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    Clinical Trial Results:
    A Phase 2, Open Label Study of Tucatinib Combined with Trastuzumab in Patients with Human Epidermal Growth Factor Receptor 2 (HER2+) Metastatic Colorectal Cancer

    Summary
    EudraCT number
    		 2020-000540-60
    Trial protocol
    		 FR   BE   IT  
    Global end of trial date
    02 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Nov 2024
    First version publication date
    16 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C4251002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03043313
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Seagen Protocol Code: SGNTUC-017
    Sponsors
    Sponsor organisation name
    Seagen Inc.
    Sponsor organisation address
    21823 30th Drive S.E., Bothell, United States, 98021
    Public contact
    Chief Medical Officer, Seagen Inc., 1 8554732436, medinfo@seagen.com
    Scientific contact
    Chief Medical Officer, Seagen Inc., 1 8554732436, medinfo@seagen.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
    22 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the antitumor activity of tucatinib given in combination with trastuzumab, in Cohorts A+B, as measured by confirmed objective response rate (cORR, per response evaluation criteria in solid tumors [RECIST] 1.1 criteria), according to blinded independent central review (BICR) assessment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jun 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 88
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Spain: 5
    Worldwide total number of subjects
    117
    EEA total number of subjects
    29
    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)
    94
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 117 participants were enrolled at a total of 56 sites in the United States, Italy, France, Belgium, and Spain. The date of first participant enrollment was 23-Jun-2017. The date of last participant randomisation was 02-Nov-2023.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tucatinib+Trastuzumab (Cohort A)
    Arm description
    		 Non-randomized cohort. Participants received Tucatinib 300 milligrams (mg) orally (PO) twice daily (BID) on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 milligram/kilogram (mg/kg) by intravenous (IV) infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until progressive disease (PD), death, withdrawal of consent, study closure, or alternative therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle.

    Investigational medicinal product name
    Tucatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle.

    Arm title
    		 Tucatinib+Trastuzumab (Cohort B)
    Arm description
    		 Randomized cohort. Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle.

    Investigational medicinal product name
    Tucatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle.

    Arm title
    		 Tucatinib Monotherapy (Cohort C)
    Arm description
    		 Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Participants who did not respond to monotherapy were given the option to receive tucatinib and trastuzumab until PD, death, withdrawal of consent, study closure, or alternative therapy based on radiographic progression (as determined by investigator assessment using response evaluation criteria in solid tumors [RECIST] version [v] 1.1), or if they had not achieved a partial response (PR) or complete response (CR) by the week 12 assessment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tucatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle.

    Number of subjects in period 1
    		Tucatinib+Trastuzumab (Cohort A) Tucatinib+Trastuzumab (Cohort B) Tucatinib Monotherapy (Cohort C)
    Started
    45
    41
    31
    Completed
    0
    0
    0
    Not completed
    45
    41
    31
         Consent withdrawn by subject
    5
    1
    1
         Death
    28
    26
    17
         Lost to follow-up
    1
    1
    -
         Participation terminated by sponsor
    11
    13
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tucatinib+Trastuzumab (Cohort A)
    Reporting group description
    		 Non-randomized cohort. Participants received Tucatinib 300 milligrams (mg) orally (PO) twice daily (BID) on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 milligram/kilogram (mg/kg) by intravenous (IV) infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until progressive disease (PD), death, withdrawal of consent, study closure, or alternative therapy.

    Reporting group title
    Tucatinib+Trastuzumab (Cohort B)
    Reporting group description
    		 Randomized cohort. Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Reporting group title
    Tucatinib Monotherapy (Cohort C)
    Reporting group description
    		 Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Participants who did not respond to monotherapy were given the option to receive tucatinib and trastuzumab until PD, death, withdrawal of consent, study closure, or alternative therapy based on radiographic progression (as determined by investigator assessment using response evaluation criteria in solid tumors [RECIST] version [v] 1.1), or if they had not achieved a partial response (PR) or complete response (CR) by the week 12 assessment.

    Reporting group values
    		 Tucatinib+Trastuzumab (Cohort A) Tucatinib+Trastuzumab (Cohort B) Tucatinib Monotherapy (Cohort C) Total
    Number of subjects
    		 45 41 31 117
    Age categorical
    Units: Participants
        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)
    		 40 34 20 94
        From 65-84 years
    		 5 7 11 23
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        median (full range (min-max))
    		 52.0 (24 to 71) 59.0 (31 to 77) 60.0 (29 to 75) -
    Sex: Female, Male
    Units: Participants
        Female
    		 19 15 16 50
        Male
    		 26 26 15 67
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 1
        Asian
    		 2 1 0 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 2 3 6
        White
    		 37 30 24 91
        More than one race
    		 1 0 0 1
        Unknown or Not Reported
    		 3 8 4 15
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 1 1 4
        Not Hispanic or Latino
    		 35 31 26 92
        Unknown or Not Reported
    		 8 9 4 21
    Region of Enrollment
    Units: Subjects
        North America
    		 45 26 17 88
        Europe
    		 0 15 14 29
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG performance status was used to assess participants disease progression, and ability to carry out daily living activities. 0=Normal activity; 1=Symptoms but ambulatory; 2=In bed less than (<)50 percent (%) of the time; 3= In bed >50% of the time; 4=100% bedridden; 5=Dead.
    Units: Subjects
        Grade 0
    		 24 28 17 69
        Grade 1
    		 20 11 14 45
        Grade 2
    		 1 2 0 3

    End points

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    End points reporting groups
    Reporting group title
    Tucatinib+Trastuzumab (Cohort A)
    Reporting group description
    		 Non-randomized cohort. Participants received Tucatinib 300 milligrams (mg) orally (PO) twice daily (BID) on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 milligram/kilogram (mg/kg) by intravenous (IV) infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until progressive disease (PD), death, withdrawal of consent, study closure, or alternative therapy.

    Reporting group title
    Tucatinib+Trastuzumab (Cohort B)
    Reporting group description
    		 Randomized cohort. Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Reporting group title
    Tucatinib Monotherapy (Cohort C)
    Reporting group description
    		 Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Participants who did not respond to monotherapy were given the option to receive tucatinib and trastuzumab until PD, death, withdrawal of consent, study closure, or alternative therapy based on radiographic progression (as determined by investigator assessment using response evaluation criteria in solid tumors [RECIST] version [v] 1.1), or if they had not achieved a partial response (PR) or complete response (CR) by the week 12 assessment.

    Subject analysis set title
    Tucatinib+Trastuzumab (Cohorts A+B)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Subject analysis set title
    Tucatinib Pre-Crossover (Cohort C)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Participants who did not respond to monotherapy were given the option to receive tucatinib and trastuzumab based on radiographic progression (as determined by investigator assessment using RECIST v1.1), or if they had not achieved a PR or CR by the week 12 assessment.

    Subject analysis set title
    Tucatinib+Trastuzumab (Cohorts A+B)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Subject analysis set title
    Tucatinib+Trastuzumab (Cohorts A+B)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Subject analysis set title
    Tucatinib Post-Crossover (Cohort C)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Subject analysis set title
    Tucatinib+Trastuzumab (Cohorts A+B)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Subject analysis set title
    Tucatinib Pre-Crossover (Cohort C)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Participants who did not respond to monotherapy were given the option to receive tucatinib and trastuzumab based on radiographic progression (as determined by investigator assessment using RECIST v1.1), or if they had not achieved a PR or CR by the week 12 assessment.

    Primary: Confirmed Objective Response Rate (cORR) per RECIST v1.1 per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B

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    End point title
    		 Confirmed Objective Response Rate (cORR) per RECIST v1.1 per Blinded Independent Central Review (BICR) in Pooled Cohorts A+B [1]
    End point description
    cORR was defined as the percentage (%) of participants with confirmed CR or PR according to RECIST v1.1. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to less than (<)1.0 centimetre (cm). PR was defined as at least a 30% decrease in post-baseline sum of the diameters (PBSD) (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline sum of the diameters (BSD). The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in the statistical analysis plan (SAP).
    End point type
    Primary
    End point timeframe
    Up to 46.6 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned for this endpoint.
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B)
    Number of subjects analysed
    84
    Units: Percentage of Participants
        number (confidence interval 95%)
    39.3 (28.8 to 50.5)
    No statistical analyses for this end point

    Secondary: ORR by 12 Weeks of Treatment per RECIST v1.1 According to BICR Assessment

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    End point title
    		 ORR by 12 Weeks of Treatment per RECIST v1.1 According to BICR Assessment
    End point description
    ORR per BICR by 12 Weeks was defined as the percentage of participants with CR or PR by 12 weeks of treatment, and before time of crossover (Cohort C), whichever comes earlier. CR was defined as the disappearance of all target lesions and each target lymph node must have reduction in short axis to more than <1.0 cm. PR was defined as at least a 30% decrease in post-baseline sum of the diameters (PBSD) (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the baseline sum of the diameters (BSD). The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in SAP.
    End point type
    Secondary
    End point timeframe
    Up to 3 months
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B) Tucatinib Pre-Crossover (Cohort C)
    Number of subjects analysed
    84
    30
    Units: Percentage of Participants
        number (confidence interval 95%)
    28.6 (19.2 to 39.5)
    3.3 (0.1 to 17.2)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) per RECIST v1.1 According to BICR Assessment

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    End point title
    		 Duration of Response (DOR) per RECIST v1.1 According to BICR Assessment
    End point description
    DOR: Time from the first objective response (CR or PR) to documented PD per RECIST v1.1 or death from any cause, whichever occurred first. CR: Disappearance of all target lesions and each target lymph node must have reduction in short axis to <1.0 cm. PR: At least 30% decrease in PBSD taking as reference the BSD. PD: At least one new malignant lesion, which also includes any lymph node that was normal at baseline (<1.0 cm short axis) and increased to >=1.0 cm short axis during follow-up or at least 20% increase in PBSD taking as reference the MSD. In addition, PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD. Full Analysis Set evaluated. Data for cohort A and B was combined as prespecified in SAP. ‘Number of Participants Analyzed’ = participants who had CR or PR. ‘99999’ = Data for median and lower or upper limits could not be estimated due to insufficient participants with event.
    End point type
    Secondary
    End point timeframe
    Up to 64.1 months
    End point values
    		 Tucatinib Pre-Crossover (Cohort C) Tucatinib+Trastuzumab (Cohorts A+B)
    Number of subjects analysed
    30
    33
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    15.2 (8.9 to 20.5)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) per RECIST v1.1 According to BICR Assessment for Pooled Cohorts A+B

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    End point title
    		 Progression-Free Survival (PFS) per RECIST v1.1 According to BICR Assessment for Pooled Cohorts A+B
    End point description
    PFS was defined as the time from start of study treatment (Cohort A) or date of randomization (Cohort B) to documented disease progression (as determined by BICR per RECIST v1.1) or death from any cause, whichever occurred first. PD was defined as: at least one new malignant lesion, which also included any lymph node that was normal at baseline (<1.0 cm short axis) and increased to more than or equal to (>=)1.0 cm short axis during follow-up or at least a 20% increase in post-baseline sum of the diameters (PBSD) taking as reference the minimum sum of the diameters (MSD). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD. The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in SAP.
    End point type
    Secondary
    End point timeframe
    Up to 64.1 months
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B)
    Number of subjects analysed
    84
    Units: Months
        median (confidence interval 95%)
    8.1 (4.2 to 10.2)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) in Pooled Cohorts A+B

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    End point title
    		 Overall Survival (OS) in Pooled Cohorts A+B
    End point description
    OS was defined as the time from start of study treatment (Cohort A) or randomization (Cohort B) to date of death due to any cause. The Full Analysis Set included all participants who were enrolled and received any amount of study treatment and had HER2+ tumors as defined by one or more protocol required local tests. Data for cohort A and B was combined as prespecified in SAP.
    End point type
    Secondary
    End point timeframe
    Up to 71.8 months
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B)
    Number of subjects analysed
    84
    Units: Months
        median (confidence interval 95%)
    23.9 (18.7 to 28.3)
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs): Interim Analysis

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    End point title
    		 Number of Participants with Adverse Events (AEs): Interim Analysis
    End point description
    AE: Any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAEs: Events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. SAE: An event that at any dose led to death; life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Relatedness judged by investigator According to NCI CTCAE version 4.03: Grade(G) 3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE. Safety analysis set evaluated. Data for cohort A and B combined as prespecified in SAP. '99999' indicated tucatinib monotherapy arm.
    End point type
    Secondary
    End point timeframe
    Up to 49.3 months
    End point values
    		 Tucatinib Pre-Crossover (Cohort C) Tucatinib+Trastuzumab (Cohorts A+B)
    Number of subjects analysed
    30
    86
    Units: Participants
        Any TEAE
    28
    82
        Tucatinib-related TEAE
    22
    63
        Trastuzumab-related TEAE
    99999
    58
        Any grade 3-5 TEAE
    8
    33
        Trastuzumab-related grade 3-5 TEAE
    99999
    6
        Tucatinib-related grade 3-5 TEAE
    2
    8
        Any Treatment-Emergent Serious AE (TESAE)
    3
    19
        Tucatinib-related TESAE
    1
    3
        Trastuzumab-related TESAE
    99999
    2
        TEAE leading to death
    0
    0
        Discontinuation of any study treatment due to TEAE
    0
    5
        Discontinuation (Disc.) of tucatinib due to TEAE
    0
    5
        Disc. of tucatinib due to tucatinib-related TEAE
    0
    2
        Discontinuation of trastuzumab due to TEAE
    99999
    3
        Disc.of trastuzumab due to trastuzumab-relatedTEAE
    99999
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with AEs: Final Analysis

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    End point title
    		 Number of Participants with AEs: Final Analysis
    End point description
    AE: Any untoward medical occurrence in a participant or clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. TEAEs: Events that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. SAE: An event that at any dose led to death; life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; persistent/significant disability/incapacity; congenital anomaly/birth defect/ important medical event. Treatment related AEs, SAEs, deaths also included. Relatedness judged by investigator according to NCI CTCAE version 4.03: Grade(G) 3=severe AE, G4=life-threatening, urgent intervention indicated, G5=death related to AE. Safety analysis set evaluated. Data for cohort A and B combined as prespecified in SAP.
    End point type
    Secondary
    End point timeframe
    Up to 65.1 months
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B) Tucatinib Post-Crossover (Cohort C)
    Number of subjects analysed
    86
    28
    Units: Participants
        Any TEAE
    82
    23
        Tucatinib-related TEAE
    64
    15
        Trastuzumab-related TEAE
    59
    13
        >= Grade 3 TEAE
    35
    9
        Tucatinib-related >= grade 3 TEAE
    8
    2
        Trastuzumab-related >= grade 3 TEAE
    6
    2
        Any TESAE
    20
    6
        Tucatinib-related TESAE
    3
    0
        Trastuzumab-related TESAE
    2
    2
        TEAE leading to death
    0
    0
        Discontinuation of any study treatment due to TEAE
    5
    2
        Disc. of tucatinib due to treatment-related TEAE
    2
    2
        Disc. of tucatinib due to tucatinib-related TEAE
    2
    2
        Disc. of trastuzumab due to treatment-related TEAE
    1
    1
        Disc.of trastuzumab due to trastuzumab-relatedTEAE
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with AEs Resulting in Dose Modification: Interim Analysis

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    End point title
    		 Number of Participants with AEs Resulting in Dose Modification: Interim Analysis
    End point description
    Dose modification included dose reduction and dose withheld by investigator due to AEs. Dose holds were defined as any instances where planned administration of the study drug was temporarily withheld or interrupted at the direction of the treating physician. Dose reductions of trastuzumab were not allowed; if trastuzumab could not be restarted after being held for a TEAE, it was discontinued. The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP. '99999' indicated tucatinib monotherapy arm.
    End point type
    Secondary
    End point timeframe
    Up to 49.3 months
    End point values
    		 Tucatinib Pre-Crossover (Cohort C) Tucatinib+Trastuzumab (Cohorts A+B)
    Number of subjects analysed
    30
    86
    Units: Participants
        Tucatinib dose held
    3
    20
        Tucatinib dose reduced
    1
    8
        Trastuzumab dose held
    99999
    24
        Trastuzumab infusion interrupted
    99999
    6
        Trastuzumab infusion stopped early
    99999
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with AEs Resulting in Dose Modification: Final Analysis

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    End point title
    		 Number of Participants with AEs Resulting in Dose Modification: Final Analysis
    End point description
    Dose modification included dose reduction and dose withheld by investigator due to AEs. Dose holds were defined as any instances where planned administration of the study drug was temporarily withheld or interrupted at the direction of the treating physician. Dose reductions of trastuzumab were not allowed; if trastuzumab could not be restarted after being held for a TEAE, it was discontinued. Drug interruption included infusion interrupted (full dose received within 24hrs). The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP.
    End point type
    Secondary
    End point timeframe
    Up to 65.1 months
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B) Tucatinib Post-Crossover (Cohort C)
    Number of subjects analysed
    86
    28
    Units: Participants
        Tucatinib dose held
    23
    7
        Tucatinib dose reduced
    9
    2
        Trastuzumab dose held
    27
    2
        Trastuzumab infusion interrupted
    6
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis

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    End point title
    		 Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Interim Analysis
    End point description
    The following hematology laboratory parameters were assessed: Hemoglobin decreased; leukocytes decreased; neutrophils decreased and platelets decreased. Treatment emergent laboratory abnormalities were defined as abnormalities that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. NCI CTCAE v4.03 was used for the laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening. The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP. Here, 'Number of Participants Analysed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 49.3 months
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B) Tucatinib Pre-Crossover (Cohort C)
    Number of subjects analysed
    85
    29
    Units: Participants
        Hemoglobin decreased, Grade 1
    28
    6
        Hemoglobin decreased, Grade 2
    8
    2
        Hemoglobin decreased, Grade 3
    3
    0
        Hemoglobin decreased, Grade 4
    0
    0
        Leukocytes decreased, Grade 1
    14
    3
        Leukocytes decreased, Grade 2
    5
    0
        Leukocytes decreased, Grade 3
    0
    0
        Leukocytes decreased, Grade 4
    0
    0
        Neutrophils decreased, Grade 1
    6
    1
        Neutrophils decreased, Grade 2
    2
    1
        Neutrophils decreased, Grade 3
    0
    0
        Neutrophils decreased, Grade 4
    0
    0
        Platelets decreased, Grade 1
    11
    1
        Platelets decreased, Grade 2
    2
    2
        Platelets decreased, Grade 3
    0
    0
        Platelets decreased, Grade 4
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis

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    End point title
    		 Number of Participants With Treatment-Emergent Laboratory Abnormalities (Hematology): Final Analysis
    End point description
    The following hematology laboratory parameters were assessed: Hemoglobin decreased; hemoglobin increased; leukocytes decreased; lymphocytes decreased; neutrophils decreased and platelets decreased. Treatment emergent laboratory abnormalities were defined as abnormalities that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. NCI CTCAE v4.03 was used for the laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening. The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP. Here, 'Number of Participants Analysed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 65.1 months
    End point values
    		 Tucatinib Post-Crossover (Cohort C) Tucatinib+Trastuzumab (Cohorts A+B)
    Number of subjects analysed
    28
    85
    Units: Participants
        Hemoglobin decreased, All grades
    9
    42
        Hemoglobin decreased, Grade 3
    0
    3
        Hemoglobin decreased, Grade 4
    0
    0
        Hemoglobin increased: All grades
    0
    3
        Hemoglobin increased: Grade 3
    0
    0
        Hemoglobin increased: Grade 4
    0
    0
        Leukocytes decreased, All grades
    5
    21
        Leukocytes decreased, Grade 3
    0
    0
        Leukocytes decreased, Grade 4
    0
    0
        Lymphocytes decreased, All grades
    11
    25
        Lymphocytes decreased, Grade 3
    1
    6
        Lymphocytes decreased, Grade 4
    0
    0
        Neutrophils decreased: All grades
    0
    10
        Neutrophils decreased: Grade 3
    0
    0
        Neutrophils decreased: Grade 4
    0
    0
        Platelets decreased, All grades
    4
    15
        Platelets decreased, Grade 3
    0
    0
        Platelets decreased, Grade 4
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis

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    End point title
    		 Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Interim Analysis
    End point description
    The following chemistry laboratory parameters were assessed: Potassium increased; potassium decreased; aspartate aminotransferase increased; alanine aminotransferase increased; creatinine increased; alkaline phosphatase increased; total bilirubin increased. Treatment emergent laboratory abnormalities were defined as abnormalities that were new or worsened on or after receiving the first dose of study treatment and up through 30 days after the last dose of study treatment. NCI CTCAE v5.0 was used for creatinine increased. NCI CTCAE v4.03 was used for the other laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening. The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP. Here, ‘Number of Participants Analysed’ signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 49.3 months
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B) Tucatinib Pre-Crossover (Cohort C)
    Number of subjects analysed
    85
    29
    Units: Participants
        Potassium increased, Grade 1
    5
    1
        Potassium increased, Grade 2
    1
    0
        Potassium increased, Grade 3
    0
    1
        Potassium increased, Grade 4
    0
    0
        Potassium decreased, Grade 1
    13
    3
        Potassium decreased, Grade 2
    0
    0
        Potassium decreased, Grade 3
    1
    1
        Potassium decreased, Grade 4
    0
    0
        Aspartate Aminotransferase increased, Grade 1
    20
    6
        Aspartate Aminotransferase increased, Grade 2
    3
    0
        Aspartate Aminotransferase increased, Grade 3
    2
    2
        Aspartate Aminotransferase increased, Grade 4
    3
    0
        Alanine Aminotransferase increased, Grade 1
    31
    4
        Alanine Aminotransferase increased, Grade 2
    4
    2
        Alanine Aminotransferase increased, Grade 3
    2
    2
        Alanine Aminotransferase increased, Grade 4
    2
    0
        Creatinine increased, Grade 1
    38
    9
        Creatinine increased, Grade 2
    11
    0
        Creatinine increased, Grade 3
    0
    0
        Creatinine increased, Grade 4
    0
    0
        Alkaline Phosphatase increased, Grade 1
    16
    4
        Alkaline Phosphatase increased, Grade 2
    4
    2
        Alkaline Phosphatase increased, Grade 3
    1
    0
        Alkaline Phosphatase increased, Grade 4
    0
    0
        Total Bilirubin increased, Grade 1
    14
    6
        Total Bilirubin increased, Grade 2
    5
    0
        Total Bilirubin increased, Grade 3
    3
    0
        Total Bilirubin increased, Grade 4
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis

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    End point title
    		 Number of Participants With Treatment-Emergent Laboratory Abnormalities (Chemistry): Final Analysis
    End point description
    Chemistry laboratory parameters: Potassium increased; potassium decreased; aspartate aminotransferase increased; alanine aminotransferase increased; creatinine increased; alkaline phosphatase increased; total bilirubin increased; albumin decreased; calcium corrected for albumin decreased; calcium corrected for albumin increased; GFR, estimated decreased; glucose decreased; glucose increased; sodium decreased; sodium increased; calcium & ionized increased. Treatment emergent laboratory abnormalities: Abnormalities that were new or worsened on or after receiving the 1st dose of study treatment & up through 30 days after last dose of treatment. NCI CTCAE v5.0: For creatinine increased & v4.03: For other laboratory parameters. Grade 1: mild; Grade 2: moderate; Grade 3: severe or clinically significant; Grade 4: life-threatening. Safety analysis set evaluated. Data for cohort A & B combined as prespecified in SAP. Number of Participants analysed= Participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 65.1 months
    End point values
    		 Tucatinib Post-Crossover (Cohort C) Tucatinib+Trastuzumab (Cohorts A+B)
    Number of subjects analysed
    28
    85
    Units: Participants
        Potassium increased, All grades
    4
    6
        Potassium increased, Grade 3
    0
    0
        Potassium increased, Grade 4
    0
    0
        Potassium decreased, All grades
    4
    15
        Potassium decreased, Grade 3
    0
    1
        Potassium decreased, Grade 4
    0
    0
        Aspartate Aminotransferase increased, All grades
    9
    29
        Aspartate Aminotransferase increased, Grade 3
    3
    2
        Aspartate Aminotransferase increased, Grade 4
    0
    3
        Alanine Aminotransferase increased, All grades
    7
    39
        Alanine Aminotransferase increased, Grade 3
    2
    2
        Alanine Aminotransferase increased, Grade 4
    0
    2
        Creatinine increased, All grades
    10
    50
        Creatinine increased, Grade 3
    0
    0
        Creatinine increased, Grade 4
    0
    0
        Alkaline Phosphatase increased, All grades
    3
    21
        Alkaline Phosphatase increased, Grade 3
    0
    1
        Alkaline Phosphatase increased, Grade 4
    0
    0
        Total Bilirubin increased, All grades
    4
    25
        Total Bilirubin increased, Grade 3
    0
    3
        Total Bilirubin increased, Grade 4
    0
    2
        Albumin decreased, All grades
    8
    23
        Albumin decreased, Grade 3
    0
    1
        Albumin decreased, Grade 4
    0
    0
        Calcium Corrected for Albumin decreased,All grades
    5
    11
        Calcium Corrected for Albumin decreased, Grade 3
    0
    0
        Calcium Corrected for Albumin decreased, Grade 4
    0
    0
        Calcium Corrected for Albumin increased,All grades
    5
    8
        Calcium Corrected for Albumin increased, Grade 3
    0
    0
        Calcium Corrected for Albumin increased, Grade 4
    0
    0
        GFR, Estimated decreased, All grades
    6
    51
        GFR, Estimated decreased, Grade 3
    0
    6
        GFR, Estimated decreased, Grade 4
    0
    0
        Glucose decreased, All grades
    1
    10
        Glucose decreased, Grade 3
    0
    0
        Glucose decreased, Grade 4
    0
    0
        Glucose increased, All grades
    9
    48
        Glucose increased, Grade 3
    0
    2
        Glucose increased, Grade 4
    0
    0
        Sodium decreased, All grades
    1
    18
        Sodium decreased, Grade 3
    0
    5
        Sodium decreased, Grade 4
    0
    0
        Sodium increased, All grades
    4
    7
        Sodium increased, Grade 3
    0
    0
        Sodium increased, Grade 4
    0
    0
        Calcium, Ionized increased: All grades
    0
    2
        Calcium, Ionized increased: Grade 3
    0
    0
        Calcium, Ionized increased: Grade 4
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Vital Signs: Final Analysis

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    End point title
    		 Number of Participants With Clinically Significant Vital Signs: Final Analysis
    End point description
    Vital signs included temperature, oxygen saturation, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and weight. Vital signs were considered clinically significant: temperature: >= 38 degree Celsius (C); oxygen saturation less than (<)88%; SBP >=120 millimeters of mercury (mmHg) or DBP >=80 mmHg; SBP >=140 mmHg or DBP >=90 mmHg; SBP >=160 mmHg or DBP >=100 mmHg and heart rate >100 beats per minute (bpm) and maximum decrease from baseline in weight in kilograms (kg). The safety analysis set included participants who received any amount of study treatment. Data for cohort A and B was combined as prespecified in SAP.
    End point type
    Secondary
    End point timeframe
    Up to 65.1 months
    End point values
    		 Tucatinib+Trastuzumab (Cohorts A+B) Tucatinib Post-Crossover (Cohort C)
    Number of subjects analysed
    86
    28
    Units: Participants
        Temperature >=38 degree C
    1
    0
        Oxygen saturation <88%
    8
    0
        SBP >= 120 mmHg or DBP >= 80 mmHg
    80
    27
        SBP >= 140 mmHg or DBP >= 90 mmHg
    49
    13
        SBP >= 160 mmHg or DBP >= 100 mmHg
    21
    4
        Heart rate > 100 bpm
    26
    5
        Maximum decrease from baseline in weight (kg)
    65
    23
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality: From start of study treatment to death by any cause (maximum up to 71.8 months); adverse events were followed during the safety reporting period (from Day 1 through 30 days after last dose of study treatment) maximum up to 65.1 months
    Adverse event reporting additional description
    Adverse events (AEs) for Cohorts A and B were analyzed together as prespecified in SAP. All-Cause Mortality is reported for all enrolled participants, regardless of whether or not they received study drug. SAEs and non-serious AEs are reported only for those patients who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Tucatinib+Trastuzumab (Cohorts A+B)
    Reporting group description
    		 Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Reporting group title
    Tucatinib Post-Crossover (Cohort C)
    Reporting group description
    		 Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Trastuzumab 8 mg/kg by IV infusion on Day 1 of Cycle 1 and 6 mg/kg on Day 1 of each subsequent cycle until PD, death, withdrawal of consent, study closure, or alternative therapy.

    Reporting group title
    Tucatinib Pre-Crossover (Cohort C)
    Reporting group description
    		 Participants received Tucatinib 300 mg PO BID on Days 1 to 21 of each 21-day cycle. Participants who did not respond to monotherapy were given the option to receive tucatinib and trastuzumab based on radiographic progression (as determined by investigator assessment using RECIST v1.1), or if they had not achieved a PR or CR by the week 12 assessment.

    Serious adverse events
    		 Tucatinib+Trastuzumab (Cohorts A+B) Tucatinib Post-Crossover (Cohort C) Tucatinib Pre-Crossover (Cohort C)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 86 (23.26%)
    6 / 28 (21.43%)
    3 / 30 (10.00%)
         number of deaths (all causes)
    54
    15
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Fatigue
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Malaise
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (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
    Radius fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (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
    Ulna fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (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
    Overdose
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Nervous system disorders
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (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
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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 disorders
    Abdominal pain
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Nausea
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Rectal perforation
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Constipation
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (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
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Duodenal obstruction
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Acute kidney injury
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (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
    Kidney infection
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Tucatinib+Trastuzumab (Cohorts A+B) Tucatinib Post-Crossover (Cohort C) Tucatinib Pre-Crossover (Cohort C)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 86 (95.35%)
    23 / 28 (82.14%)
    28 / 30 (93.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 86 (17.44%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    20
    0
    0
    Lymphoedema
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    1
    1
    0
    Thrombosis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 28 (7.14%)
    5 / 30 (16.67%)
         occurrences all number
    4
    2
    5
    Pyrexia
         subjects affected / exposed
    18 / 86 (20.93%)
    6 / 28 (21.43%)
    3 / 30 (10.00%)
         occurrences all number
    27
    9
    4
    Oedema peripheral
         subjects affected / exposed
    7 / 86 (8.14%)
    2 / 28 (7.14%)
    2 / 30 (6.67%)
         occurrences all number
    8
    2
    2
    Influenza like illness
         subjects affected / exposed
    7 / 86 (8.14%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    8
    1
    0
    Fatigue
         subjects affected / exposed
    37 / 86 (43.02%)
    3 / 28 (10.71%)
    6 / 30 (20.00%)
         occurrences all number
    44
    3
    6
    Chills
         subjects affected / exposed
    16 / 86 (18.60%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    17
    3
    0
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    Peripheral swelling
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Pain
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Social circumstances
    Pregnancy of partner
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Nipple pain
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 86 (17.44%)
    4 / 28 (14.29%)
    2 / 30 (6.67%)
         occurrences all number
    18
    4
    2
    Dyspnoea
         subjects affected / exposed
    12 / 86 (13.95%)
    2 / 28 (7.14%)
    3 / 30 (10.00%)
         occurrences all number
    15
    2
    3
    Epistaxis
         subjects affected / exposed
    7 / 86 (8.14%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    7
    1
    0
    Nasal congestion
         subjects affected / exposed
    8 / 86 (9.30%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    13
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 86 (4.65%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    9
    3
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    6 / 86 (6.98%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    10
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    7
    1
    0
    Productive cough
         subjects affected / exposed
    6 / 86 (6.98%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    8
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    Dysphonia
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    2
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Sinus pain
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Wheezing
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 86 (10.47%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    9
    0
    0
    Insomnia
         subjects affected / exposed
    7 / 86 (8.14%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    8
    0
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    8 / 86 (9.30%)
    0 / 28 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    8
    0
    3
    Ejection fraction decreased
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    8
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 86 (5.81%)
    3 / 28 (10.71%)
    3 / 30 (10.00%)
         occurrences all number
    5
    6
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 86 (5.81%)
    2 / 28 (7.14%)
    2 / 30 (6.67%)
         occurrences all number
    6
    5
    2
    Weight increased
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    4
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    4 / 86 (4.65%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    18 / 86 (20.93%)
    4 / 28 (14.29%)
    0 / 30 (0.00%)
         occurrences all number
    19
    8
    0
    Fall
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    Procedural pain
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    2
    0
    1
    Contusion
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 28 (3.57%)
    2 / 30 (6.67%)
         occurrences all number
    7
    1
    2
    Dysgeusia
         subjects affected / exposed
    4 / 86 (4.65%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    4
    1
    1
    Headache
         subjects affected / exposed
    9 / 86 (10.47%)
    3 / 28 (10.71%)
    3 / 30 (10.00%)
         occurrences all number
    12
    3
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    7 / 86 (8.14%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    8
    0
    1
    Neurotoxicity
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    1
    Restless legs syndrome
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    Syncope
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    2
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 86 (10.47%)
    3 / 28 (10.71%)
    1 / 30 (3.33%)
         occurrences all number
    10
    4
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Vertigo
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    2
    1
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    1
    3
    0
    Blepharospasm
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Cataract
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Dry eye
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Eye pruritus
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    8
    0
    0
    Gastrointestinal disorders
    Proctalgia
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    1
    Nausea
         subjects affected / exposed
    29 / 86 (33.72%)
    2 / 28 (7.14%)
    5 / 30 (16.67%)
         occurrences all number
    35
    2
    6
    Flatulence
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 28 (7.14%)
    1 / 30 (3.33%)
         occurrences all number
    3
    2
    1
    Diarrhoea
         subjects affected / exposed
    57 / 86 (66.28%)
    11 / 28 (39.29%)
    10 / 30 (33.33%)
         occurrences all number
    77
    19
    11
    Constipation
         subjects affected / exposed
    12 / 86 (13.95%)
    2 / 28 (7.14%)
    4 / 30 (13.33%)
         occurrences all number
    14
    2
    4
    Abdominal pain upper
         subjects affected / exposed
    6 / 86 (6.98%)
    2 / 28 (7.14%)
    2 / 30 (6.67%)
         occurrences all number
    9
    2
    2
    Abdominal pain lower
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    11 / 86 (12.79%)
    2 / 28 (7.14%)
    6 / 30 (20.00%)
         occurrences all number
    19
    2
    7
    Abdominal distension
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    1
    Abdominal discomfort
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    2
    2
    0
    Stomatitis
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 28 (7.14%)
    3 / 30 (10.00%)
         occurrences all number
    1
    2
    3
    Vomiting
         subjects affected / exposed
    14 / 86 (16.28%)
    4 / 28 (14.29%)
    2 / 30 (6.67%)
         occurrences all number
    20
    4
    3
    Oral pain
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    Dry mouth
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    Dyspepsia
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    4
    0
    1
    Food poisoning
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    3
    1
    0
    Glossodynia
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Noninfective gingivitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    2
    0
    1
    Tooth loss
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Haematochezia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 28 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    1
    0
    2
    Eructation
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Proctitis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Salivary hypersecretion
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Hepatic pain
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    9 / 86 (10.47%)
    3 / 28 (10.71%)
    1 / 30 (3.33%)
         occurrences all number
    12
    4
    1
    Onychoclasis
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    1
    Nail disorder
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    2
    2
    0
    Dry skin
         subjects affected / exposed
    8 / 86 (9.30%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    9
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    17 / 86 (19.77%)
    0 / 28 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    21
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    7 / 86 (8.14%)
    1 / 28 (3.57%)
    2 / 30 (6.67%)
         occurrences all number
    11
    1
    2
    Ecchymosis
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Erythema
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Onychomadesis
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    5
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Pain of skin
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    3
    2
    0
    Haematuria
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    Pollakiuria
         subjects affected / exposed
    4 / 86 (4.65%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 86 (5.81%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    7
    0
    0
    Muscle spasms
         subjects affected / exposed
    7 / 86 (8.14%)
    3 / 28 (10.71%)
    2 / 30 (6.67%)
         occurrences all number
    7
    3
    2
    Hypercreatinaemia
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    1
    Back pain
         subjects affected / exposed
    16 / 86 (18.60%)
    6 / 28 (21.43%)
    1 / 30 (3.33%)
         occurrences all number
    17
    6
    1
    Arthralgia
         subjects affected / exposed
    16 / 86 (18.60%)
    4 / 28 (14.29%)
    2 / 30 (6.67%)
         occurrences all number
    20
    5
    3
    Myalgia
         subjects affected / exposed
    11 / 86 (12.79%)
    0 / 28 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    18
    0
    3
    Pain in extremity
         subjects affected / exposed
    8 / 86 (9.30%)
    1 / 28 (3.57%)
    1 / 30 (3.33%)
         occurrences all number
    13
    1
    2
    Flank pain
         subjects affected / exposed
    4 / 86 (4.65%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    Muscular weakness
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    1
    1
    0
    Arthritis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 86 (4.65%)
    4 / 28 (14.29%)
    4 / 30 (13.33%)
         occurrences all number
    8
    7
    6
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 28 (7.14%)
    0 / 30 (0.00%)
         occurrences all number
    3
    2
    0
    COVID-19
         subjects affected / exposed
    6 / 86 (6.98%)
    3 / 28 (10.71%)
    0 / 30 (0.00%)
         occurrences all number
    6
    3
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Gingival abscess
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    2
    1
    0
    Hordeolum
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    1
    1
    0
    Influenza
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Nail infection
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    4
    1
    0
    Otitis media
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Pneumonia
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Rash pustular
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinitis
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Kidney infection
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 86 (19.77%)
    2 / 28 (7.14%)
    4 / 30 (13.33%)
         occurrences all number
    22
    2
    4
    Hypokalaemia
         subjects affected / exposed
    5 / 86 (5.81%)
    0 / 28 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    5
    0
    3
    Dehydration
         subjects affected / exposed
    7 / 86 (8.14%)
    1 / 28 (3.57%)
    0 / 30 (0.00%)
         occurrences all number
    11
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 28 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    0
    Hyponatraemia
         subjects affected / exposed
    3 / 86 (3.49%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    4
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 28 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2017
    Side effects of Tucatinib updated based on Pharmacy review of investigator's brochure (IB). Side effects of Trastuzumab updated based on Pharmacy review of IB.
    20 Oct 2017
    Section 15.14 has been updated with added information regarding the administration of Tucatinib. Section 15.16, additional information was added to the Potential Drug Interactions paragraph. Sections 15.297-98 Nursing Guidelines have been added for Trastuzumab.
    21 Sep 2018
    Added language was inserted for clarification regarding Adverse Event-Specific Dose Modifications.
    19 Apr 2019
    Trastuzumab reproductive risks; language was added for precautionary measures for pregnant females.
    10 Sep 2019
    Removed, information related to suspected unexpected serious adverse reactions (SUSAR), suspected adverse reaction, and expedited and routine reporting were covered by Seattle Genetics SOPs and were outside of the scope of the individual site(s). removed events of interest as ACCRU’s definition does not align with Seattle Genetics’ definition. Updated the language on death to align with the Seattle Genetics standard language. Added the language on reporting of serious events to align with the Seattle Genetics standard language. Removed the table for reporting timeframes and mechanisms and added the updated information on SAEs (per Seattle Genetics standard SAE reporting language) in section 10.7, on adverse events of special interest (AESI) in section 10.73, and on pregnancies in section 10.83. Updated the information on reporting of pregnancies.
    01 Nov 2019
    Addition of 2 cohorts to the study: tucatinib given in combination with trastuzumab (Cohort B) and tucatinib monotherapy (Cohort C). Cohort B was added to assess efficacy (confirmed Objective Response Rate [cORR]) and safety of the dual therapy for metastatic colorectal cancer (mCRC) participants. Cohort C was added to better characterize the antitumor activity of tucatinib when used as a monotherapy. Planned enrollment was increased from 40 to 110 participants. As of Amendment 8, 70 newly enrolled participants will be randomized to either tucatinib given in combination with trastuzumab (40 participants randomized to Cohort B) or tucatinib monotherapy (30 participants randomized to Cohort C).
    21 Dec 2020
    Removed requirement to report overdose events or dosing errors following the SAE reporting process.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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