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    Clinical Trial Results:
    A Randomized Phase 2 Study of AP26113 in Patients with ALK-positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated with Crizotinib

    Summary
    EudraCT number
    		 2013-002134-21
    Trial protocol
    		 DE   ES   IT   NL   DK   AT   BE   SE   NO  
    Global end of trial date
    27 Feb 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Mar 2021
    First version publication date
    29 Jun 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    AP26113-13-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02094573
    WHO universal trial number (UTN)
    		 U1111-1196-8246
    Sponsors
    Sponsor organisation name
    Takeda Development Center Americas, Inc.
    Sponsor organisation address
    One Takeda Parkway, Deerfield, IL, United States, 60015
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.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
    27 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to evaluate the efficacy and safety of two different dosing regimens of brigatinib (AP26113) in participants with ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on therapy with crizotinib.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jun 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 46
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 46
    Worldwide total number of subjects
    222
    EEA total number of subjects
    101
    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)
    170
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 71 investigative sites in the United States, Canada, Europe, Australia, and Asia from 04 Jun 2014 to 27 February 2020.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) who had progressed on crizotinib were enrolled to receive brigatinib 90 mg, once daily or brigatinib 90-180 mg, once daily.

    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
    		 Brigatinib 90 mg
    Arm description
    		 Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    AP26113
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    AP26113 tablets and capsules.

    Arm title
    		 Brigatinib 90 mg - 180 mg
    Arm description
    		 Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brigatinib
    Investigational medicinal product code
    AP26113
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AP26113 tablets and capsules.

    Number of subjects in period 1
    		Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Started
    112
    110
    Treated
    109
    110
    Completed
    0
    0
    Not completed
    112
    110
         Adverse event, serious fatal
    11
    3
         Physician decision
    4
    4
         Clinical Progressive Disease
    9
    13
         Documented Progressive Disease (RECIST 1.1)
    63
    50
         Adverse event, non-fatal
    4
    14
         Subject Received a New Systemic Anticancer Therapy
    1
    -
         Non-compliance with study drug
    1
    1
         Withdrawal by Subject
    6
    8
         Randomized but not Treated
    3
    -
         Site Terminated by Sponsor
    10
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brigatinib 90 mg
    Reporting group description
    		 Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).

    Reporting group title
    Brigatinib 90 mg - 180 mg
    Reporting group description
    		 Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).

    Reporting group values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg Total
    Number of subjects
    		 112 110 222
    Age Categorical
    Units: Subjects
        18-49 years
    		 50 33 83
        50-64 years
    		 40 47 87
        65-74 years
    		 20 23 43
        ≥75 years
    		 2 7 9
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.5 ( 13.03 ) 55.4 ( 12.98 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 62 64 126
        Male
    		 50 46 96
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 72 76 148
        Black or African American
    		 1 2 3
        Asian
    		 39 30 69
        Unknown
    		 0 2 2
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 5 8 13
        Not Hispanic or Latino
    		 107 102 209
    Region of Enrollment
    Units: Subjects
        Australia
    		 3 6 9
        Austria
    		 3 6 9
        Belgium
    		 3 2 5
        Canada
    		 2 1 3
        Denmark
    		 2 6 8
        France
    		 4 2 6
        Germany
    		 7 7 14
        Hong Kong
    		 6 0 6
        Italy
    		 15 14 29
        Netherlands
    		 6 6 12
        Norway
    		 1 1 2
        Singapore
    		 4 3 7
        Spain
    		 5 7 12
        Sweden
    		 2 2 4
        Switzerland
    		 0 1 1
        United Kingdom
    		 2 1 3
        United States
    		 21 25 46
        Korea, Republic Of
    		 26 20 46

    End points

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    End points reporting groups
    Reporting group title
    Brigatinib 90 mg
    Reporting group description
    		 Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).

    Reporting group title
    Brigatinib 90 mg - 180 mg
    Reporting group description
    		 Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).

    Primary: Confirmed Objective Response Rate (ORR) as Assessed by Investigator

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    End point title
    		 Confirmed Objective Response Rate (ORR) as Assessed by Investigator [1]
    End point description
    ORR assessed by investigator, defined as percentage of participants with confirmed complete response(CR)or partial response(PR)as per response evaluation criteria in solid tumors (RECIST)v1.1(confirmed ≥4 weeks after initial response),after initiation of study treatment.CR(target lesion):Disappearance of all extranodal lesions,all pathological lymph nodes must have decreased to<10mm in short axis.CR(non-target lesion):Disappearance of all extranodal lesions, all lymph nodes must be non-pathological in size(<10mm short axis),normalization of tumor marker level.PR:≥30% decrease in sum of longest diameters(SLD)of target lesions,with baseline sum diameters as reference.Exact 2-sided 97.5% confidence interval was calculated.Treatment regimen was considered to have achieved primary objective when lower bound of 97.5% confidence interval is >20%.ITT Population:all participants who were randomized to each regimen regardless of whether they received study drug or adhered to assigned dose.
    End point type
    Primary
    End point timeframe
    Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 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: Not applicable
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    112
    110
    Units: percentage of participants
        number (confidence interval 97.5%)
    45.5 (34.8 to 56.5)
    57.3 (46.1 to 67.9)
    No statistical analyses for this end point

    Secondary: Confirmed Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC)

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    End point title
    		 Confirmed Objective Response Rate (ORR) as Assessed by Independent Review Committee (IRC)
    End point description
    ORR assessed by the IRC, was defined as the percentage of the participants with CR or PR according to RECIST v1.1 (confirmed ≥4 weeks after initial response), after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. The exact 2-sided 95% confidence interval was calculated. ITT Population: all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.
    End point type
    Secondary
    End point timeframe
    Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    112
    110
    Units: percentage of participants
        number (confidence interval 95%)
    51.8 (42.1 to 61.3)
    56.4 (46.6 to 65.8)
    No statistical analyses for this end point

    Secondary: Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants with Measurable Active Brain Metastases

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    End point title
    		 Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants with Measurable Active Brain Metastases
    End point description
    Confirmed intracranial CNS ORR was defined as percentage of participants with CR or PR in intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, with Baseline sum diameters as reference.ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to assigned dose. Participants with measurable active brain metastases at Baseline were evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    19
    15
    Units: percentage of participants
    number (confidence interval 95%)
        CNS ORR
    47.4 (24.4 to 71.1)
    73.3 (44.9 to 92.2)
    No statistical analyses for this end point

    Secondary: Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants with Only Non-measurable Active Brain Metastases

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    End point title
    		 Confirmed Intracranial Central Nervous System Objective Response Rate (CNS ORR) in Participants with Only Non-measurable Active Brain Metastases
    End point description
    Confirmed intracranial CNS ORR is defined as percentage of participants with CR or PR in intracranial CNS per modification of RECIST v1.1 as evaluated by IRC after initiation of study drug. Confirmed responses were those that persisted on repeat imaging 4 weeks or more after initial response. CR for target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis). CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in SLD of target lesions, taking as reference Baseline sum diameters.ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants with only non-measurable active brain metastases at Baseline were evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    33
    36
    Units: percentage of participants
        number (confidence interval 95%)
    12.1 (3.4 to 28.2)
    16.7 (6.4 to 32.8)
    No statistical analyses for this end point

    Secondary: Intracranial CNS Progression Free Survival (PFS) in Participants with Active Brain Metastases

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    End point title
    		 Intracranial CNS Progression Free Survival (PFS) in Participants with Active Brain Metastases
    End point description
    Intracranial CNS PFS as evaluated by IRC is defined as the time interval from the date of the first dose of the study drug until the first date at which intracranial CNS disease progression, an increase of 20% or more in the sum of diameters of intracranial CNS target lesions, unequivocal progression of non-target lesions, or the appearance of new lesions in the intracranial CNS, was objectively documented by a scan, or death due to any cause, whichever occurred first.The analysis was based on the Kaplan-Meier (KM) Estimates. ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants with active brain metastases whether it was measurable or non-measurable at baseline were evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or approximately up to 29 months
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    52
    51
    Units: months
        median (confidence interval 95%)
    12.8 (9.0 to 18.4)
    12.8 (9.1 to 21.1)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    		 Time to Response
    End point description
    Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Participants who had confirmed CR or PR were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to approximately 69 months
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    51
    63
    Units: months
        median (full range (min-max))
    1.8 (1.7 to 11.1)
    1.9 (1.0 to 35.0)
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response was defined as time interval from time that measurement criteria are first met for CR/PR (whichever is first recorded) until first date that progressive disease is objectively documented or death.Patients without progressive disease or death were censored at last valid response assessment.CR (target lesion): Disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis.CR (non-target lesion): Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level.PR:≥30% decrease in SLD of target lesions, taking as reference the baseline sum diameters.The analysis was based on Kaplan-Meier (KM) Estimates.ITT Population:participants who were randomized to each regimen regardless of whether they received study drug or adhered to assigned dose. Participants who had confirmed CR or PR were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to approximately 69 months
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    51
    63
    Units: months
        median (confidence interval 95%)
    12.0 (9.2 to 19.4)
    13.8 (10.8 to 17.6)
    No statistical analyses for this end point

    Secondary: Time on Treatment

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    End point title
    		 Time on Treatment
    End point description
    Time on treatment was defined as the time from the first to the last dose of study drug. For participants who have not discontinued, time on treatment was censored as of the last dose of the study drug. Safety Population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to approximately 69 months
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    109
    110
    Units: days
        median (full range (min-max))
    402.0 (1 to 1882)
    522.0 (2 to 2030)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR was defined as percentage of randomized participants who were confirmed to have achieved CR or PR or have a best overall response as stable disease (SD) for 6 weeks or more after initiation of study drug. CR for target lesion: Disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD was defined as at least a 20% increase in sum of diameters of target lesions. ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to assigned dose.
    End point type
    Secondary
    End point timeframe
    Screening, at 8-week intervals thereafter (on Day 1 of every odd-numbered Cycle of 28-days) through 15 Cycles and every 3 Cycles thereafter until disease progression or up to end of the study (approximately up to 69 months)
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    112
    110
    Units: percentage of participants
        number (confidence interval 95%)
    81.3 (72.8 to 88.0)
    86.4 (78.5 to 92.2)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including Baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader). The analysis was based on the Kaplan-Meier (KM) Estimates. ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.
    End point type
    Secondary
    End point timeframe
    Up to approximately 69 months
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    112
    110
    Units: months
        median (confidence interval 95%)
    9.2 (7.4 to 11.1)
    15.6 (11.1 to 18.5)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause. Intracranial OS was calculated by Kaplan-Meier estimation. ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose.9999999 = Upper limit of 95% confidence interval was not estimable due to low number of participants with event.
    End point type
    Secondary
    End point timeframe
    Up to approximately 69 months
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    112
    110
    Units: months
    median (confidence interval 95%)
        Overall Survival
    25.9 (18.2 to 45.8)
    40.6 (32.5 to 9999999)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)
    End point description
    An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurs after receiving study drug. Safety Population included all participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days following the last dose of study drug (approximately up to 69 months)
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    109
    110
    Units: participants
    109
    110
    No statistical analyses for this end point

    Secondary: Pre-dose Brigatinib Plasma Concentration

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    End point title
    		 Pre-dose Brigatinib Plasma Concentration
    End point description
    ITT Population included all participants who were randomized to each regimen regardless of whether they received study drug or adhered to the assigned dose. Here, number of participants analyzed is the participants who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 Cycles 2, 3, 4 and 5 (each Cycle of 28-days) pre-dose
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    112
    110
    Units: ng/ml
    arithmetic mean (standard deviation)
        Cycle 2 (n=101, 97)
    295.2 ( 252.0 )
    520.0 ( 321.9 )
        Cycle 3 (n=91, 92)
    263.9 ( 238.9 )
    537.0 ( 360.3 )
        Cycle 4 (n=80, 87)
    236.1 ( 188.0 )
    564.7 ( 415.0 )
        Cycle 5 (n=80, 79)
    256.4 ( 282.3 )
    579.7 ( 396.7 )
    No statistical analyses for this end point

    Secondary: Patient-reported Symptoms Global Health Status/Quality of Life (QoL) Scores

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    End point title
    		 Patient-reported Symptoms Global Health Status/Quality of Life (QoL) Scores
    End point description
    Patient-reported symptoms global health status/quality of life (QoL) scores based on questions 29 and 30 of European Organisation for Research and Treatment of Cancer(EORTC)QLQ-C30.First 28 questions used 4-point scale(1=not at all to 4=very much)for evaluating 5 functional scales (physical,role,cognitive,emotional,social functioning);3 symptom scales(fatigue,pain,and nausea/vomiting);last 2 questions coded on 7-point scale(1=very poor to 7=excellent).Also included Six single-item scales(dyspnea,insomnia,appetite loss,constipation,diarrhea,financial difficulties).Raw scores were linearly transformed to obtain score 0-100,where higher score represents better level of functioning.9999=Standard deviation(SD)was not evaluable for 1 participant.99999 =No participant was analyzed for time point.ITT Population:all participants randomized to each regimen regardless of whether they received study drug or adhered to assigned dose.’n’=number of participants evaluable at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline and at each 28-day cycle up to end of the study (up to approximately 69 months)
    End point values
    		 Brigatinib 90 mg Brigatinib 90 mg - 180 mg
    Number of subjects analysed
    112
    110
    Units: unit on a scale
    arithmetic mean (standard deviation)
        Baseline (n=108, 108)
    52.39 ( 27.42 )
    58.49 ( 23.40 )
        Cycle 2 (n=101, 97)
    64.19 ( 20.73 )
    65.72 ( 19.54 )
        Cycle 3 (n=91, 91)
    65.57 ( 24.06 )
    68.50 ( 20.52 )
        Cycle 4 (n=84, 89)
    69.44 ( 20.59 )
    66.95 ( 20.89 )
        Cycle 5 (n=82, 85)
    70.12 ( 20.28 )
    71.86 ( 17.63 )
        Cycle 6 (n=79, 82)
    70.15 ( 20.18 )
    71.24 ( 18.66 )
        Cycle 7 (n=77, 80)
    67.42 ( 20.29 )
    70.21 ( 21.66 )
        Cycle 8 (n=73, 78)
    67.24 ( 22.79 )
    69.87 ( 20.42 )
        Cycle 9 (n=70, 75)
    68.45 ( 22.61 )
    68.67 ( 21.35 )
        Cycle 10 (n=65, 70)
    71.79 ( 20.61 )
    67.98 ( 23.25 )
        Cycle 11 (n=61, 70)
    72.54 ( 19.56 )
    68.45 ( 21.37 )
        Cycle 12 (n=61, 65)
    68.03 ( 23.08 )
    70.51 ( 21.35 )
        Cycle 13 (n=58, 64)
    70.11 ( 19.93 )
    72.79 ( 19.20 )
        Cycle 14 (n=55, 57)
    69.55 ( 20.04 )
    70.76 ( 19.42 )
        Cycle 15 (n=54, 58)
    70.06 ( 21.08 )
    70.83 ( 20.66 )
        Cycle 16 (n=50, 58)
    68.17 ( 22.94 )
    72.27 ( 18.36 )
        Cycle 17 (n=48, 61)
    73.61 ( 18.78 )
    69.81 ( 20.36 )
        Cycle 18 (n=43, 58)
    67.64 ( 22.80 )
    71.55 ( 17.94 )
        Cycle 19 (n=43, 55)
    69.57 ( 23.14 )
    72.12 ( 20.49 )
        Cycle 20 (n=40, 52)
    66.04 ( 24.05 )
    72.76 ( 18.53 )
        Cycle 21 (n=39, 50)
    69.23 ( 22.87 )
    69.83 ( 19.04 )
        Cycle 22 (n=36, 46)
    72.69 ( 21.70 )
    71.20 ( 18.90 )
        Cycle 23 (n=35, 47)
    72.38 ( 21.93 )
    71.10 ( 20.10 )
        Cycle 24 (n=32, 42)
    72.66 ( 19.66 )
    71.43 ( 15.74 )
        Cycle 25 (n=34, 39)
    71.57 ( 21.72 )
    70.09 ( 19.38 )
        Cycle 26 (n=32, 36)
    71.88 ( 22.28 )
    69.68 ( 20.43 )
        Cycle 27 (n=33, 36)
    71.46 ( 20.94 )
    70.83 ( 21.96 )
        Cycle 28 (n=31, 37)
    71.24 ( 22.24 )
    69.59 ( 20.24 )
        Cycle 29 (n=30, 37)
    70.00 ( 21.73 )
    71.17 ( 22.27 )
        Cycle 30 (n=29, 34)
    69.25 ( 21.72 )
    70.83 ( 18.03 )
        Cycle 31 (n=26, 33)
    75.64 ( 17.63 )
    69.95 ( 18.15 )
        Cycle 32 (n=25, 31)
    73.00 ( 20.02 )
    70.97 ( 20.28 )
        Cycle 33 (n=25, 32)
    71.67 ( 20.41 )
    70.31 ( 20.84 )
        Cycle 34 (n=21, 31)
    72.62 ( 20.61 )
    69.62 ( 20.70 )
        Cycle 35 (n=21, 31)
    72.22 ( 18.88 )
    66.67 ( 22.97 )
        Cycle 36 (n=20, 30)
    68.33 ( 22.72 )
    71.67 ( 19.89 )
        Cycle 37 (n=20, 30)
    73.33 ( 19.42 )
    72.50 ( 19.47 )
        Cycle 38 (n=18, 29)
    68.98 ( 22.10 )
    72.99 ( 17.49 )
        Cycle 39 (n=17, 26)
    68.63 ( 25.09 )
    73.72 ( 19.96 )
        Cycle 40 (n=17, 26)
    71.57 ( 24.13 )
    69.87 ( 23.10 )
        Cycle 41 (n=17, 26)
    72.55 ( 21.20 )
    68.27 ( 22.98 )
        Cycle 42 (n=17, 24)
    72.06 ( 21.84 )
    72.57 ( 20.78 )
        Cycle 43 (n=17, 23)
    67.65 ( 24.63 )
    71.01 ( 22.17 )
        Cycle 44 (n=17, 22)
    72.55 ( 20.57 )
    73.48 ( 19.35 )
        Cycle 45 (n=14, 22)
    66.67 ( 19.88 )
    72.35 ( 22.03 )
        Cycle 46 (n=15, 22)
    70.56 ( 19.12 )
    71.59 ( 20.52 )
        Cycle 47 (n=14, 21)
    60.12 ( 25.36 )
    73.02 ( 19.88 )
        Cycle 48 (n=13, 21)
    65.38 ( 20.93 )
    74.60 ( 19.80 )
        Cycle 49 (n=13, 20)
    57.69 ( 24.88 )
    71.67 ( 22.69 )
        Cycle 50 (n=13, 20)
    61.54 ( 26.47 )
    70.00 ( 24.54 )
        Cycle 51 (n=12, 21)
    63.19 ( 23.96 )
    69.05 ( 22.69 )
        Cycle 52 (n=12, 21)
    56.94 ( 22.71 )
    72.22 ( 22.26 )
        Cycle 53 (n=12, 20)
    61.11 ( 21.42 )
    70.83 ( 23.02 )
        Cycle 54 (n=12, 19)
    61.81 ( 25.24 )
    71.49 ( 20.47 )
        Cycle 55 (n=10, 19)
    63.33 ( 26.12 )
    72.37 ( 20.42 )
        Cycle 56 (n=9, 18)
    63.89 ( 23.94 )
    73.61 ( 19.23 )
        Cycle 57 (n=10, 17)
    65.00 ( 19.95 )
    73.53 ( 19.37 )
        Cycle 58 (n=10, 14)
    65.00 ( 25.09 )
    70.83 ( 20.61 )
        Cycle 59 (n=9, 14)
    64.81 ( 25.27 )
    71.43 ( 19.81 )
        Cycle 60 (n=8, 9)
    70.83 ( 27.82 )
    73.15 ( 19.44 )
        Cycle 61 (n=7, 8)
    71.43 ( 28.41 )
    78.13 ( 19.89 )
        Cycle 62 (n=5, 7)
    66.67 ( 23.57 )
    79.76 ( 15.85 )
        Cycle 63 (n=4, 7)
    58.33 ( 31.91 )
    78.57 ( 17.91 )
        Cycle 64 (n=3, 7)
    61.11 ( 34.69 )
    77.38 ( 20.81 )
        Cycle 65 (n=2, 6)
    75.00 ( 35.36 )
    76.39 ( 22.62 )
        Cycle 66 (n=2, 4)
    75.00 ( 35.36 )
    77.08 ( 31.46 )
        Cycle 67 (n=2, 1)
    75.00 ( 35.36 )
    41.67 ( 9999 )
        Cycle 68 (n=0, 1)
    99999 ( 99999 )
    41.67 ( 9999 )
        Cycle 69 (n=0, 1)
    99999 ( 99999 )
    58.33 ( 9999 )
        Cycle 70 (n=0, 1)
    99999 ( 99999 )
    41.67 ( 9999 )
        Cycle 71 (n=0, 1)
    99999 ( 99999 )
    41.67 ( 9999 )
        Cycle 72 (n=0, 1)
    99999 ( 99999 )
    75.00 ( 9999 )
        End of Treatment (n=80, 68)
    52.29 ( 28.25 )
    61.15 ( 23.15 )
        Follow-Up 30 Days After Last Dose (n=43, 45)
    61.05 ( 30.58 )
    61.67 ( 23.33 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days following the last dose of study drug (approximately up to 69 months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    AP26113 90 mg - 180 mg
    Reporting group description
    		 Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in cycle 2 and onward Cycles of 28 days until disease progression or intolerable toxicity (median duration of exposure was 522 days).

    Reporting group title
    AP26113 90 mg
    Reporting group description
    		 Brigatinib 90 mg, tablets, orally, once daily in each Cycle of 28 days until disease progression or intolerable toxicity (median duration of exposure was 402 days).

    Serious adverse events
    		 AP26113 90 mg - 180 mg AP26113 90 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    69 / 110 (62.73%)
    58 / 109 (53.21%)
         number of deaths (all causes)
    14
    22
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm Progression
         subjects affected / exposed
    8 / 110 (7.27%)
    15 / 109 (13.76%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 15
         deaths causally related to treatment / all
    0 / 7
    0 / 9
    Malignant Pleural Effusion
         subjects affected / exposed
    4 / 110 (3.64%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases To Central Nervous System
         subjects affected / exposed
    3 / 110 (2.73%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Metastases To Meninges
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowens Disease
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases To Liver
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases To Peritoneum
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic Malignant Melanoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid Cancer
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Associated Fever
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Behcets Syndrome
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iliac Artery Stenosis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General Physical Health Deterioration
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Site Thrombosis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Euthanasia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    10 / 110 (9.09%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    11 / 11
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 110 (4.55%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary Embolism
         subjects affected / exposed
    2 / 110 (1.82%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory Failure
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophagobronchial Fistula
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    2 / 110 (1.82%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device Occlusion
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head Injury
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation Necrosis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation Pneumonitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Laceration
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 110 (0.91%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous System Disorder
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 110 (0.91%)
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Simple Partial Seizures
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 110 (1.82%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive Disorder
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperaesthesia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial Pressure Increased
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Paraesthesia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic Clonic Movements
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph Node Pain
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo Positional
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular Oedema
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food Poisoning
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth Socket Haemorrhage
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis Acute
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice Cholestatic
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Function Abnormal
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis Allergic
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic Dermatomyositis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash Erythematous
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Necrosis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    13 / 110 (11.82%)
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Appendicitis
         subjects affected / exposed
    2 / 110 (1.82%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 110 (0.91%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis Bacterial
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tuberculous Pleurisy
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma Infection
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased Appetite
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AP26113 90 mg - 180 mg AP26113 90 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 110 (95.45%)
    108 / 109 (99.08%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    35 / 110 (31.82%)
    21 / 109 (19.27%)
         occurrences all number
    49
    27
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    41 / 110 (37.27%)
    34 / 109 (31.19%)
         occurrences all number
    53
    40
    Pyrexia
         subjects affected / exposed
    11 / 110 (10.00%)
    23 / 109 (21.10%)
         occurrences all number
    14
    48
    Asthenia
         subjects affected / exposed
    19 / 110 (17.27%)
    16 / 109 (14.68%)
         occurrences all number
    27
    20
    Oedema Peripheral
         subjects affected / exposed
    14 / 110 (12.73%)
    13 / 109 (11.93%)
         occurrences all number
    14
    23
    Non-Cardiac Chest Pain
         subjects affected / exposed
    5 / 110 (4.55%)
    6 / 109 (5.50%)
         occurrences all number
    7
    9
    Influenza Like Illness
         subjects affected / exposed
    9 / 110 (8.18%)
    8 / 109 (7.34%)
         occurrences all number
    11
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    45 / 110 (40.91%)
    35 / 109 (32.11%)
         occurrences all number
    67
    54
    Dyspnoea
         subjects affected / exposed
    31 / 110 (28.18%)
    28 / 109 (25.69%)
         occurrences all number
    40
    37
    Oropharyngeal Pain
         subjects affected / exposed
    11 / 110 (10.00%)
    12 / 109 (11.01%)
         occurrences all number
    12
    17
    Dysphonia
         subjects affected / exposed
    7 / 110 (6.36%)
    8 / 109 (7.34%)
         occurrences all number
    7
    20
    Productive Cough
         subjects affected / exposed
    9 / 110 (8.18%)
    10 / 109 (9.17%)
         occurrences all number
    11
    10
    Haemoptysis
         subjects affected / exposed
    8 / 110 (7.27%)
    4 / 109 (3.67%)
         occurrences all number
    9
    4
    Dyspnoea Exertional
         subjects affected / exposed
    2 / 110 (1.82%)
    6 / 109 (5.50%)
         occurrences all number
    2
    7
    Epistaxis
         subjects affected / exposed
    8 / 110 (7.27%)
    4 / 109 (3.67%)
         occurrences all number
    10
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 110 (13.64%)
    20 / 109 (18.35%)
         occurrences all number
    16
    22
    Anxiety
         subjects affected / exposed
    11 / 110 (10.00%)
    3 / 109 (2.75%)
         occurrences all number
    12
    3
    Investigations
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    41 / 110 (37.27%)
    24 / 109 (22.02%)
         occurrences all number
    73
    40
    Amylase Increased
         subjects affected / exposed
    20 / 110 (18.18%)
    16 / 109 (14.68%)
         occurrences all number
    37
    23
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    22 / 110 (20.00%)
    15 / 109 (13.76%)
         occurrences all number
    35
    22
    Lipase Increased
         subjects affected / exposed
    23 / 110 (20.91%)
    15 / 109 (13.76%)
         occurrences all number
    54
    18
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    10 / 110 (9.09%)
    3 / 109 (2.75%)
         occurrences all number
    15
    3
    Alanine Aminotransferase Increased
         subjects affected / exposed
    18 / 110 (16.36%)
    15 / 109 (13.76%)
         occurrences all number
    29
    16
    Weight Decreased
         subjects affected / exposed
    7 / 110 (6.36%)
    8 / 109 (7.34%)
         occurrences all number
    7
    8
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    6 / 110 (5.45%)
    7 / 109 (6.42%)
         occurrences all number
    9
    7
    Blood Creatinine Increased
         subjects affected / exposed
    8 / 110 (7.27%)
    5 / 109 (4.59%)
         occurrences all number
    11
    9
    Electrocardiogram Qt Prolonged
         subjects affected / exposed
    8 / 110 (7.27%)
    4 / 109 (3.67%)
         occurrences all number
    13
    5
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 110 (6.36%)
    2 / 109 (1.83%)
         occurrences all number
    7
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    6 / 110 (5.45%)
    1 / 109 (0.92%)
         occurrences all number
    8
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    44 / 110 (40.00%)
    39 / 109 (35.78%)
         occurrences all number
    76
    82
    Dizziness
         subjects affected / exposed
    22 / 110 (20.00%)
    18 / 109 (16.51%)
         occurrences all number
    25
    24
    Paraesthesia
         subjects affected / exposed
    12 / 110 (10.91%)
    13 / 109 (11.93%)
         occurrences all number
    17
    15
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    10 / 110 (9.09%)
    8 / 109 (7.34%)
         occurrences all number
    12
    8
    Memory Impairment
         subjects affected / exposed
    11 / 110 (10.00%)
    4 / 109 (3.67%)
         occurrences all number
    11
    5
    Seizure
         subjects affected / exposed
    11 / 110 (10.00%)
    4 / 109 (3.67%)
         occurrences all number
    14
    4
    Hypoaesthesia
         subjects affected / exposed
    6 / 110 (5.45%)
    5 / 109 (4.59%)
         occurrences all number
    6
    6
    Cognitive Disorder
         subjects affected / exposed
    6 / 110 (5.45%)
    3 / 109 (2.75%)
         occurrences all number
    6
    4
    Tremor
         subjects affected / exposed
    6 / 110 (5.45%)
    2 / 109 (1.83%)
         occurrences all number
    7
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 110 (7.27%)
    8 / 109 (7.34%)
         occurrences all number
    11
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    13 / 110 (11.82%)
    3 / 109 (2.75%)
         occurrences all number
    16
    3
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    9 / 110 (8.18%)
    7 / 109 (6.42%)
         occurrences all number
    11
    8
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    55 / 110 (50.00%)
    47 / 109 (43.12%)
         occurrences all number
    86
    82
    Diarrhoea
         subjects affected / exposed
    51 / 110 (46.36%)
    34 / 109 (31.19%)
         occurrences all number
    163
    64
    Vomiting
         subjects affected / exposed
    39 / 110 (35.45%)
    44 / 109 (40.37%)
         occurrences all number
    106
    83
    Constipation
         subjects affected / exposed
    28 / 110 (25.45%)
    29 / 109 (26.61%)
         occurrences all number
    39
    36
    Abdominal Pain
         subjects affected / exposed
    10 / 110 (9.09%)
    13 / 109 (11.93%)
         occurrences all number
    15
    16
    Dyspepsia
         subjects affected / exposed
    8 / 110 (7.27%)
    8 / 109 (7.34%)
         occurrences all number
    10
    8
    Stomatitis
         subjects affected / exposed
    10 / 110 (9.09%)
    5 / 109 (4.59%)
         occurrences all number
    21
    5
    Dry Mouth
         subjects affected / exposed
    11 / 110 (10.00%)
    4 / 109 (3.67%)
         occurrences all number
    12
    4
    Abdominal Pain Upper
         subjects affected / exposed
    13 / 110 (11.82%)
    11 / 109 (10.09%)
         occurrences all number
    17
    13
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 110 (3.64%)
    6 / 109 (5.50%)
         occurrences all number
    4
    6
    Pruritus
         subjects affected / exposed
    15 / 110 (13.64%)
    12 / 109 (11.01%)
         occurrences all number
    19
    13
    Dermatitis Acneiform
         subjects affected / exposed
    4 / 110 (3.64%)
    7 / 109 (6.42%)
         occurrences all number
    4
    7
    Rash Erythematous
         subjects affected / exposed
    14 / 110 (12.73%)
    9 / 109 (8.26%)
         occurrences all number
    16
    13
    Dry Skin
         subjects affected / exposed
    3 / 110 (2.73%)
    8 / 109 (7.34%)
         occurrences all number
    4
    12
    Rash Maculo-Papular
         subjects affected / exposed
    7 / 110 (6.36%)
    3 / 109 (2.75%)
         occurrences all number
    9
    4
    Rash Pruritic
         subjects affected / exposed
    8 / 110 (7.27%)
    2 / 109 (1.83%)
         occurrences all number
    9
    3
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    9 / 110 (8.18%)
    3 / 109 (2.75%)
         occurrences all number
    10
    3
    Musculoskeletal and connective tissue disorders
    Muscle Spasms
         subjects affected / exposed
    28 / 110 (25.45%)
    17 / 109 (15.60%)
         occurrences all number
    37
    30
    Arthralgia
         subjects affected / exposed
    21 / 110 (19.09%)
    19 / 109 (17.43%)
         occurrences all number
    25
    26
    Back Pain
         subjects affected / exposed
    30 / 110 (27.27%)
    16 / 109 (14.68%)
         occurrences all number
    35
    22
    Pain in extremity
         subjects affected / exposed
    15 / 110 (13.64%)
    17 / 109 (15.60%)
         occurrences all number
    17
    23
    Myalgia
         subjects affected / exposed
    17 / 110 (15.45%)
    7 / 109 (6.42%)
         occurrences all number
    24
    11
    Musculoskeletal Pain
         subjects affected / exposed
    15 / 110 (13.64%)
    9 / 109 (8.26%)
         occurrences all number
    19
    10
    Musculoskeletal Chest Pain
         subjects affected / exposed
    10 / 110 (9.09%)
    7 / 109 (6.42%)
         occurrences all number
    15
    8
    Neck Pain
         subjects affected / exposed
    13 / 110 (11.82%)
    4 / 109 (3.67%)
         occurrences all number
    17
    4
    Muscular Weakness
         subjects affected / exposed
    4 / 110 (3.64%)
    6 / 109 (5.50%)
         occurrences all number
    5
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    15 / 110 (13.64%)
    15 / 109 (13.76%)
         occurrences all number
    32
    25
    Upper Respiratory Tract Infection
         subjects affected / exposed
    10 / 110 (9.09%)
    13 / 109 (11.93%)
         occurrences all number
    13
    18
    Urinary Tract Infection
         subjects affected / exposed
    13 / 110 (11.82%)
    9 / 109 (8.26%)
         occurrences all number
    20
    17
    Pneumonia
         subjects affected / exposed
    15 / 110 (13.64%)
    3 / 109 (2.75%)
         occurrences all number
    16
    4
    Bronchitis
         subjects affected / exposed
    6 / 110 (5.45%)
    5 / 109 (4.59%)
         occurrences all number
    9
    6
    Sinusitis
         subjects affected / exposed
    8 / 110 (7.27%)
    3 / 109 (2.75%)
         occurrences all number
    10
    6
    Herpes Zoster
         subjects affected / exposed
    6 / 110 (5.45%)
    1 / 109 (0.92%)
         occurrences all number
    7
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    27 / 110 (24.55%)
    32 / 109 (29.36%)
         occurrences all number
    31
    36
    Hyperglycaemia
         subjects affected / exposed
    9 / 110 (8.18%)
    6 / 109 (5.50%)
         occurrences all number
    10
    7
    Hyponatraemia
         subjects affected / exposed
    8 / 110 (7.27%)
    5 / 109 (4.59%)
         occurrences all number
    16
    7
    Hypokalaemia
         subjects affected / exposed
    6 / 110 (5.45%)
    7 / 109 (6.42%)
         occurrences all number
    9
    18

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Feb 2014
    The primary purpose of this amendment was to make following changes: Adjusted the study design to allow for randomization into two different study arms, each with a different dosing regimen (90 mg QD or 180 mg QD with a 7-day lead-in at 90 mg QD). Increased enrollment projections to fill both study arms (and added at least 6 more months to accrue participants). Updated the statistical testing methods to address both study arms. Updated clinical summary of data from the phase 1/2 study of brigatinib, including an assessment of respiratory events and reports of early onset pulmonary syndrome. Updated sections describing sampling for molecular genetic testing to allow for analysis of various tumor and plasma biomarkers as is feasible at different sites. Modified the wording of protocol eligibility criteria (Inclusion criteria 1, 2, 3, 6, 10 and 13; Exclusion criteria 6) to further clarify the type of participants to be enrolled. Updated the tissue and blood sample procedures (described separately) to occur only at screening and end-of-treatment for molecular genetics and added specifics for anaplastic lymphoma kinase (ALK) fluorescence in situ hybridization (FISH) testing. Updated the pharmacokinetic (PK) collection procedures to include slightly more frequent sampling in Cycles 3, 4, and 5. Updated Schedule of Events Table to include: randomization (on Day 1), a Day 8 visit, an assessment of brain MRI at screening, addition of ALK FISH testing (at screening), adjustments to descriptions of tissue and plasma sampling for molecular genetic testing. Added a section on continuing treatment after disease progression, by study arm. Added a section on re-escalation after dose modification. Added a section describing the Data Monitoring Committee. Updated the information in Appendix E (drugs with a risk of Torsades de Pointes). Made minor grammatical, punctuation, and spelling changes; updated per sponsor personnel changes; and updated all hyperlinks and access dates.
    29 Jul 2014
    The primary purpose of this amendment was to make following changes: Updated eligibility criteria (inclusion criteria 4, 6; Exclusion criteria 6, 7 and 16) to remove some restrictions on prior treatments, clarified restrictions for participants with central nervous system (CNS) activity, and added an exclusion for pregnant/breastfeeding women. Removed dietary restrictions based on clinical pharmacology testing results. Allowed for adding a couple additional postbaseline time points for plasma biomarker sampling. Updated the statistical sections to specify the analysis populations for efficacy and safety and clarified testing methodologies. Updated the description of procedures, as follows: added a reminder to monitor for visual dysfunction, added creatine kinase to the blood draw assessments and specified that all glucose and insulin draws should be fasted, added more frequent pregnancy testing, and specified a two-hour window for the final PK time point. Added guidelines for dose modifications (due to AEs) specific to QT prolongation, per the suggestion from a competent authority. Updated the AE severity definitions by removing relationship to study drug, which does not determine severity (general template change). Updated the definition of overdose and how to handle overdoses per standard reporting guidelines. Made minor grammatical, punctuation, and spelling changes and updated per sponsor personnel changes.

    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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