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    Clinical Trial Results:
    A Phase 2, Multicenter, Open-label Study of DS-8201a in Subjects with HER2-expressing Advanced Colorectal Cancer

    Summary
    EudraCT number
    2017-003466-28
    Trial protocol
    GB   ES   IT  
    Global end of trial date
    10 Nov 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    18 Aug 2021
    First version publication date
    28 Jun 2021
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Report has been updated with final data.

    Trial information

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    Trial identification
    Sponsor protocol code
    DS8201-A-J203
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03384940
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    JAPIC CTI: 173808
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo Inc.
    Sponsor organisation address
    211 Mt. Airy Rd., Basking Ridge, NJ, United States, 07920
    Public contact
    Global Clinical Director, Daiichi Sankyo Inc., +1 908992 6400, CTRinfo@dsi.com
    Scientific contact
    Global Clinical Director, Daiichi Sankyo Inc., +1 908992 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
    Final
    Date of interim/final analysis
    10 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the objective response rate (ORR) of DS-8201a in HER2-expressing advanced metastatic colorectal cancer patients
    Protection of trial subjects
    The study protocol, amendments, the informed consent form(s) (ICF[s]), and information sheets were approved by the appropriate and applicable Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs). The study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Feb 2018
    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: 4
    Country: Number of subjects enrolled
    Japan: 26
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    Italy: 41
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    86
    EEA total number of subjects
    45
    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)
    56
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 86 participants who met all inclusion criteria and no exclusion criteria were enrolled and treated at clinic centers in Japan, United States, Spain, and Italy.

    Pre-assignment
    Screening details
    After tissue screening, a total of 86 participants were eligible based on confirmation of HER2 status.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    This was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    DS-8201a Cohort A
    Arm description
    Participants in Cohort A were HER2-positive (IHC 3+ or IHC 2+/ISH+) who received DS-8201a once every 3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Trastuzumab deruxtecan
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DS-8201a was administered as a sterile intravenous (IV) solution at a dose of the 6.4 mg/kg every 3 weeks (Q3W).

    Arm title
    DS-8201a Cohort B
    Arm description
    Participants in Cohort B were HER2 IHC 2+/ISH - who received DS-8201a once every 3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Trastuzumab deruxtecan
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DS-8201a was administered as a sterile intravenous (IV) solution at a dose of the 6.4 mg/kg every 3 weeks (Q3W).

    Arm title
    DS-8201a Cohort C
    Arm description
    Participants in Cohort C were HER2/IHC 1+ who received DS-8201a once every 3 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-8201a
    Investigational medicinal product code
    Other name
    Trastuzumab deruxtecan
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    DS-8201a was administered as a sterile intravenous (IV) solution at a dose of the 6.4 mg/kg every 3 weeks (Q3W).

    Number of subjects in period 1
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Started
    53
    15
    18
    Completed
    0
    0
    0
    Not completed
    53
    15
    18
         Progressive disease
    36
    11
    13
         Death
    2
    1
    -
         Physician decision
    1
    1
    -
         Clinical progression
    4
    -
    3
         Not specified
    -
    -
    1
         Adverse event, non-fatal
    7
    1
    1
         Consent withdrawn by subject
    3
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DS-8201a Cohort A
    Reporting group description
    Participants in Cohort A were HER2-positive (IHC 3+ or IHC 2+/ISH+) who received DS-8201a once every 3 weeks.

    Reporting group title
    DS-8201a Cohort B
    Reporting group description
    Participants in Cohort B were HER2 IHC 2+/ISH - who received DS-8201a once every 3 weeks.

    Reporting group title
    DS-8201a Cohort C
    Reporting group description
    Participants in Cohort C were HER2/IHC 1+ who received DS-8201a once every 3 weeks.

    Reporting group values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C Total
    Number of subjects
    53 15 18 86
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    35 8 13 56
        From 65-84 years
    18 7 5 30
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.5 ± 11.72 61.5 ± 11.95 58.5 ± 9.97 -
    Gender categorical
    Units: Subjects
        Female
    28 5 7 40
        Male
    25 10 11 46

    End points

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    End points reporting groups
    Reporting group title
    DS-8201a Cohort A
    Reporting group description
    Participants in Cohort A were HER2-positive (IHC 3+ or IHC 2+/ISH+) who received DS-8201a once every 3 weeks.

    Reporting group title
    DS-8201a Cohort B
    Reporting group description
    Participants in Cohort B were HER2 IHC 2+/ISH - who received DS-8201a once every 3 weeks.

    Reporting group title
    DS-8201a Cohort C
    Reporting group description
    Participants in Cohort C were HER2/IHC 1+ who received DS-8201a once every 3 weeks.

    Primary: Number of Participants With Best Objective Response Based on Independent Central Review (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Number of Participants With Best Objective Response Based on Independent Central Review (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer [1]
    End point description
    Best objective response was reported based on independent central review. As per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions.
    End point type
    Primary
    End point timeframe
    Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 18 months post-dose
    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 statistics were used to assess this outcome.
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Number of subjects
    number (not applicable)
        Confirmed CR
    0
    0
    0
        Confirmed PR
    24
    0
    0
        Confirmed SD
    20
    9
    4
        Confirmed PD
    5
    5
    10
        Confirmed Non-evaluable
    4
    1
    4
        Unconfirmed CR
    0
    0
    0
        Unconfirmed PR
    26
    0
    0
        Unconfirmed SD
    18
    9
    4
        Unconfirmed PD
    5
    5
    10
        Unconfirmed Non-evaluable
    4
    1
    4
    No statistical analyses for this end point

    Primary: Number of Participants With Objective Response Rate Based on Independent Central Review (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Number of Participants With Objective Response Rate Based on Independent Central Review (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer [2]
    End point description
    Objective response rate (defined as CR+PR) was reported based on independent central review. As per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.
    End point type
    Primary
    End point timeframe
    Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 18 months post-dose
    Notes
    [2] - 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 statistics were used to assess this outcome.
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Number of subjects
    number (not applicable)
        Confirmed CR+PR
    24
    0
    0
        Confirmed CR+PR (within 3 months)
    10
    0
    0
        Confirmed CR+PR (within 6 months)
    23
    0
    0
        Confirmed CR+PR (within 9 months)
    24
    0
    0
        Confirmed CR+PR (within 12 months)
    24
    0
    0
        Unconfirmed CR+PR
    26
    0
    0
        Unconfirmed CR+PR (within 3 months)
    20
    0
    0
        Unconfirmed CR+PR (within 6 months)
    25
    0
    0
        Unconfirmed CR+PR (within 9 months)
    25
    0
    0
        Unconfirmed CR+PR (within 12 months)
    25
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Best Objective Response Based on Investigator (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Number of Participants With Best Objective Response Based on Investigator (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer
    End point description
    Best objective response was reported based on investigator. As per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions.
    End point type
    Secondary
    End point timeframe
    Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 18 months post-dose
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Number of subjects
    number (not applicable)
        Confirmed CR
    0
    0
    0
        Confirmed PR
    25
    0
    0
        Confirmed SD
    18
    7
    6
        Confirmed PD
    6
    7
    8
        Confirmed Non-evaluable
    4
    1
    4
        Unconfirmed CR
    0
    0
    0
        Unconfirmed PR
    28
    0
    0
        Unconfirmed SD
    15
    7
    6
        Unconfirmed PD
    6
    7
    8
        Unconfirmed Non-evaluable
    4
    1
    4
    No statistical analyses for this end point

    Secondary: Number of Participants With Objective Response Rate Based on Investigator (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Number of Participants With Objective Response Rate Based on Investigator (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer
    End point description
    Objective response rate (defined as CR+PR) was reported based on investigator. As per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.
    End point type
    Secondary
    End point timeframe
    Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 18 months post-dose
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Number of subjects
    number (not applicable)
        Confirmed CR+PR
    25
    0
    0
        Unconfirmed CR+PR
    28
    0
    0
    No statistical analyses for this end point

    Secondary: Duration of Response (Confirmed and Unconfirmed) Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Duration of Response (Confirmed and Unconfirmed) Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer [3]
    End point description
    Duration of response (DoR) is defined as the time from the date of the first documentation of an objective response (CR[disappearance of all target lesions] or PR [at least a 30% decrease in the sum of diameters of target lesions]) to the date of the first documentation of PD (at least a 20% increase in the sum of diameters of target lesions). Duration of response was measured for responding participants (CR or PR) only. Month was calculated as (duration of response days × 12)/365.25 for duration of response and calculated as (time to response days × 12)/365.25 for time to response.
    End point type
    Secondary
    End point timeframe
    Date of first documentation of objective response (CR or PR) up to date of first documentation of PD, up to approximately 18 months post-dose
    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 statistics were used to assess this outcome.
    End point values
    DS-8201a Cohort A
    Number of subjects analysed
    53
    Units: Months
    median (confidence interval 95%)
        Confirmed DoR
    7.0 (5.8 to 9.5)
        Unconfirmed DoR
    7.0 (5.8 to 9.5)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Disease Control Rate (Confirmed and Unconfirmed) Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer
    End point description
    Disease control rate (DCR) was defined as the proportion of participants who achieved a best overall response of CR + PR + SD based on independent central review and investigator assessment. As per RECIST v1.1, CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions).
    End point type
    Secondary
    End point timeframe
    Baseline up to withdrawal of consent, progressive disease, or unacceptable toxicity (whichever occurs first), up to 18 months post-dose
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Number of subjects
    number (not applicable)
        Confirmed CR+PR+SD (Independent Central Review)
    44
    9
    4
        Unconfirmed CR+PR+SD (Independent Central Review)
    44
    9
    4
        Confirmed CR+PR+SD (Investigator)
    43
    7
    6
        Unconfirmed CR+PR+SD (Investigator)
    43
    7
    6
    No statistical analyses for this end point

    Secondary: Progression-Free Survival Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Progression-Free Survival Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer
    End point description
    Progression-free survival (PFS) is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic progressive disease (PD) via independent radiologic facility review or death due to any cause. PD was defined as at least a 20% increase in the sum of diameters of target lesions.
    End point type
    Secondary
    End point timeframe
    Date of first dose to date of first objective documentation of PD or death (whichever occurs first), up to approximately 18 months
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Months
    median (confidence interval 95%)
        Progression-free survival
    6.9 (4.1 to 6.9)
    2.1 (1.4 to 4.1)
    1.4 (1.3 to 2.1)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival at Various Time Points Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Progression-Free Survival at Various Time Points Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer
    End point description
    Progression-free survival (PFS) is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic progressive disease (PD) via independent radiologic facility review or death due to any cause. PD was defined as at least a 20% increase in the sum of diameters of target lesions. Point estimates at 3, 6, 9, and 12 months are based on Kaplan-Meier estimate. CI is computed using the Brookmeyer-Crowley method. The point estimate percentage (95% confidence interval) at 3, 6, 9, and 12 months is being reported.
    End point type
    Secondary
    End point timeframe
    Date of first dose to date of first objective documentation of PD or death (whichever occurs first), up to approximately 18 months
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Months
    median (confidence interval 95%)
        Progression-free survival at 3 months
    74.4 (60.0 to 84.3)
    38.3 (13.0 to 63.6)
    7.5 (0.5 to 28.3)
        Progression-free survival at 6 months
    55 (40.0 to 67.8)
    0 (0 to 0)
    0 (0 to 0)
        Progression-free survival at 9 months
    34.1 (19.7 to 49.1)
    0 (0 to 0)
    0 (0 to 0)
        Progression-free survival at 12 months
    19.0 (7.5 to 34.3)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Overall Survival Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Overall Survival Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer
    End point description
    Overall survival (OS) is defined as the time from the date of first dose to the date of death from any cause. There is no data for the upper confidence interval for Cohort B as not enough events occurred to estimate the confidence interval and it is denoted as 99.9 as N/A cannot be entered in this field.
    End point type
    Secondary
    End point timeframe
    Time from the date of first dose to date of death from any cause, up to approximately 18 months
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Months
    median (confidence interval 95%)
        Overall survival
    15.5 (8.8 to 20.8)
    7.3 (3.0 to 99.9)
    7.7 (2.2 to 13.9)
    No statistical analyses for this end point

    Secondary: Overall Survival at Various Time Points Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer

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    End point title
    Overall Survival at Various Time Points Based on Independent Central Review Following DS-8201a Treatment in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Advanced Colorectal Cancer
    End point description
    Overall survival (OS) is defined as the time from the date of first dose to the date of death from any cause. The point estimate percentage (95% confidence interval) at 3, 6, 9, and 12 months is being reported.
    End point type
    Secondary
    End point timeframe
    Time from the date of first dose to date of death from any cause, up to approximately 18 months
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Months
    median (confidence interval 95%)
        Overall survival at 3 months
    86.8 (74.3 to 93.5)
    86.7 (56.4 to 96.5)
    77.0 (49.7 to 90.7)
        Overall survival at 6 months
    73.6 (59.5 to 83.4)
    53.3 (26.3 to 74.4)
    57.8 (31.0 to 77.3)
        Overall survival at 9 months
    62.0 (47.5 to 73.5)
    38.1 (14.6 to 61.6)
    43.3 (18.9 to 65.7)
        Overall survival at 12 months
    60.0 (45.5 to 71.8)
    38.1 (14.6 to 61.6)
    28.9 (9.3 to 52.3)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer

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    End point title
    Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer
    End point description
    Maximum serum concentration (Cmax) of DS-8201a and total anti-HER2 antibody was assessed.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Day 1, before infusion (BI), end of infusion (EOI); Day 8; Day 15; Cycle 2: Day 1, BI and EOI; Cycle 3: Day 1, BI, EOI, 4 hours after start of drug, and 7 hours after start of drug; Cycles 4 and 6: Day 1, BI and EOI
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: ug/mL
    arithmetic mean (standard deviation)
        DS-8201a
    135 ± 32.7
    123 ± 29.5
    122 ± 41.5
        Total anti-HER2 antibody
    130 ± 35.1
    106 ± 24.6
    109 ± 35.4
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) of MAAA-11181a Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer

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    End point title
    Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) of MAAA-11181a Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer
    End point description
    Maximum serum concentration (Cmax) of MAAA-1181a was assessed.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Day 1, before infusion (BI), end of infusion (EOI); Day 8; Day 15; Cycle 2: Day 1, BI and EOI; Cycle 3: Day 1, BI, EOI, 4 hours after start of drug, and 7 hours after start of drug; Cycles 4 and 6: Day 1, BI and EOI
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: ng/mL
    arithmetic mean (standard deviation)
        MAAA-1181a
    15.8 ± 7.67
    12.9 ± 6.40
    15.1 ± 5.30
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Time to Maximum Serum Concentration (Tmax) Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer

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    End point title
    Pharmacokinetic Parameter Time to Maximum Serum Concentration (Tmax) Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer
    End point description
    Time to maximum serum concentration (Tmax) of DS-8201a, total anti-HER2 antibody, and MAAA-1181a was assessed.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Day 1, before infusion (BI), end of infusion (EOI); Day 8; Day 15; Cycle 2: Day 1, BI and EOI; Cycle 3: Day 1, BI, EOI, 4 hours after start of drug, and 7 hours after start of drug; Cycles 4 and 6: Day 1, BI and EOI
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: hours
    arithmetic mean (full range (min-max))
        DS-8201a (n=52, 6, 18)
    1.95 (1.42 to 8.75)
    1.72 (1.25 to 5.08)
    3.00 (0.88 to 6.92)
        Total anti-HER2 antibody (n=52, 6, 18)
    1.72 (1.42 to 6.95)
    1.68 (1.25 to 7.08)
    1.93 (0.88 to 6.92)
        MAAA-1181a (n=52, 6, 18)
    5.17 (1.75 to 8.75)
    5.00 (3.83 to 6.97)
    5.25 (3.83 to 7.00)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUC) Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer

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    End point title
    Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUC) Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer
    End point description
    Area under the concentration-time curve (AUC) from dosing until 21 days (AUC21d) and the last quantifiable concentration (AUClast) of DS-8201a and total anti-HER2 antibody were assessed.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Day 1, before infusion (BI), end of infusion (EOI); Day 8; Day 15; Cycle 2: Day 1, BI and EOI; Cycle 3: Day 1, BI, EOI, 4 hours after start of drug, and 7 hours after start of drug; Cycles 4 and 6: Day 1, BI and EOI
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: ug*d/mL
    arithmetic mean (standard deviation)
        DS-8201a:AUC21d (n=51,13,16)
    610 ± 198
    571 ± 208
    577 ± 219
        DS-8201a:AUClast (n=53,15,18)
    600 ± 204
    559 ± 211
    577 ± 237
        Total anti-HER2 antibody:AUC21d (n=50,13,16)
    661 ± 218
    569 ± 224
    574 ± 219
        Total anti-HER2 antibody:AUClast (n=53,15,18)
    638 ± 235
    558 ± 225
    555 ± 224
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUC) of MAAA-1181a Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer

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    End point title
    Pharmacokinetic Parameter Area Under the Concentration-time Curve (AUC) of MAAA-1181a Following Treatment With DS-8201a in Participants With HER2-expressing Advanced Colorectal Cancer
    End point description
    Area under the concentration-time curve (AUC) from dosing until 21 days (AUC21d) and the last quantifiable concentration (AUClast) of MAAA-1181a were assessed.
    End point type
    Secondary
    End point timeframe
    Cycle 1: Day 1, before infusion (BI), end of infusion (EOI); Day 8; Day 15; Cycle 2: Day 1, BI and EOI; Cycle 3: Day 1, BI, EOI, 4 hours after start of drug, and 7 hours after start of drug; Cycles 4 and 6: Day 1, BI and EOI
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: ng*d/mL
    arithmetic mean (standard deviation)
        MAAA-1181a:AUC21d (n=45,12,11)
    60.2 ± 42.7
    45.0 ± 28.1
    55.1 ± 19.6
        MAAA-1181a:AUClast (n=53, 15, 18)
    59.5 ± 42.1
    47.1 ± 29.4
    62.5 ± 19.6
    No statistical analyses for this end point

    Secondary: Treatment-Emergent Adverse Events (TEAEs) Reported By ≥20% Of Participants Following Treatment With DS-8201a in Subjects With HER2-expressing Advanced Colorectal Cancer

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    End point title
    Treatment-Emergent Adverse Events (TEAEs) Reported By ≥20% Of Participants Following Treatment With DS-8201a in Subjects With HER2-expressing Advanced Colorectal Cancer
    End point description
    A treatment-emergent adverse event (TEAE) is defined as any adverse event not present prior to the initiation of drug treatment or any adverse event already present that worsens in intensity or frequency following exposure to the drug treatment. TEAEs were graded using National Cancer Institute (NCI)-CTCAE version 4.03.
    End point type
    Secondary
    End point timeframe
    From the date of signing the informed consent form up to 40 (+7) days after last dose, up to approximately 18 months
    End point values
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Number of subjects analysed
    53
    15
    18
    Units: Number of subjects
    number (not applicable)
        Any TEAE
    53
    15
    18
        Nausea
    37
    9
    7
        Anaemia
    21
    4
    6
        Decreased appetite
    18
    5
    7
        Fatigue
    21
    7
    3
        Neutrophil count decreased
    20
    2
    4
        Platelet count decreased
    17
    4
    7
        Vomiting
    23
    3
    1
        Diarrhoea
    19
    0
    4
        Alopecia
    12
    4
    1
        Constipation
    10
    3
    1
        Hypokalaemia
    9
    1
    4
        Aspartate aminotransferase increased
    6
    1
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the date of signing the informed consent form up to 40 (+7) days after last dose, up to approximately 18 months.
    Adverse event reporting additional description
    A treatment-emergent adverse event (TEAE) was defined as an AE that occurred, having been absent before the first dose of study drug, or having worsened in severity or seriousness after initiation of the study drug until 40 (+7) days after the last dose of the study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    DS-8201a Cohort A
    Reporting group description
    Participants in Cohort A were HER2-positive (IHC 3+ or IHC 2+/ISH+) who received DS-8201a once every 3 weeks.

    Reporting group title
    DS-8201a Cohort B
    Reporting group description
    Participants in Cohort B were HER2/IHC 1+ who received DS-8201a once every 3 weeks.

    Reporting group title
    DS-8201a Cohort C
    Reporting group description
    Participants in Cohort C were HER2 IHC 2+/ISH - who received DS-8201a once every 3 weeks.

    Serious adverse events
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 53 (37.74%)
    6 / 15 (40.00%)
    12 / 18 (66.67%)
         number of deaths (all causes)
    36
    10
    12
         number of deaths resulting from adverse events
    2
    1
    0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 15 (13.33%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Meningism
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal ulcer
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    DS-8201a Cohort A DS-8201a Cohort B DS-8201a Cohort C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 53 (100.00%)
    15 / 15 (100.00%)
    18 / 18 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    3
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    Retinal vein occlusion
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 53 (11.32%)
    2 / 15 (13.33%)
    3 / 18 (16.67%)
         occurrences all number
    6
    2
    3
    Disease progression
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Fatigue
         subjects affected / exposed
    21 / 53 (39.62%)
    7 / 15 (46.67%)
    3 / 18 (16.67%)
         occurrences all number
    21
    7
    3
    Fluid retention
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    Generalised oedema
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Malaise
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 15 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    5
    0
    4
    Oedema
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    8 / 53 (15.09%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    8
    1
    1
    Pyrexia
         subjects affected / exposed
    8 / 53 (15.09%)
    1 / 15 (6.67%)
    3 / 18 (16.67%)
         occurrences all number
    8
    1
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    1
    Mood altered
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 53 (9.43%)
    1 / 15 (6.67%)
    3 / 18 (16.67%)
         occurrences all number
    5
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 53 (11.32%)
    1 / 15 (6.67%)
    4 / 18 (22.22%)
         occurrences all number
    6
    1
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 15 (6.67%)
    2 / 18 (11.11%)
         occurrences all number
    3
    1
    2
    Blood calcium decreased
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 15 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    5
    0
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    2
    0
    2
    Blood magnesium decreased
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    2
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 15 (13.33%)
    0 / 18 (0.00%)
         occurrences all number
    2
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    20 / 53 (37.74%)
    2 / 15 (13.33%)
    4 / 18 (22.22%)
         occurrences all number
    20
    2
    4
    Platelet count decreased
         subjects affected / exposed
    17 / 53 (32.08%)
    4 / 15 (26.67%)
    7 / 18 (38.89%)
         occurrences all number
    17
    4
    7
    Weight decreased
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    5
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    11 / 53 (20.75%)
    1 / 15 (6.67%)
    2 / 18 (11.11%)
         occurrences all number
    11
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    21 / 53 (39.62%)
    4 / 15 (26.67%)
    6 / 18 (33.33%)
         occurrences all number
    21
    4
    6
    Leukocytosis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    5
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 53 (15.09%)
    2 / 15 (13.33%)
    0 / 18 (0.00%)
         occurrences all number
    8
    2
    0
    Dyspnoea
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 15 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    3
    0
    Interstitial lung disease
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 15 (20.00%)
    1 / 18 (5.56%)
         occurrences all number
    4
    3
    1
    Productive cough
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    2
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    1
    Headache
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    2
    1
    0
    Paraesthesia
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    2
    0
    1
    Vasogenic cerebral oedema
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    5
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Keratitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 53 (15.09%)
    2 / 15 (13.33%)
    0 / 18 (0.00%)
         occurrences all number
    8
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    3
    1
    0
    Abdominal sepsis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Ascites
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    10 / 53 (18.87%)
    3 / 15 (20.00%)
    1 / 18 (5.56%)
         occurrences all number
    10
    3
    1
    Diarrhoea
         subjects affected / exposed
    19 / 53 (35.85%)
    0 / 15 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    19
    0
    4
    Gastritis
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Ileus paralytic
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Intestinal obstruction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Intestinal prolapse
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    37 / 53 (69.81%)
    9 / 15 (60.00%)
    7 / 18 (38.89%)
         occurrences all number
    37
    9
    7
    Small intestinal obstruction
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Stomatitis
         subjects affected / exposed
    6 / 53 (11.32%)
    2 / 15 (13.33%)
    1 / 18 (5.56%)
         occurrences all number
    6
    2
    1
    Vomiting
         subjects affected / exposed
    23 / 53 (43.40%)
    3 / 15 (20.00%)
    1 / 18 (5.56%)
         occurrences all number
    23
    3
    1
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Cholecystitis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    1
    Dysuria
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Hydronephrosis
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    2
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    12 / 53 (22.64%)
    4 / 15 (26.67%)
    1 / 18 (5.56%)
         occurrences all number
    12
    4
    1
    Flushing
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Jaundice
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    Back pain
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    5
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 15 (13.33%)
    0 / 18 (0.00%)
         occurrences all number
    2
    2
    0
    Myalgia
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Cancer pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Decreased appetite
         subjects affected / exposed
    18 / 53 (33.96%)
    5 / 15 (33.33%)
    7 / 18 (38.89%)
         occurrences all number
    18
    5
    7
    Dehydration
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    2
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    2
    0
    1
    Hypokalaemia
         subjects affected / exposed
    9 / 53 (16.98%)
    1 / 15 (6.67%)
    4 / 18 (22.22%)
         occurrences all number
    9
    1
    4
    Hypomagnesaemia
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Cystitis
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 15 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    0
    Fungal infection
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Lung infection
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 15 (6.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Sepsis
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 15 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    3
    0
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 53 (9.43%)
    1 / 15 (6.67%)
    1 / 18 (5.56%)
         occurrences all number
    5
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2017
    Revised inclusion and exclusion criteria, adjustments made to dose modifications, managing adverse events, and to the description of prior/concomitant palliative radiotherapy, and modified screening criteria
    25 Jan 2018
    Updated risks and benefits for study subjects, clarified inclusion/exclusion criteria and conditions for troponin test, revised safety management and dose modification guidance for subjects, and clarified the safety profile for DS-8201a
    05 Jul 2018
    Clarified definitions relevant to Screening criteria and adverse event reporting, additional subgroup analysis for prior treatment with HER2 targeted regimen
    26 Apr 2019
    Clarified ILD biomarkers for analysis, revised ILD monitoring plan and dose modification language, and clarified reporting of ILD events
    03 Jul 2020
    Added exploring endpoint for COVID-19 infection, modified inclusion criteria and dose modification guidelines, updated list of prohibited medications and permitted therapies, updated blood sampling for COVID-19 and evaluations for ILD/pneumonitis, amended PK assessments, updated AE, SAE, and AESI reporting procedures

    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
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