 22 14 115
        More than one race
    1 1 0 0 0 0 2
        Unknown or Not Reported
    7 15 1 7 1 2 33
    Region of Enrollment
    Units: Subjects
        Canada
    0 1 0 0 0 2 3
        Austria
    0 1 0 0 0 0 1
        Belgium
    4 8 0 3 3 0 18
        United States
    11 24 7 12 7 10 71
        Italy
    0 4 0 2 9 0 15
        Israel
    1 2 0 1 1 1 6
        Australia
    2 2 1 2 1 1 9
        France
    7 14 1 7 1 2 32
        Spain
    2 2 0 1 1 1 7

    End points

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    End points reporting groups
    Reporting group title
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer
    Reporting group description
    Abemaciclib 200 milligram (mg) was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants with hormone receptor positive (HR+), hormone epidermal growth factor receptor 2 positive (HER2+) breast cancer receiving concurrent trastuzumab, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part B Abemaciclib: HR+, HER2- Breast Cancer
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part C Abemaciclib: Surgical Resection
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+, HER2+ breast cancer, NSCLC, or melanoma with intracranial lesions for which surgical resection is clinically indicated receiving concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours for 5-14 days prior to surgical resection. Dosing may resume following wound healing on a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC)
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants with NSCLC receiving concurrent gemcitabine or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part E Abemaciclib: Melanoma
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Reporting group title
    Part F Abemaciclib: HR+ Breast Cancer, NSCLC, or Melanoma
    Reporting group description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+ (either HER2+ or HER2-) breast cancer, NSCLC, or melanoma and leptomeningeal metastases received concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Subject analysis set title
    Part A Abemaciclib: HR+, HER2+ Breast Cancer
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants with hormone receptor positive HR+, HER2+ breast cancer receiving concurrent trastuzumab, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Subject analysis set title
    Part D Abemaciclib: NSCLC
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants with NSCLC receiving concurrent gemcitabine or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.

    Subject analysis set title
    Part A 150 mg Abemaciclib: HR+, HER2+ Breast Cancer
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Participants with HR+, HER2+ breast cancer received 150 mg abemaciclib orally once every 12 hours on days 1-21 of a 21-day cycle.

    Subject analysis set title
    Part B 200 mg Abemaciclib: HR+, HER2- Breast Cancer
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Participants with HR+, HER2- breast cancer received 200 mg abemaciclib given orally once every 12 hours on days 1-21 of a 21-day cycle.

    Subject analysis set title
    Part C 200 mg Abemaciclib: Surgical Resection
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Participants with HR+ breast cancer, NSCLC, or melanoma with intracranial lesions for which surgical resection is clinically indicated received 200 mg abemaciclib given orally once every 12 hours for 5-14 days prior to surgical resection.

    Subject analysis set title
    Part D 200 mg Abemaciclib: NSCLC
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Participants with NSCLC received 200 mg abemaciclib given orally once every 12 hours on days 1-21 of a 21-day cycle.

    Subject analysis set title
    Part E 200 mg Abemaciclib: Melanoma
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Participants with melanoma received 200 mg abemaciclib given orally once every 12 hours on days 1-21 of a 21-day cycle.

    Subject analysis set title
    Part F 200 mg Abemaciclib: HR+ Breast Cancer, NSCLC, Melanoma
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Participants with HR+ (either HER2+ or HER2-) breast cancer, NSCLC, or melanoma and leptomeningeal metastases received 200 mg abemaciclib given orally once every 12 hours on days 1-21 of a 21-day cycle.

    Primary: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Intracranial Response Rate (OIRR)

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    End point title
    Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR): Objective Intracranial Response Rate (OIRR) [1] [2]
    End point description
    OIRR is the percentage of participants with a (CR) or (PR) based on the Response Assessment in Neuro-Oncology Brain Metastasis (RANO-BM) response criteria. CR is measurable target lesions, the disappearance of all central nervous system (CNS) target lesions for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. PR is at least a 30% decrease in the sum longest duration (LD) of CNS target lesions, taking as reference the baseline sum LD for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved clinically. Nontarget lesions requires disappearance CNS non-target lesions and no new CNS lesions. Stable disease (SD) is less than (<)30% decrease relative to baseline but <20% increase in sum LD relative to nadir. Progressive disease (PD) is greater than or equal to (≥) 20% increase in sum LD relative to nadir and a relative increase of 20%, ≥1 lesion must increase by absolute value of ≥5 millimeter (mm).
    End point type
    Primary
    End point timeframe
    Baseline to Objective Disease Progression (Up to 36 Months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This is single arm cohort study, no comparison between arms were analyzed.
    [2] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    23 [3]
    52 [4]
    23 [5]
    22 [6]
    Units: percentage of participants
        number (not applicable)
    0
    5.8
    0
    0
    Notes
    [3] - All participants who had evaluable OIRR data per RANO-BM.
    [4] - All participants who had evaluable OIRR data per RANO-BM.
    [5] - All participants who had evaluable OIRR data per RANO-BM.
    [6] - All participants who had evaluable OIRR data per RANO-BM.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with CR, PR, Stable Disease (SD), Progressive Disease (PD), or Not Evaluable (NE): Best Overall Intracranial Response (BOIR)

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    End point title
    Percentage of Participants with CR, PR, Stable Disease (SD), Progressive Disease (PD), or Not Evaluable (NE): Best Overall Intracranial Response (BOIR) [7]
    End point description
    Percentage of Participants with BOIR was categorized as CR, PR, SD, PD or NE, as defined by RANO-BM, from baseline until the earliest of objective progression according to brain metastases response criteria or start of new anticancer therapy. CR is measurable target lesions, the disappearance of all CNS target lesions for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. PR is at least a 30% decrease in the sum LD of CNS target lesions, taking as reference the baseline sum LD for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved clinically. SD is <30% decrease relative to baseline but <20% increase in sum LD relative to nadir. PD is greater than or equal to (≥) 20% increase in sum LD relative to nadir and a relative increase of 20%, ≥1 lesion must increase by absolute value of ≥5 mm. NE is absent (no abnormality; normal), or non-evaluable (NE).
    End point type
    Secondary
    End point timeframe
    Baseline to Earliest Objective Progression or Start of New Anticancer Therapy (Up to 36 Months)
    Notes
    [7] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    23 [8]
    52 [9]
    23 [10]
    22 [11]
    Units: percentage of participants
    number (not applicable)
        Partial Response
    0
    5.8
    0
    0
        Stable Disease
    52.2
    65.4
    43.5
    31.8
        Progressive Disease
    47.8
    28.8
    56.5
    68.2
        Not Evaluable
    0
    0
    0
    0
    Notes
    [8] - All participants who had evaluable OIRR data per RANO-BM.
    [9] - All participants who had evaluable OIRR data per RANO-BM.
    [10] - All participants who had evaluable OIRR data per RANO-BM.
    [11] - All participants who had evaluable OIRR data per RANO-BM.
    No statistical analyses for this end point

    Secondary: Duration of CR or PR: Duration of Intracranial Response (DOIR)

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    End point title
    Duration of CR or PR: Duration of Intracranial Response (DOIR) [12]
    End point description
    DOIR is measured from the date of first evidence of a confirmed response (CR or PR), as defined by RANO-BM, to the date objective progression or death from any cause. CR is measurable target lesions, the disappearance of all CNS target lesions for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. PR is at least a 30% decrease in the sum LD of CNS target lesions, taking as reference the baseline sum LD for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved clinically. Participants who have neither progressed nor died were censored on the day of their last radiographic tumor assessment or on the date of response. PD is greater than or equal to (≥) 20% increase in sum LD relative to nadir and a relative increase of 20%, ≥1 lesion must increase by absolute value of ≥5 mm. DOIR was summarized using Kaplan-Meier estimates.
    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)
    Notes
    [12] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    0 [13]
    3 [14]
    0 [15]
    0 [16]
    Units: Months
        median (full range (min-max))
    ( to )
    8.8 (3.0 to 14.3)
    ( to )
    ( to )
    Notes
    [13] - All participants who had evaluable OIRR data per RANO-BM.
    [14] - All participants who had evaluable OIRR data per RANO-BM.
    [15] - All participants who had evaluable OIRR data per RANO-BM.
    [16] - All participants who had evaluable OIRR data per RANO-BM.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Best Overall Intracranial Response (BOIR) of CR, PR, or SD: Intracranial Disease Control Rate (IDCR)

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    End point title
    Percentage of Participants with Best Overall Intracranial Response (BOIR) of CR, PR, or SD: Intracranial Disease Control Rate (IDCR) [17]
    End point description
    Percentage of participants with BOIR of CR, PR, or SD: IDCR, as defined by RANO-BM is reported. CR is measurable target lesions, the disappearance of all central nervous system CNS target lesions for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. PR is at least a 30% decrease in the sum LD of CNS target lesions, taking as reference the baseline sum LD for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved clinically. Nontarget lesions requires disappearance CNS non-target lesions and no new CNS lesions. SD is less than (<)30% decrease relative to baseline but <20% increase in sum LD relative to nadir. PD is greater than or equal to (≥) 20% increase in sum LD relative to nadir and a relative increase of 20%, ≥1 lesion must increase by absolute value of ≥5 mm.
    End point type
    Secondary
    End point timeframe
    Baseline to Disease Progression or Start of New Anticancer Therapy (Up to 36 Months)
    Notes
    [17] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    23 [18]
    52 [19]
    23 [20]
    22 [21]
    Units: percentage of participants
        number (not applicable)
    52.2
    71.2
    43.5
    31.8
    Notes
    [18] - All participants who had evaluable OIRR data per RANO-BM.
    [19] - All participants who had evaluable OIRR data per RANO-BM.
    [20] - All participants who had evaluable OIRR data per RANO-BM.
    [21] - All participants who had evaluable OIRR data per RANO-BM.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with BOIR of CR, PR, or SD with Duration of SD for at Least 6 Months: Intracranial Clinical Benefit Rate (ICBR)

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    End point title
    Percentage of Participants with BOIR of CR, PR, or SD with Duration of SD for at Least 6 Months: Intracranial Clinical Benefit Rate (ICBR) [22]
    End point description
    ICBR is the percentage of participants with BOIR of CR, PR, or SD with duration of SD for at least 6 months, as defined by RANO-BM. CR is measurable target lesions, the disappearance of all CNS target lesions for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. PR is at least a 30% decrease in the sum LD of CNS target lesions, taking as reference the baseline sum LD for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved clinically. SD is <30% decrease relative to baseline but <20% increase in sum LD relative to nadir. PD is greater than or equal to (≥) 20% increase in sum LD relative to nadir and a relative increase of 20%, ≥1 lesion must increase by absolute value of ≥5 mm.
    End point type
    Secondary
    End point timeframe
    Baseline to Disease Progression or Start of New Anticancer Therapy (Up to 36 Months)
    Notes
    [22] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    23 [23]
    52 [24]
    23 [25]
    22 [26]
    Units: percentage of participants
        number (not applicable)
    13.0
    26.9
    26.1
    9.1
    Notes
    [23] - All participants who had evaluable OIRR data per RANO-BM.
    [24] - All participants who had evaluable OIRR data per RANO-BM.
    [25] - All participants who had evaluable OIRR data per RANO-BM.
    [26] - All participants who had evaluable OIRR data per RANO-BM.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS) [27]
    End point description
    OS was measured from baseline to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for a particular analysis, OS was censored for that analysis at the date of last contact prior to the data inclusion cutoff date (contacts considered in the determination of last contact date include adverse event (AE) date, tumor assessment date, visit date, and last known alive date). OS was summarized using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    Baseline to the Date of Death from Any Cause (Up to 5 Years)
    Notes
    [27] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    27 [28]
    58 [29]
    28 [30]
    23 [31]
    Units: percentage of participants
        median (confidence interval 95%)
    10.06 (4.21 to 14.30)
    13.38 (9.60 to 20.84)
    7.13 (3.65 to 9.37)
    2.93 (1.22 to 4.31)
    Notes
    [28] - All participants who received at least one dose of study drug.
    [29] - All participants who received at least one dose of study drug.
    [30] - All participants who received at least one dose of study drug.
    [31] - All participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a Best Response of CR or PR: Extracranial Objective Response Rate (EORR)

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    End point title
    Percentage of Participants with a Best Response of CR or PR: Extracranial Objective Response Rate (EORR) [32]
    End point description
    The percentage of participants with a best response of CR or PR objective response rate is complete response (CR) + partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines. CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions. PD is defined as at least a 20% increase in the sum LD of CNS target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) and the 20% increase must be at least one lesion must increase by an absolute value of ≥5 mm to be considered progression.
    End point type
    Secondary
    End point timeframe
    Baseline to Disease Progression (Up to 36 Months)
    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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    27 [33]
    58 [34]
    28 [35]
    23 [36]
    Units: percentage of participants
        number (not applicable)
    0
    1.7
    3.6
    0
    Notes
    [33] - All participants who received at least one dose of study drug.
    [34] - All participants who received at least one dose of study drug.
    [35] - All participants who received at least one dose of study drug.
    [36] - All participants who received at least one dose of study drug.
    No statistical analyses for this end point

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

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    End point title
    Percentage of Participants with a Best Overall Response of CR, PR, or SD: Extracranial Disease Control Rate (EDCR) [37]
    End point description
    Disease control rate (DCR) (CR+ PR+ SD) per RECIST v1.1. is defined as the percentage of participants with best overall response of CR, PR, or SD. CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions. PD is defined as at least a 20% increase in the sum LD of CNS target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study) and the 20% increase must be at least one lesion must increase by an absolute value of ≥5 mm to be considered progression.
    End point type
    Secondary
    End point timeframe
    Baseline to Disease Progression or Start of New Anticancer Therapy (Up to 36 Months)
    Notes
    [37] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    27 [38]
    58 [39]
    28 [40]
    23 [41]
    Units: percentage of participants
        number (not applicable)
    40.7
    51.7
    39.3
    26.1
    Notes
    [38] - All participants who received at least one dose of study drug.
    [39] - All participants who received at least one dose of study drug.
    [40] - All participants who received at least one dose of study drug.
    [41] - All participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Bi-compartmental

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    End point title
    Progression Free Survival (PFS) Bi-compartmental [42]
    End point description
    PFS was measured from baseline to objective progression (intracranial or extracranial) as defined by (RANO-BM.) or death from any cause. Participants who have neither progressed nor died were censored at the day of their last radiographic tumor assessment. PD is greater than or equal to (≥) 20% increase in sum LD relative to nadir and a relative increase of 20%, ≥1 lesion must increase by absolute value of ≥5 mm. PFS was summarized using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    Baseline to Objective Disease Progression or Death from Any Cause (Up to 36 Months)
    Notes
    [42] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    27 [43]
    58 [44]
    28 [45]
    23 [46]
    Units: Months
        median (confidence interval 95%)
    2.07 (1.35 to 3.32)
    4.41 (2.60 to 5.46)
    1.45 (1.35 to 2.76)
    1.22 (1.02 to 1.55)
    Notes
    [43] - All participants who received at least one dose of study drug.
    [44] - All participants who received at least one dose of study drug.
    [45] - All participants who received at least one dose of study drug.
    [46] - All participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Neurologic Symptoms on the MD Anderson Inventory-Brain Tumor (MDASI-BT) Subscale

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    End point title
    Change from Baseline in Neurologic Symptoms on the MD Anderson Inventory-Brain Tumor (MDASI-BT) Subscale [47]
    End point description
    The MDASI-BT is an instrument to assess multi-symptoms in participants with brain tumor metastases (including those with brain metastases secondary to breast cancer). The MDASI-BT of participants with a change from baseline is reported as mean core symptoms, mean brain tumor symptoms, and symptom groupings (mean focal neurologic deficit, mean generalized/disease status symptoms, and mean gastrointestinal symptoms). The mean of all symptom subscale items was calculated where 0 equals “not present” and 10 equals “as bad as you can imagine.” A change from baseline with negative values indicate improvement, positive values indicate worsening.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 3 (Up to 63 Days)
    Notes
    [47] - 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: All participants who had evaluable OIRR data with at least one measurable brain lesion at baseline (per RANO-BM) and for whom at least one post-baseline overall response assessment for intracranial disease is available. Parts C and F were exploratory per protocol.
    End point values
    Part A Abemaciclib: Hormone Receptor (HR+) HER2+ Breast Cancer Part B Abemaciclib: HR+, HER2- Breast Cancer Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) Part E Abemaciclib: Melanoma
    Number of subjects analysed
    11 [48]
    35 [49]
    10 [50]
    7 [51]
    Units: units on a scale
    arithmetic mean (standard deviation)
        mean core symptom severity
    -0.98 ± 0.86
    -0.17 ± 0.99
    -0.38 ± 1.19
    -0.53 ± 0.62
        mean brain tumor symptom severity
    -0.47 ± 0.57
    -0.29 ± 1.05
    -0.10 ± 1.22
    0.31 ± 1.11
        mean focal neurologic deficit symptom severity
    -0.84 ± 0.92
    -0.36 ± 1.23
    -0.44 ± 0.58
    0.54 ± 1.16
        mean generalized disease status
    -0.47 ± 1.03
    0 ± 1.39
    0.28 ± 1.51
    0.01 ± 0.89
        mean gastrointestinal symptom
    -1.35 ± 2.11
    0.40 ± 1.91
    1.00 ± 1.46
    0 ± 0.29
    Notes
    [48] - All participants had at least 1 baseline and an evaluable post baseline assessment.
    [49] - All participants had at least 1 baseline and an evaluable post baseline assessment.
    [50] - All participants had at least 1 baseline and an evaluable post baseline assessment.
    [51] - All participants had at least 1 baseline and an evaluable post baseline assessment.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Steady State Minimum Concentration (Cmin) of Abemaciclib and its Metabolites LSN2839567 (M2), LSN3106726 (M20), and LSN3106729 (M18)

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    End point title
    Pharmacokinetics (PK): Steady State Minimum Concentration (Cmin) of Abemaciclib and its Metabolites LSN2839567 (M2), LSN3106726 (M20), and LSN3106729 (M18)
    End point description
    A PK plasma sample was taken prior to abemaciclib dose to analyze the minimum concentrations of abemaciclib and its metabolites (Cmin) - Individual Cmin values were averaged if there were 3 or more available data points, otherwise individual data are reported.
    End point type
    Secondary
    End point timeframe
    Parts A, B, D, E, F, Cycle 3, Day 1: Predose; Part C, Cycle 4, Day 1: Predose
    End point values
    Part A 150 mg Abemaciclib: HR+, HER2+ Breast Cancer Part B 200 mg Abemaciclib: HR+, HER2- Breast Cancer Part C 200 mg Abemaciclib: Surgical Resection Part D 200 mg Abemaciclib: NSCLC Part E 200 mg Abemaciclib: Melanoma Part F 200 mg Abemaciclib: HR+ Breast Cancer, NSCLC, Melanoma
    Number of subjects analysed
    3 [52]
    12 [53]
    1 [54]
    5 [55]
    2 [56]
    4 [57]
    Units: nanogram/milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Abemaciclib
    133 ± 13.4
    120 ± 186
    0 ± 0
    306 ± 33.5
    0 ± 0
    142 ± 80.0
        LSN2839567 (M2)
    72.6 ± 8.23
    77.3 ± 121
    0 ± 0
    100 ± 77.5
    0 ± 0
    68.5 ± 150
        LSN3106726 (M20)
    158 ± 25.0
    133 ± 160
    0 ± 0
    203 ± 43.3
    0 ± 0
    122 ± 137
        LSN3106729 (M18)
    36.8 ± 39.3
    42.4 ± 85.6
    0 ± 0
    28.9 ± 108
    0 ± 0
    27.0 ± 242
    Notes
    [52] - All participants who had evaluable PK data. geometric coefficient of variation is a percent.
    [53] - All participants who had evaluable PK data.
    [54] - Abemaciclib value 256 ng/mL (M2) value 98.8 ng/mL (M20) value 181 ng/mL (M18) value 28.2 ng/mL
    [55] - All participants who had evaluable PK data.
    [56] - Abemaciclib: 99.7 and 222 ng/mL (M2) 61.6 and 90.7 (M20) 109 and 172 (M18) 22.2 and 44.2
    [57] - All participants who had evaluable PK data.
    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
    I3Y-MC-JPBO
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Study Part A Abemaciclib: HR+, HER2+ Breast Cancer
    Reporting group description
    -

    Reporting group title
    Study Part B Abemaciclib: HR+, HER2- Breast Cancer
    Reporting group description
    -

    Reporting group title
    Study Part E Abemaciclib: Melanoma
    Reporting group description
    -

    Reporting group title
    Study Part D Abemaciclib: NSCLC
    Reporting group description
    -

    Reporting group title
    Study Part F Abemaciclib HR+ Breast Cancer, NSCLC, or Melanoma
    Reporting group description
    -

    Reporting group title
    Study Part C Abemaciclib: Surgery
    Reporting group description
    -

    Serious adverse events
    Study Part A Abemaciclib: HR+, HER2+ Breast Cancer Study Part B Abemaciclib: HR+, HER2- Breast Cancer Study Part E Abemaciclib: Melanoma Study Part D Abemaciclib: NSCLC Study Part F Abemaciclib HR+ Breast Cancer, NSCLC, or Melanoma Study Part C Abemaciclib: Surgery
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 27 (22.22%)
    16 / 58 (27.59%)
    4 / 23 (17.39%)
    8 / 28 (28.57%)
    7 / 17 (41.18%)
    3 / 9 (33.33%)
         number of deaths (all causes)
    0
    1
    0
    3
    0
    1
         number of deaths resulting from adverse events
    0
    1
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    tumour pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    embolism
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    shock haemorrhagic
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    general physical health deterioration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    aspiration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cough
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pulmonary hypertension
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 58 (1.72%)
    1 / 23 (4.35%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    mental status changes
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ankle fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    acute coronary syndrome
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    1 / 23 (4.35%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cardiac failure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    aphasia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ataxia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    brain oedema
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    seizure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 58 (0.00%)
    1 / 23 (4.35%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    glaucoma
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    diarrhoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    enterocolitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    haemorrhoidal haemorrhage
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    lower gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pancreatitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    hepatocellular injury
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    jaundice cholestatic
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    chronic kidney disease
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    lung infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    shunt infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    skin infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    1 / 23 (4.35%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    dehydration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    2 / 23 (8.70%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hypercalcaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Study Part A Abemaciclib: HR+, HER2+ Breast Cancer Study Part B Abemaciclib: HR+, HER2- Breast Cancer Study Part E Abemaciclib: Melanoma Study Part D Abemaciclib: NSCLC Study Part F Abemaciclib HR+ Breast Cancer, NSCLC, or Melanoma Study Part C Abemaciclib: Surgery
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 27 (85.19%)
    55 / 58 (94.83%)
    16 / 23 (69.57%)
    27 / 28 (96.43%)
    16 / 17 (94.12%)
    8 / 9 (88.89%)
    Vascular disorders
    embolism
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    hypertension
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    4
    0
    0
    0
    3
    hypotension
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    1
    1
    0
    General disorders and administration site conditions
    chills
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    fatigue
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    9 / 27 (33.33%)
    28 / 58 (48.28%)
    4 / 23 (17.39%)
    11 / 28 (39.29%)
    9 / 17 (52.94%)
    2 / 9 (22.22%)
         occurrences all number
    9
    31
    4
    16
    9
    2
    gait disturbance
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    4 / 58 (6.90%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    4
    0
    2
    0
    0
    general physical health deterioration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    2 / 23 (8.70%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    influenza like illness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 58 (5.17%)
    1 / 23 (4.35%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    3
    1
    0
    0
    1
    localised oedema
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    3
    0
    0
    0
    0
    malaise
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    oedema peripheral
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    3 / 23 (13.04%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    3
    1
    1
    1
    non-cardiac chest pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    0
    1
    2
    1
    pyrexia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    3
    0
    3
    0
    0
    Reproductive system and breast disorders
    breast pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 58 (8.62%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    7
    0
    0
    1
    0
    dyspnoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    9 / 58 (15.52%)
    0 / 23 (0.00%)
    5 / 28 (17.86%)
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    1
    9
    0
    5
    2
    2
    epistaxis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    nasal congestion
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    oropharyngeal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    sinus pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    agitation
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 58 (1.72%)
    2 / 23 (8.70%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    anxiety
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 58 (5.17%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    3
    1
    2
    0
    0
    confusional state
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    5 / 28 (17.86%)
    1 / 17 (5.88%)
    2 / 9 (22.22%)
         occurrences all number
    2
    2
    0
    8
    1
    2
    depression
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 58 (6.90%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    4
    0
    1
    0
    0
    insomnia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 58 (5.17%)
    1 / 23 (4.35%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    3
    1
    1
    0
    2
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    4 / 58 (6.90%)
    2 / 23 (8.70%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    6 / 9 (66.67%)
         occurrences all number
    3
    4
    2
    4
    2
    7
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 27 (14.81%)
    2 / 58 (3.45%)
    4 / 23 (17.39%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    3 / 9 (33.33%)
         occurrences all number
    4
    2
    4
    2
    3
    3
    blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 58 (1.72%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    3 / 9 (33.33%)
         occurrences all number
    1
    1
    1
    5
    1
    4
    blood bilirubin increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    blood creatinine increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 58 (8.62%)
    2 / 23 (8.70%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    1
    6
    3
    4
    2
    1
    haemoglobin increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    international normalised ratio increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    weight decreased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    6 / 58 (10.34%)
    1 / 23 (4.35%)
    4 / 28 (14.29%)
    2 / 17 (11.76%)
    2 / 9 (22.22%)
         occurrences all number
    0
    6
    2
    5
    2
    2
    weight increased
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    0
    2
    1
    Injury, poisoning and procedural complications
    contusion
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    fall
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 58 (6.90%)
    0 / 23 (0.00%)
    3 / 28 (10.71%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    6
    0
    3
    0
    0
    fracture
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    incision site pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    skin laceration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    vascular access complication
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Cardiac disorders
    palpitations
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Nervous system disorders
    amnesia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    aphasia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    3
    0
    1
    0
    0
    balance disorder
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    cognitive disorder
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    dizziness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    8 / 58 (13.79%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    2
    8
    0
    1
    1
    1
    disturbance in attention
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    dysarthria
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    dysgeusia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    0
    0
    1
    2
    headache
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    14 / 58 (24.14%)
    2 / 23 (8.70%)
    4 / 28 (14.29%)
    3 / 17 (17.65%)
    2 / 9 (22.22%)
         occurrences all number
    2
    23
    3
    4
    3
    3
    hemiparesis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    neuropathy
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    12 / 58 (20.69%)
    1 / 23 (4.35%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    19
    2
    1
    0
    2
    peripheral motor neuropathy
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    presyncope
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    seizure
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 58 (5.17%)
    3 / 23 (13.04%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    5
    3
    3
    2
    0
    0
    somnolence
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    tremor
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    12 / 58 (20.69%)
    2 / 23 (8.70%)
    5 / 28 (17.86%)
    5 / 17 (29.41%)
    4 / 9 (44.44%)
         occurrences all number
    3
    14
    5
    6
    5
    7
    haemorrhagic diathesis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    leukocytosis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    leukopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    7 / 58 (12.07%)
    3 / 23 (13.04%)
    4 / 28 (14.29%)
    3 / 17 (17.65%)
    4 / 9 (44.44%)
         occurrences all number
    2
    10
    5
    6
    3
    6
    lymphopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 27 (14.81%)
    6 / 58 (10.34%)
    1 / 23 (4.35%)
    4 / 28 (14.29%)
    3 / 17 (17.65%)
    3 / 9 (33.33%)
         occurrences all number
    4
    9
    2
    7
    3
    8
    neutropenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    6 / 27 (22.22%)
    17 / 58 (29.31%)
    5 / 23 (21.74%)
    7 / 28 (25.00%)
    2 / 17 (11.76%)
    4 / 9 (44.44%)
         occurrences all number
    8
    32
    8
    9
    2
    6
    thrombocytopenia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 27 (14.81%)
    11 / 58 (18.97%)
    3 / 23 (13.04%)
    8 / 28 (28.57%)
    3 / 17 (17.65%)
    4 / 9 (44.44%)
         occurrences all number
    5
    12
    4
    11
    3
    5
    Ear and labyrinth disorders
    hypoacusis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    Eye disorders
    diplopia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    eye pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    photopsia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    vision blurred
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 58 (5.17%)
    1 / 23 (4.35%)
    3 / 28 (10.71%)
    2 / 17 (11.76%)
    1 / 9 (11.11%)
         occurrences all number
    1
    3
    1
    3
    2
    1
    Gastrointestinal disorders
    abdominal distension
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    abdominal pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    9 / 58 (15.52%)
    5 / 23 (21.74%)
    2 / 28 (7.14%)
    4 / 17 (23.53%)
    2 / 9 (22.22%)
         occurrences all number
    3
    14
    5
    2
    4
    4
    anal incontinence
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    ascites
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    constipation
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    9 / 58 (15.52%)
    2 / 23 (8.70%)
    7 / 28 (25.00%)
    3 / 17 (17.65%)
    0 / 9 (0.00%)
         occurrences all number
    2
    11
    2
    7
    3
    0
    diarrhoea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    15 / 27 (55.56%)
    45 / 58 (77.59%)
    5 / 23 (21.74%)
    15 / 28 (53.57%)
    6 / 17 (35.29%)
    4 / 9 (44.44%)
         occurrences all number
    26
    100
    6
    21
    6
    6
    dry mouth
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 58 (6.90%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    2
    4
    1
    2
    1
    0
    dysphagia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    gastritis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 58 (8.62%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    5
    0
    0
    0
    0
    haemorrhoids
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    nausea
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    9 / 27 (33.33%)
    26 / 58 (44.83%)
    1 / 23 (4.35%)
    8 / 28 (28.57%)
    7 / 17 (41.18%)
    2 / 9 (22.22%)
         occurrences all number
    11
    32
    1
    10
    10
    2
    oral pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    stomatitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    2
    1
    0
    0
    1
    1
    vomiting
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    7 / 27 (25.93%)
    20 / 58 (34.48%)
    1 / 23 (4.35%)
    4 / 28 (14.29%)
    5 / 17 (29.41%)
    2 / 9 (22.22%)
         occurrences all number
    8
    31
    1
    4
    6
    2
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    0
    0
    0
    1
    dry skin
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 58 (6.90%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    5
    1
    2
    0
    0
    rash
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    3
    6
    0
    0
    1
    0
    skin ulcer
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    1
    2
    0
    0
    cystitis noninfective
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    urinary incontinence
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    urinary retention
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 58 (5.17%)
    1 / 23 (4.35%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    4
    1
    0
    0
    0
    back pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    1 / 23 (4.35%)
    3 / 28 (10.71%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    4
    1
    3
    2
    0
    bone pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    2 / 23 (8.70%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    7
    3
    0
    0
    0
    flank pain
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 58 (3.45%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    muscle spasms
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 58 (8.62%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    5
    0
    0
    0
    2
    muscular weakness
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    7 / 27 (25.93%)
    4 / 58 (6.90%)
    2 / 23 (8.70%)
    2 / 28 (7.14%)
    4 / 17 (23.53%)
    2 / 9 (22.22%)
         occurrences all number
    8
    5
    2
    2
    4
    2
    myalgia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 58 (6.90%)
    3 / 23 (13.04%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    5
    3
    0
    0
    0
    pain in extremity
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 58 (8.62%)
    3 / 23 (13.04%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    5
    3
    0
    0
    1
    Infections and infestations
    ear infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    sinusitis
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    urinary tract infection
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 58 (5.17%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    19 / 58 (32.76%)
    2 / 23 (8.70%)
    7 / 28 (25.00%)
    2 / 17 (11.76%)
    2 / 9 (22.22%)
         occurrences all number
    4
    19
    2
    10
    2
    2
    dehydration
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    6 / 58 (10.34%)
    1 / 23 (4.35%)
    3 / 28 (10.71%)
    0 / 17 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    6
    1
    4
    0
    0
    hyperglycaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    2 / 28 (7.14%)
    1 / 17 (5.88%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    hyperkalaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 58 (1.72%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    1
    0
    0
    0
    9
    hypermagnesaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    hypernatraemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    hypoalbuminaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    hypocalcaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 58 (0.00%)
    0 / 23 (0.00%)
    0 / 28 (0.00%)
    3 / 17 (17.65%)
    4 / 9 (44.44%)
         occurrences all number
    2
    0
    0
    0
    3
    5
    hypokalaemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    4 / 27 (14.81%)
    11 / 58 (18.97%)
    1 / 23 (4.35%)
    2 / 28 (7.14%)
    2 / 17 (11.76%)
    2 / 9 (22.22%)
         occurrences all number
    7
    17
    1
    2
    2
    5
    hyponatraemia
    alternative dictionary used: MedDRA 22.0
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 58 (1.72%)
    1 / 23 (4.35%)
    1 / 28 (3.57%)
    3 / 17 (17.65%)
    2 / 9 (22.22%)
         occurrences all number
    4
    2
    1
    1
    3
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2015
    Protocol amendment (a) Incorporated patients with brain metastases secondary to NSCLC or Replaced CDK 4/6 with CDK4 and CDK6 for clarity Updated accordingly to incorporate NSCLC and melanoma information and clarify breast cancer Included Parts D and E and clarified previously Irradiated progressive lesions; Specified parts for HR+ and HER2+ breast cancer patients, and NSCLC patients with respect to concomitant/concurrent therapies; Clarified use of trastuzumab in HER2+ breast cancer patient parts; Clarified Parts for breast cancer patients Incorporated male birth control and sperm donation language Updated exclusion criteria breast cancer patients; parts for evidence of leptomeningeal metastases; parts for previous treatment with CDK4 and CDK6 inhibitor; deleted criterion Clarified discontinuation of abemaciclib Incorporated NSCLC and melanoma language and updated study design illustration Updated treatment regimens, modified supportive management for diarrhea, permitted combination therapies, surgery/surgical resection, efficacy assessments and measures, drug concentration Incorporated NSCLC and melanoma information in sample size Updated the Parts in secondary outcomes and methodology, trail making tests, drug concentrations in samples, health outcomes analyses, and interim analyses Updated Study Schedule Incorporated RANO-BM and RANO LM information Modified sampling and sampling summary Parts
    08 Feb 2019
    Protocol amendment (d) Included TBL and VTE in abbreviations Incorporated rationale for Amendment (d) to update safety monitoring Information for hepatic conditions, renal function, and VTEs. Modified alignment with safety updates. Updated requirements for AE/SAE reporting Incorporated safety monitoring language for hepatic conditions, renal function, and VTEs. CYPs text updated to align with abemaciclib program information

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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