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    Clinical Trial Results:
    A Phase 2, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With T-DM1.

    Summary
    EudraCT number
    2016-004986-18
    Trial protocol
    ES   BE   GB   FR   IT  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Mar 2020
    First version publication date
    29 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DS8201-A-U201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03248492
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Project Moniker: DESTINY-Breast01
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, United States, 07920
    Public contact
    Contact for Clinical Trial Information, Daiichi Sankyo Inc., 1 908-992-6400, CTRinfo@dsi.com
    Scientific contact
    Contact for Clinical Trial Information, Daiichi Sankyo Inc., 1 908-992-6400, CTRinfo@dsi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    21 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    •Objective response rate (ORR) per imaging assessment - Percentage of participants with objective response was assessed every six weeks from Cycle 1 Day 1 through disease progression, by independent central imaging facility review based on RECIST version 1.1
    Protection of trial subjects
    The informed consent form was approved by the Ethics Committee or the Institutional Review Board. The study was conducted according to GCP and ethical principles that have their origin in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 77
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Japan: 56
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Worldwide total number of subjects
    253
    EEA total number of subjects
    80
    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)
    189
    From 65 to 84 years
    61
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 253 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomized to treatment (Part 1) or received DS-8201a at the recommended dose (Part 2).

    Pre-assignment
    Screening details
    In Part 1, subjects were randomized 1:1:1 to either 5.4 mg/kg, 6.4 mg/kg, or 7.4 mg/kg dose of DS-8201a. Two doses randomized 1:1 (6.4 mg/kg and 7.4 mg/kg) were further evaluated. In Part 2, all T-DM1 resistant refractory participants (Cohort 2a) or T-DM1 intolerant (Cohort 2b) received DS-8201a at the recommended dose.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Part 1 of the study was randomized and consisted of the PK stage and Dose Finding stage. Part 2 was not randomized and all subjects received DS-8201a at the recommended dose determined in Part 1.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 1: DS-8201a Low Dose
    Arm description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a low dose (5.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DS-8201a is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered as low, medium and high intravenous (IV) doses for Part 1 of the trial. The dose for Part 2 will be determined based on results from Part 1.

    Arm title
    Part 1: DS-8201a Medium Dose
    Arm description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a medium dose (6.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DS-8201a is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered as low, medium and high intravenous (IV) doses for Part 1 of the trial. The dose for Part 2 will be determined based on results from Part 1.

    Arm title
    Part 1: DS-8201a High Dose
    Arm description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a high dose (7.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DS-8201a is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered as low, medium and high intravenous (IV) doses for Part 1 of the trial. The dose for Part 2 will be determined based on results from Part 1.

    Arm title
    Part 2a: DS-8201a Low Dose
    Arm description
    All T-DM1 resistant/refractory (R/R) participants who were treated at the recommended (5.4 mg/kg) dose in Part 2a in the continuation phase.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DS-8201a is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered as low, medium and high intravenous (IV) doses for Part 1 of the trial. The dose for Part 2 will be determined based on results from Part 1.

    Arm title
    Part 2b (Exploratory): DS-8201a Low Dose
    Arm description
    All participants who were previously treated with T-DM1 and were randomized to receive DS8201a low dose (5.4 mg/kg) in Part 2b in the continuation phase.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DS-8201a is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered as low, medium and high intravenous (IV) doses for Part 1 of the trial. The dose for Part 2 will be determined based on results from Part 1.

    Number of subjects in period 1
    Part 1: DS-8201a Low Dose Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 2a: DS-8201a Low Dose Part 2b (Exploratory): DS-8201a Low Dose
    Started
    50
    48
    21
    130
    4
    Completed
    0
    0
    0
    0
    0
    Not completed
    50
    48
    21
    130
    4
         Death
    1
    -
    -
    6
    -
         Physician decision
    1
    -
    1
    2
    -
         Progressive disease per RECIST v1.1
    16
    12
    9
    22
    -
         Not specified
    -
    1
    -
    4
    -
         Adverse event, non-fatal
    6
    6
    8
    8
    1
         Consent withdrawn by subject
    3
    3
    -
    3
    1
         Ongoing
    23
    26
    3
    85
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: DS-8201a Low Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a low dose (5.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 1: DS-8201a Medium Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a medium dose (6.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 1: DS-8201a High Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a high dose (7.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 2a: DS-8201a Low Dose
    Reporting group description
    All T-DM1 resistant/refractory (R/R) participants who were treated at the recommended (5.4 mg/kg) dose in Part 2a in the continuation phase.

    Reporting group title
    Part 2b (Exploratory): DS-8201a Low Dose
    Reporting group description
    All participants who were previously treated with T-DM1 and were randomized to receive DS8201a low dose (5.4 mg/kg) in Part 2b in the continuation phase.

    Reporting group values
    Part 1: DS-8201a Low Dose Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 2a: DS-8201a Low Dose Part 2b (Exploratory): DS-8201a Low Dose Total
    Number of subjects
    50 48 21 130 4 253
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0
        Adults (18-64 years)
    35 33 16 101 4 189
        From 65-84 years
    14 15 5 27 0 61
        85 years and over
    1 0 0 2 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.9 ± 11.3 55.8 ± 13.0 54.4 ± 10.5 55.4 ± 11.9 49.8 ± 9.2 -
    Gender categorical
    Units: Subjects
        Female
    50 48 21 130 4 253
        Male
    0 0 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 1 0 0 1 2
        Asian
    22 22 12 47 1 104
        Native Hawaiian or Other Pacific Islander
    1 0 0 0 0 1
        Black or African American
    2 0 1 1 1 5
        White
    24 23 8 76 1 132
        More than one race
    1 1 0 2 0 4
        Unknown or Not Reported
    0 1 0 4 0 5
    Region of Enrollment
    Units: Subjects
        South Korea
    7 7 0 25 1 40
        Belgium
    0 2 0 7 0 9
        United States
    15 14 10 36 2 77
        Japan
    16 15 11 14 0 56
        Italy
    0 1 0 8 1 10
        United Kingdom
    0 0 0 12 0 12
        France
    2 1 0 17 0 20
        Spain
    10 8 0 11 0 29
    Subject analysis sets

    Subject analysis set title
    Part 1 and Part 2a: DS-8201a Low Dose
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All T-DM1 resistant/refractory (R/R) participants who were treated in Part 1 or Part 2a at the recommended (5.4 mg/kg) dose.

    Subject analysis set title
    Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants who were previously treated with T-DM1 and were randomized to receive DS8201a low dose (5.4 mg/kg) in Part 1 or Part 2a or Part 2b.

    Subject analysis sets values
    Part 1 and Part 2a: DS-8201a Low Dose Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Number of subjects
    180
    184
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    136
    140
        From 65-84 years
    41
    41
        85 years and over
    3
    3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.1 ± 11.8
    56.0 ± 11.7
    Gender categorical
    Units: Subjects
        Female
    180
    184
        Male
    0
    0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0
    1
        Asian
    69
    70
        Native Hawaiian or Other Pacific Islander
    1
    1
        Black or African American
    3
    4
        White
    100
    101
        More than one race
    3
    3
        Unknown or Not Reported
    4
    4
    Region of Enrollment
    Units: Subjects
        South Korea
    32
    33
        Belgium
    7
    7
        United States
    51
    53
        Japan
    30
    30
        Italy
    8
    9
        United Kingdom
    12
    12
        France
    19
    19
        Spain
    21
    21

    End points

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    End points reporting groups
    Reporting group title
    Part 1: DS-8201a Low Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a low dose (5.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 1: DS-8201a Medium Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a medium dose (6.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 1: DS-8201a High Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a high dose (7.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 2a: DS-8201a Low Dose
    Reporting group description
    All T-DM1 resistant/refractory (R/R) participants who were treated at the recommended (5.4 mg/kg) dose in Part 2a in the continuation phase.

    Reporting group title
    Part 2b (Exploratory): DS-8201a Low Dose
    Reporting group description
    All participants who were previously treated with T-DM1 and were randomized to receive DS8201a low dose (5.4 mg/kg) in Part 2b in the continuation phase.

    Subject analysis set title
    Part 1 and Part 2a: DS-8201a Low Dose
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All T-DM1 resistant/refractory (R/R) participants who were treated in Part 1 or Part 2a at the recommended (5.4 mg/kg) dose.

    Subject analysis set title
    Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants who were previously treated with T-DM1 and were randomized to receive DS8201a low dose (5.4 mg/kg) in Part 1 or Part 2a or Part 2b.

    Primary: Objective Response Rate as Confirmed by Independent Central Review Following Intravenous Administration of 5.4 mg/kg DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set)

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    End point title
    Objective Response Rate as Confirmed by Independent Central Review Following Intravenous Administration of 5.4 mg/kg DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [1]
    End point description
    The number of participants with objective response was assessed every six weeks from Cycle 1 Day 1 through discontinuation of treatment, by independent central imaging facility review based on RECIST version 1.1.
    End point type
    Primary
    End point timeframe
    At least 6 months after last participant enrolled received first dose up to 19 months (data cut off of 21 March 2019)
    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: Descriptive analyses were performed based on the study groups and the study drug administered for this outcome.
    End point values
    Part 1 and Part 2a: DS-8201a Low Dose Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Number of subjects analysed
    180
    184
    Units: participants
        number (not applicable)
    109
    111
    No statistical analyses for this end point

    Secondary: Objective Response Rate as Confirmed By the Investigator Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set)

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    End point title
    Objective Response Rate as Confirmed By the Investigator Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [2]
    End point description
    The number of participants with objective response is assessed every six weeks from Cycle 1 Day 1 through discontinuation of treatment. Investigator-assessed objective response rate (ORR) was defined as the proportion of participants who achieved a best overall response of complete response or partial response based on local radiologists/ investigators' tumor assessments.
    End point type
    Secondary
    End point timeframe
    At least 6 months after last participant enrolled received first dose up to 19 months (data cut off of 21 March 2019)
    Notes
    [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: Descriptive analyses were performed based on the study groups and the study drug administered for this outcome.
    End point values
    Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 1 and Part 2a: DS-8201a Low Dose Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Number of subjects analysed
    48
    21
    180
    184
    Units: participants
        number (not applicable)
    37
    18
    116
    118
    No statistical analyses for this end point

    Secondary: Best Overall Tumor Response as Confirmed By the Investigator Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set)

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    End point title
    Best Overall Tumor Response as Confirmed By the Investigator Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [3]
    End point description
    Best overall tumor response was defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) by the investigator based on RECIST v1.1. Participants who were non-evaluable (NE) are also reported.
    End point type
    Secondary
    End point timeframe
    At least 6 months after last participant enrolled received first dose up to 19 months (data cut off of 21 March 2019)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and the study drug administered for this outcome.
    End point values
    Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 1 and Part 2a: DS-8201a Low Dose Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Number of subjects analysed
    48
    21
    180
    184
    Units: participants
    number (not applicable)
        Complete response
    3
    0
    4
    6
        Partial response
    34
    18
    112
    112
        Stable disease
    10
    3
    59
    61
        Progressive disease
    0
    0
    4
    4
        Non-evaluable
    1
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Disease Control Rate and Clinical Benefit Rate as Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set)

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    End point title
    Disease Control Rate and Clinical Benefit Rate as Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [4]
    End point description
    Number of participants with controlled disease and who received clinical benefit from treatment as assessed by independent central review. DCR was defined as the proportion of participants who achieved a best overall response of complete response, partial response, or stable disease. CBR was defined as the proportion of participants who achieved a best overall response of complete response or partial response or more than 6 months of stable disease.
    End point type
    Secondary
    End point timeframe
    At least 6 months after last participant enrolled received first dose up to 19 months (data cut off of 21 March 2019)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and the study drug administered for this outcome.
    End point values
    Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 1 and Part 2a: DS-8201a Low Dose Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Number of subjects analysed
    48
    21
    180
    184
    Units: participants
    number (not applicable)
        Disease control rate
    47
    21
    175
    179
        Clinical benefit rate
    41
    20
    127
    130
    No statistical analyses for this end point

    Secondary: Duration of Response (Complete Response or Partial Response) as Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set)

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    End point title
    Duration of Response (Complete Response or Partial Response) as Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [5]
    End point description
    The estimated duration of confirmed response (complete response [CR] or partial response [PR]) was assessed by independent central review. Duration of response was defined as the time interval between the date of first documentation of objective response (CR or PR) and the date of the first objective documentation of disease progression or death due to any cause.
    End point type
    Secondary
    End point timeframe
    At least 6 months after last participant enrolled received first dose up to 19 months (data cut off of 21 March 2019)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and the study drug administered for this outcome.
    End point values
    Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 1 and Part 2a: DS-8201a Low Dose Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Number of subjects analysed
    33 [6]
    17 [7]
    109 [8]
    111 [9]
    Units: months
        number (confidence interval 95%)
    8.3 (8.3 to 8.3)
    6.0 (4.8 to 8.3)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [6] - Participants with complete response (CR) or partial response (PR) were analyzed.
    [7] - Participants with complete response (CR) or partial response (PR) were analyzed.
    [8] - Participants with complete response (CR) or partial response (PR) were analyzed.
    [9] - Participants with complete response (CR) or partial response (PR) were analyzed.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival Estimate As Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set)

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    End point title
    Progression-Free Survival Estimate As Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [10]
    End point description
    The point estimate of progression-free survival (PFS) is reported. PFS was defined as the time interval between the date of randomization/registration and the first documentation of disease progression or death due to any cause.
    End point type
    Secondary
    End point timeframe
    At least 6 months after last participant enrolled received first dose up to 19 months (data cut off of 21 March 2019)
    Notes
    [10] - 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: Descriptive analyses were performed based on the study groups and the study drug administered for this outcome.
    End point values
    Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 1 and Part 2a: DS-8201a Low Dose Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Number of subjects analysed
    48
    21
    180
    184
    Units: months
        number (confidence interval 95%)
    0 (0 to 0)
    9.5 (7.4 to 13.2)
    10.6 (10.6 to 10.6)
    10.6 (10.6 to 10.6)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Sum of Diameters Over Time as Determined by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set)

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    End point title
    Percent Change From Baseline in Sum of Diameters Over Time as Determined by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [11]
    End point description
    Best percent change in sum of diameters of measurable tumors was based on RECIST 1.1. The best percent change was defined as the percent change in the smallest sum of diameters from all post-baseline tumor assessments, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 6, 12, 18, 24, 30, 36 post dose (as of data cut off of 21 March 2019)
    Notes
    [11] - 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: Descriptive analyses were performed based on the study groups and the study drug administered for this outcome.
    End point values
    Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 1 and Part 2a: DS-8201a Low Dose Part 1 + Part 2a + Part 2b: DS-8201a Low Dose
    Number of subjects analysed
    48
    21
    180
    184
    Units: percent change from baseline
    arithmetic mean (standard deviation)
        Baseline to Week 6 (n=43, 21, 164, 167)
    -26.2 ± 18.3
    -32.9 ± 25.4
    -26.9 ± 21.6
    -26.9 ± 22.5
        Baseline to Week 12 (n=20, 21, 152, 154)
    -39.6 ± 22.7
    -43.6 ± 28.1
    -39.9 ± 24.5
    -40.1 ± 24.9
        Baseline to Week 18 (n=37, 19, 136, 138)
    -50.1 ± 22.1
    -58.5 ± 29.4
    -44.4 ± 27.8
    -44.9 ± 28.0
        Baseline to Week 24 (n=31, 17, 124, 125)
    -56.3 ± 22.1
    -61.9 ± 32.0
    -49.2 ± 30.6
    -49.3 ± 30.5
        Baseline to Week 30 (n=30, 15, 80, 81)
    -59.1 ± 26.1
    -63.9 ± 32.2
    -51.2 ± 29.2
    -51.5 ± 29.2
        Baseline to Week 36 (n=24, 9, 46, 46)
    -61.0 ± 26.7
    -54.6 ± 32.2
    -55.5 ± 29.9
    -55.5 ± 29.9
        Best percent change from baseline(n=43,21,166,169)
    -59.5 ± 28.2
    -65.3 ± 27.7
    -50.5 ± 28.3
    -50.6 ± 28.8
    No statistical analyses for this end point

    Secondary: Overall Summary of Treatment-emergent Adverse Events (TEAEs) Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Safety Analysis Set)

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    End point title
    Overall Summary of Treatment-emergent Adverse Events (TEAEs) Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Safety Analysis Set)
    End point description
    TEAEs were assessed by severity and seriousness according to unique criteria. Severity described the intensity of an event and was graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, where Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening consequences; urgent intervention indicated; and Grade 5: Death related to AE. Serious TEAEs were defined as any untoward medical occurrence that at any dose results in death, is life threatening, requires inpatient hospitalization, or causes prolongation of existing hospitalization.
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 47 post last dose (as of data cut off date of 21 March 2019)
    End point values
    Part 1: DS-8201a Low Dose Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 2a: DS-8201a Low Dose Part 2b (Exploratory): DS-8201a Low Dose
    Number of subjects analysed
    50
    48
    21
    130
    4
    Units: participants
    number (not applicable)
        Any TEAE
    50
    48
    21
    129
    4
        Drug-related TEAEs
    50
    47
    21
    128
    4
        Drug-related TEAEs of CTCAE ≥Grade 3
    26
    32
    16
    48
    3
        Any serious TEAE
    11
    6
    8
    25
    0
        Drug-related serious TEAEs
    6
    4
    5
    10
    0
        TEAEs associated with drug discontinuation
    6
    6
    8
    8
    1
        Related TEAEs associated with drug discontinuation
    6
    6
    8
    7
    1
        TEAEs associated with dose reduction
    13
    19
    11
    21
    3
        Drug-related TEAEs associated with dose reduction
    11
    18
    11
    20
    3
        TEAEs associated with dose interruption
    19
    16
    12
    36
    2
        Related TEAEs associated with drug interruption
    17
    13
    11
    29
    2
        TEAEs associated with death
    1
    1
    2
    8
    0
        Drug-related TEAEs associated with death
    0
    0
    1
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event (AE) data were collected from Day 0 through Day 47 post last dose of study drug (as of data cutoff date of 21 March 2019).
    Adverse event reporting additional description
    A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that occurred, having been absent before the first dose of study drug, or had worsened in severity or seriousness after the initiating the study drug until 47 days after last dose of the study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Part 1: DS-8201a Low Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a low dose (5.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 1: DS-8201a Medium Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a medium dose (6.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 1: DS-8201a High Dose
    Reporting group description
    T-DM1 resistant/refractory (R/R) participants randomized to receive DS-8201a high dose (7.4 mg/kg) in the pharmacokinetic (PK) and dose-finding phases.

    Reporting group title
    Part 2a: DS-8201a Low Dose
    Reporting group description
    All T-DM1 resistant/refractory (R/R) participants who were treated at the recommended (5.4 mg/kg) dose in Part 2a in the continuation phase.

    Reporting group title
    Part 2b (Exploratory): DS-8201a Low Dose
    Reporting group description
    All participants who were previously treated with T-DM1 and were randomized to receive DS8201a low dose (5.4 mg/kg) in Part 2b in the continuation phase.

    Serious adverse events
    Part 1: DS-8201a Low Dose Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 2a: DS-8201a Low Dose Part 2b (Exploratory): DS-8201a Low Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 50 (22.00%)
    6 / 48 (12.50%)
    8 / 21 (38.10%)
    25 / 130 (19.23%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    6
    7
    8
    13
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Disease progression
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Reproductive system and breast disorders
    Genital hemorrhage
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Ilium fracture
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    2 / 21 (9.52%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    2 / 21 (9.52%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Febrile neutropenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Hematuria
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Shock hemorrhagic
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Dyspnoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Interstitial lung disease
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory failure
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Presyncope
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal abscess
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Abdominal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    2 / 130 (1.54%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Ascites
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Dysphagia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Intestinal obstruction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    3 / 130 (2.31%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 48 (4.17%)
    0 / 21 (0.00%)
    3 / 130 (2.31%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal hemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Vomiting
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    2 / 130 (1.54%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Cholecystitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Pyelonephritis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Flank pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Muscular weakness
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Hyperkalemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypokalemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    2 / 130 (1.54%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Hyponatraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Influenza
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Lung infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Lymphangitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Parotitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    3 / 130 (2.31%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Soft tissue infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Urinary tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    2 / 130 (1.54%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part 1: DS-8201a Low Dose Part 1: DS-8201a Medium Dose Part 1: DS-8201a High Dose Part 2a: DS-8201a Low Dose Part 2b (Exploratory): DS-8201a Low Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    48 / 48 (100.00%)
    21 / 21 (100.00%)
    129 / 130 (99.23%)
    4 / 4 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    4 / 130 (3.08%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    4
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 50 (18.00%)
    7 / 48 (14.58%)
    0 / 21 (0.00%)
    15 / 130 (11.54%)
    1 / 4 (25.00%)
         occurrences all number
    9
    7
    0
    15
    1
    Fatigue
         subjects affected / exposed
    21 / 50 (42.00%)
    24 / 48 (50.00%)
    11 / 21 (52.38%)
    65 / 130 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    21
    24
    11
    65
    2
    Malaise
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 48 (6.25%)
    5 / 21 (23.81%)
    2 / 130 (1.54%)
    0 / 4 (0.00%)
         occurrences all number
    3
    3
    5
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 48 (4.17%)
    0 / 21 (0.00%)
    10 / 130 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    10
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 48 (12.50%)
    0 / 21 (0.00%)
    8 / 130 (6.15%)
    0 / 4 (0.00%)
         occurrences all number
    2
    6
    0
    8
    0
    Pyrexia
         subjects affected / exposed
    2 / 50 (4.00%)
    10 / 48 (20.83%)
    4 / 21 (19.05%)
    11 / 130 (8.46%)
    0 / 4 (0.00%)
         occurrences all number
    2
    10
    4
    11
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 48 (4.17%)
    2 / 21 (9.52%)
    7 / 130 (5.38%)
    0 / 4 (0.00%)
         occurrences all number
    3
    2
    2
    7
    0
    Dizziness
         subjects affected / exposed
    6 / 50 (12.00%)
    4 / 48 (8.33%)
    1 / 21 (4.76%)
    9 / 130 (6.92%)
    1 / 4 (25.00%)
         occurrences all number
    6
    4
    1
    9
    1
    Insomnia
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 48 (10.42%)
    5 / 21 (23.81%)
    6 / 130 (4.62%)
    0 / 4 (0.00%)
         occurrences all number
    5
    5
    5
    6
    0
    Injury, poisoning and procedural complications
    Infusion-related reaction
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 50 (14.00%)
    4 / 48 (8.33%)
    7 / 21 (33.33%)
    10 / 130 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    7
    4
    7
    10
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 50 (18.00%)
    5 / 48 (10.42%)
    7 / 21 (33.33%)
    14 / 130 (10.77%)
    0 / 4 (0.00%)
         occurrences all number
    9
    5
    7
    14
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 48 (8.33%)
    6 / 21 (28.57%)
    7 / 130 (5.38%)
    0 / 4 (0.00%)
         occurrences all number
    1
    4
    6
    7
    0
    Blood bilirubin increased
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 48 (6.25%)
    5 / 21 (23.81%)
    7 / 130 (5.38%)
    0 / 4 (0.00%)
         occurrences all number
    4
    3
    5
    7
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 48 (0.00%)
    3 / 21 (14.29%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    3
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    3 / 130 (2.31%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    1
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 50 (2.00%)
    6 / 48 (12.50%)
    1 / 21 (4.76%)
    4 / 130 (3.08%)
    0 / 4 (0.00%)
         occurrences all number
    1
    6
    1
    4
    0
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 48 (10.42%)
    2 / 21 (9.52%)
    11 / 130 (8.46%)
    0 / 4 (0.00%)
         occurrences all number
    3
    5
    2
    11
    0
    Neutrophil count decreased
         subjects affected / exposed
    16 / 50 (32.00%)
    17 / 48 (35.42%)
    12 / 21 (57.14%)
    21 / 130 (16.15%)
    0 / 4 (0.00%)
         occurrences all number
    16
    17
    12
    21
    0
    Platelet count decreased
         subjects affected / exposed
    8 / 50 (16.00%)
    11 / 48 (22.92%)
    7 / 21 (33.33%)
    16 / 130 (12.31%)
    0 / 4 (0.00%)
         occurrences all number
    8
    11
    7
    16
    0
    Troponin I increased
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    5 / 50 (10.00%)
    6 / 48 (12.50%)
    4 / 21 (19.05%)
    6 / 130 (4.62%)
    1 / 4 (25.00%)
         occurrences all number
    5
    6
    4
    6
    1
    White blood cell count decreased
         subjects affected / exposed
    12 / 50 (24.00%)
    15 / 48 (31.25%)
    13 / 21 (61.90%)
    20 / 130 (15.38%)
    0 / 4 (0.00%)
         occurrences all number
    12
    15
    13
    20
    0
    Hypokalemia
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 48 (6.25%)
    4 / 21 (19.05%)
    16 / 130 (12.31%)
    0 / 4 (0.00%)
         occurrences all number
    3
    3
    4
    16
    0
    Cardiac disorders
    Mitral valve incompetence
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 50 (18.00%)
    7 / 48 (14.58%)
    4 / 21 (19.05%)
    23 / 130 (17.69%)
    0 / 4 (0.00%)
         occurrences all number
    9
    7
    4
    23
    0
    Dyspnoea
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 48 (0.00%)
    2 / 21 (9.52%)
    19 / 130 (14.62%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    2
    19
    0
    Epistaxis
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 48 (6.25%)
    1 / 21 (4.76%)
    16 / 130 (12.31%)
    0 / 4 (0.00%)
         occurrences all number
    6
    3
    1
    16
    0
    Hypoxia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    2 / 130 (1.54%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    2
    1
    Interstitial lung disease
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 48 (6.25%)
    5 / 21 (23.81%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences all number
    4
    3
    5
    1
    0
    Pneumonitis
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 48 (2.08%)
    2 / 21 (9.52%)
    5 / 130 (3.85%)
    0 / 4 (0.00%)
         occurrences all number
    4
    1
    2
    5
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    16 / 50 (32.00%)
    20 / 48 (41.67%)
    10 / 21 (47.62%)
    31 / 130 (23.85%)
    0 / 4 (0.00%)
         occurrences all number
    16
    20
    10
    31
    0
    Leukopenia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    1 / 21 (4.76%)
    3 / 130 (2.31%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    3
    1
    Lymphopenia
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    8 / 130 (6.15%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    8
    0
    Neutropenia
         subjects affected / exposed
    7 / 50 (14.00%)
    6 / 48 (12.50%)
    5 / 21 (23.81%)
    13 / 130 (10.00%)
    1 / 4 (25.00%)
         occurrences all number
    7
    6
    5
    13
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 48 (8.33%)
    2 / 21 (9.52%)
    5 / 130 (3.85%)
    1 / 4 (25.00%)
         occurrences all number
    2
    4
    2
    5
    1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Dysgeusia
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 48 (10.42%)
    1 / 21 (4.76%)
    8 / 130 (6.15%)
    1 / 4 (25.00%)
         occurrences all number
    4
    5
    1
    8
    1
    Headache
         subjects affected / exposed
    7 / 50 (14.00%)
    10 / 48 (20.83%)
    2 / 21 (9.52%)
    26 / 130 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    7
    10
    2
    26
    1
    Neuropathy peripheral
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 48 (2.08%)
    2 / 21 (9.52%)
    7 / 130 (5.38%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    2
    7
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 48 (8.33%)
    2 / 21 (9.52%)
    9 / 130 (6.92%)
    0 / 4 (0.00%)
         occurrences all number
    3
    4
    2
    9
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    4 / 50 (8.00%)
    5 / 48 (10.42%)
    3 / 21 (14.29%)
    16 / 130 (12.31%)
    0 / 4 (0.00%)
         occurrences all number
    4
    5
    3
    16
    0
    Keratitis
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 48 (6.25%)
    1 / 21 (4.76%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences all number
    2
    3
    1
    1
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 48 (6.25%)
    0 / 21 (0.00%)
    3 / 130 (2.31%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    3
    0
    Visual impairment
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 48 (4.17%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    0
    1
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    3 / 130 (2.31%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    3
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    2 / 21 (9.52%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Abdominal distension
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 48 (4.17%)
    3 / 21 (14.29%)
    16 / 130 (12.31%)
    0 / 4 (0.00%)
         occurrences all number
    5
    2
    3
    16
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    8 / 130 (6.15%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    8
    0
    Ascites
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 48 (6.25%)
    1 / 21 (4.76%)
    3 / 130 (2.31%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    1
    3
    0
    Constipation
         subjects affected / exposed
    16 / 50 (32.00%)
    17 / 48 (35.42%)
    10 / 21 (47.62%)
    46 / 130 (35.38%)
    1 / 4 (25.00%)
         occurrences all number
    16
    17
    10
    46
    1
    Diarrhea
         subjects affected / exposed
    15 / 50 (30.00%)
    13 / 48 (27.08%)
    4 / 21 (19.05%)
    33 / 130 (25.38%)
    1 / 4 (25.00%)
         occurrences all number
    15
    13
    4
    33
    1
    Dyspepsia
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 48 (10.42%)
    0 / 21 (0.00%)
    19 / 130 (14.62%)
    0 / 4 (0.00%)
         occurrences all number
    3
    5
    0
    19
    0
    Dysphagia
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 48 (0.00%)
    2 / 21 (9.52%)
    4 / 130 (3.08%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    4
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 50 (16.00%)
    2 / 48 (4.17%)
    2 / 21 (9.52%)
    7 / 130 (5.38%)
    0 / 4 (0.00%)
         occurrences all number
    8
    2
    2
    7
    0
    Haemorrhoids
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 48 (4.17%)
    1 / 21 (4.76%)
    5 / 130 (3.85%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    1
    5
    1
    Nausea
         subjects affected / exposed
    38 / 50 (76.00%)
    40 / 48 (83.33%)
    13 / 21 (61.90%)
    101 / 130 (77.69%)
    2 / 4 (50.00%)
         occurrences all number
    38
    40
    13
    101
    2
    Stomatitis
         subjects affected / exposed
    10 / 50 (20.00%)
    13 / 48 (27.08%)
    4 / 21 (19.05%)
    11 / 130 (8.46%)
    2 / 4 (50.00%)
         occurrences all number
    10
    13
    4
    11
    2
    Toothache
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    23 / 50 (46.00%)
    19 / 48 (39.58%)
    7 / 21 (33.33%)
    58 / 130 (44.62%)
    2 / 4 (50.00%)
         occurrences all number
    23
    19
    7
    58
    2
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    1 / 21 (4.76%)
    1 / 130 (0.77%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    25 / 50 (50.00%)
    28 / 48 (58.33%)
    8 / 21 (38.10%)
    61 / 130 (46.92%)
    2 / 4 (50.00%)
         occurrences all number
    25
    28
    8
    61
    2
    Dry skin
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 48 (2.08%)
    1 / 21 (4.76%)
    7 / 130 (5.38%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    1
    7
    0
    Nail disorder
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    7 / 130 (5.38%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    7
    0
    Pruritus
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 48 (6.25%)
    0 / 21 (0.00%)
    4 / 130 (3.08%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    4
    0
    Rash
         subjects affected / exposed
    1 / 50 (2.00%)
    6 / 48 (12.50%)
    1 / 21 (4.76%)
    10 / 130 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    1
    6
    1
    10
    0
    Skin hyperpigmentation
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 48 (0.00%)
    2 / 21 (9.52%)
    4 / 130 (3.08%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    2
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 48 (6.25%)
    1 / 21 (4.76%)
    8 / 130 (6.15%)
    0 / 4 (0.00%)
         occurrences all number
    3
    3
    1
    8
    0
    Back pain
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 48 (4.17%)
    3 / 21 (14.29%)
    14 / 130 (10.77%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    31
    14
    0
    Muscle spasms
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 48 (2.08%)
    1 / 21 (4.76%)
    8 / 130 (6.15%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    8
    0
    Myalgia
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 48 (6.25%)
    0 / 21 (0.00%)
    7 / 130 (5.38%)
    0 / 4 (0.00%)
         occurrences all number
    4
    3
    0
    7
    0
    Neck pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 48 (2.08%)
    2 / 21 (9.52%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    Pain in extremity
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 48 (8.33%)
    2 / 21 (9.52%)
    3 / 130 (2.31%)
    0 / 4 (0.00%)
         occurrences all number
    2
    4
    2
    3
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 50 (30.00%)
    21 / 48 (43.75%)
    6 / 21 (28.57%)
    37 / 130 (28.46%)
    1 / 4 (25.00%)
         occurrences all number
    15
    21
    6
    37
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 48 (6.25%)
    4 / 21 (19.05%)
    5 / 130 (3.85%)
    0 / 4 (0.00%)
         occurrences all number
    1
    3
    4
    5
    0
    Hypomagnesemia
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 48 (0.00%)
    3 / 21 (14.29%)
    4 / 130 (3.08%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    3
    4
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 48 (2.08%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences all number
    3
    1
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 48 (6.25%)
    1 / 21 (4.76%)
    2 / 130 (1.54%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    1
    2
    0
    Cystitis
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 48 (4.17%)
    1 / 21 (4.76%)
    2 / 130 (1.54%)
    1 / 4 (25.00%)
         occurrences all number
    2
    2
    1
    2
    1
    Herpes zoster
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 48 (0.00%)
    0 / 21 (0.00%)
    1 / 130 (0.77%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 48 (4.17%)
    2 / 21 (9.52%)
    3 / 130 (2.31%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    2
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 48 (6.25%)
    3 / 21 (14.29%)
    8 / 130 (6.15%)
    0 / 4 (0.00%)
         occurrences all number
    5
    3
    3
    8
    0
    Pharyngitis
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 48 (6.25%)
    0 / 21 (0.00%)
    0 / 130 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 50 (12.00%)
    1 / 48 (2.08%)
    1 / 21 (4.76%)
    10 / 130 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    6
    1
    1
    10
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 50 (8.00%)
    3 / 48 (6.25%)
    2 / 21 (9.52%)
    12 / 130 (9.23%)
    1 / 4 (25.00%)
         occurrences all number
    4
    3
    2
    12
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2017
    Revised study title, included additional endpoints, clarified randomization schedule and forms of the drug product, confirmed the analysis sets to be used, and updated information regarding dose modifications, adverse events of special interest, and study assessments.
    22 Jan 2018
    Updated phototoxicity study data, clarified patient enrollment procedures, updated inclusion and exclusion criteria, and revised dose modification guidance.
    27 Jul 2018
    Updated the starting dose of study drug in Part 2, included and/or revised dose modification criteria, clarified patient follow-up procedures, updated timing of relevant study assessments.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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