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    Clinical Trial Results:
    An Open Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early Stage HER2+ Breast Cancer Treated with Neratinib and Intensive Loperamide Prophylaxis

    Summary
    EudraCT number
    		 2015-004374-15
    Trial protocol
    		 ES   AT  
    Global end of trial date
    22 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2022
    First version publication date
    28 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PUMA-NER-6201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02400476
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Puma Biotechnology
    Sponsor organisation address
    10880 Wilshire Blvd, Suite 2150, Los Angeles, United States, 90024
    Public contact
    Clinical Trials Information Desk, Puma Biotechnology, Inc., +1 4242486500, clinicaltrials@pumabiotechnology.com
    Scientific contact
    Clinical Trials Information Desk, Puma Biotechnology, Inc., +1 4242486500, clinicaltrials@pumabiotechnology.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the incidence and severity of diarrhea in patients with early stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab.
    Protection of trial subjects
    Study commencement required prior written approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). Clinical trial data were monitored at regular intervals by the Sponsor or their representative throughout the study to verify compliance to study protocol, completeness, accuracy and consistency of the data and adherence to local regulations on the conduct of clinical research. Patients were discontinued from investigational product(s) (IP) in the following circumstances: disease recurrence (as determined by the Investigator), death, unacceptable toxicity, or other specified withdrawal criterion.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Australia: 86
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    United States: 413
    Worldwide total number of subjects
    563
    EEA total number of subjects
    37
    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)
    487
    From 65 to 84 years
    75
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The institutional review board/independent ethics committee must review and approve the protocol and informed consent form (ICF) before any subjects provide consent.

    Pre-assignment
    Screening details
    		 Each subject must participate in the informed consent process and sign and date an Informed Consent Form (ICF) for this protocol before any protocol-required procedures are performed.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Loperamide
    Arm description
    		 Patients in the Loperamide Arm were enrolled under the original protocol as well as patients enrolled under amendments 1 and 2. Patients enrolled under Original Protocol received mandatory low dose loperamide prophylaxis for 2 cycles + neratinib 240 mg/day for all thirteen (13) 28-day cycles. Patients enrolled under Amendment 1 or 2 received mandatory high dose loperamide prophylaxis for 2 cycles + neratinib 240 mg/day for all thirteen (13) 28-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    loperamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For patients enrolled under the Original Protocol: Initial dose of 4 mg (2 tablets/capsules) with the first dose of neratinib, followed by 2 mg (1 tablet/capsule) every 4 hours for the first 3 days. After the first 3 days, loperamide 2 mg every 6 to 8 hours through the first 2 cycles of therapy (56 days) from start of neratinib. For patients enrolled under Amendment 1 and Amendment 2: For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients 3 times a day (total 12 mg a day). The initial dose of loperamide 4 mg will be self-administered orally with the first dose of neratinib. After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally twice a day (total 8 mg a day) through the first 2 cycles of therapy (Day 56) from start of neratinib dosing.

    Investigational medicinal product name
    neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib (240 mg; provided as six 40-mg tablets) will be self-administered orally by patients on a daily basis, starting with Cycle 1/Day 1. Neratinib must be taken with food, preferably in the morning; however, neratinib may be taken in the evening. Neratinib will be given continuously for one year (364 days) in thirteen (13) 28-day cycles, with no rest between cycles.

    Arm title
    		 Budesonide
    Arm description
    		 Patients enrolled in the Budesonide Arm (under Amendment 3) received mandatory high dose loperamide prophylaxis for two (2) cycles + budesonide for one (1) cycle + neratinib 240 mg/day for all thirteen (13) 28-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib (240 mg; provided as six 40-mg tablets) will be self-administered orally by patients on a daily basis, starting with Cycle 1/Day 1. Neratinib must be taken with food, preferably in the morning; however, neratinib may be taken in the evening. Neratinib will be given continuously for one year (364 days) in thirteen (13) 28-day cycles, with no rest between cycles.

    Investigational medicinal product name
    loperamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients 3 times a day (total 12 mg a day). The initial dose of loperamide 4 mg will be self-administered orally with the first dose of neratinib. After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally twice a day (total 8 mg a day) through the first 2 cycles of therapy (Day 56) from start of neratinib dosing.

    Investigational medicinal product name
    budesonide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For patients enrolled under Amendment 3 and who participate in the initial cohort that will evaluate budesonide, patients will self-administer oral budesonide at a dose of 9 mg once daily with or without food, for the first treatment cycle (28 days), to be taken with neratinib and intensive loperamide prophylaxis.

    Arm title
    		 Colestipol
    Arm description
    		 Patients enrolled in the Colestipol Arm (under amendment 4) received mandatory high dose loperamide prophylaxis + colestipol for one (1) cycle + neratinib 240 mg/day for all thirteen (13) 28-day cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib (240 mg; provided as six 40-mg tablets) will be self-administered orally by patients on a daily basis, starting with Cycle 1/Day 1. Neratinib must be taken with food, preferably in the morning; however, neratinib may be taken in the evening. Neratinib will be given continuously for one year (364 days) in thirteen (13) 28-day cycles, with no rest between cycles.

    Investigational medicinal product name
    loperamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the first 14 days, the initial dose of loperamide 4 mg will be self-administered orally with the first dose of neratinib, followed by loperamide 4 mg (2 tablets/capsules) self-administered orally by patients 3 times a day (total 12 mg a day). After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally twice a day (total 8 mg a day), for 1 cycle [28 days], and then as needed (PRN) (not to exceed 16 mg per day).

    Investigational medicinal product name
    colestipol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For patients who participate in the evaluation of colestipol, patients will self-administer colestipol at a dose of 2 g twice daily for the first treatment cycle, to be taken at least 2 hours after, but at least 4 hours before, neratinib and intensive loperamide prophylaxis.

    Arm title
    		 Colestipol + Loperamide PRN
    Arm description
    		 Patients enrolled in the Colestipol + Loperamide PRN Arm (under amendment 5) received loperamide as needed + colestipol for 1 cycle + neratinib 240 mg/day all 13 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib (240 mg; provided as six 40-mg tablets) will be self-administered orally by patients on a daily basis, starting with Cycle 1/Day 1. Neratinib must be taken with food, preferably in the morning; however, neratinib may be taken in the evening. Neratinib will be given continuously for one year (364 days) in thirteen (13) 28-day cycles, with no rest between cycles.

    Investigational medicinal product name
    loperamide PRN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients on a PRN (as needed) basis, from the start of neratinib dosing with a goal of titrating to 1-2 bowel movements a day (not to exceed 16 mg per day).

    Investigational medicinal product name
    colestipol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For patients who participate in the evaluation of colestipol, patients will self-administer colestipol at a dose of 2 g twice daily for the first treatment cycle, to be taken at least 2 hours after, but at least 4 hours before, neratinib and loperamide.

    Arm title
    		 Neratinib Dose Escalation
    Arm description
    		 Patients enrolled in the Neratinib Dose Escalation Arm (under Amendments 6 and 6.1) received 120 mg neratinib daily for Week 1 (C1D1 – C1D7), followed by 160 mg neratinib daily for Week 2 (C1D8 – C1D14), followed by 240 mg neratinib daily starting at Week 3 and thereafter (C1D15 to EOT). Loperamide was administered on an as-needed basis only.
    Arm type
    		 Experimental

    Investigational medicinal product name
    loperamide PRN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients on a PRN (as needed) basis, from the start of neratinib dosing with a goal of titrating to 1-2 bowel movements a day (not to exceed 16 mg per day).

    Investigational medicinal product name
    neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients enrolled under Amendment 6 and Amendment 6.1 will receive neratinib at a starting dose of 120 mg/day with dose escalation (ie, total dose 120 mg daily for Week 1, 160 mg daily for the Week 2, and 240 mg daily for Week 3 and thereafter, until End of Treatment, up to 364 days).

    Arm title
    		 Neratinib Dose Escalation Scheme 2
    Arm description
    		 Patients enrolled in the Neratinib Dose Escalation Scheme 2 Arm (under Amendments 7 and 7.1) received 160 mg neratinib daily for Weeks 1 and 2 (C1D1 – C1D14), followed by 200 mg neratinib daily for Weeks 3 and 4 (C1D15 – C1D28), followed by 240 mg neratinib daily starting at Week 5 and thereafter (C2D1 to EOT). Loperamide was administered on an as-needed basis only.
    Arm type
    		 Experimental

    Investigational medicinal product name
    loperamide PRN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients on a PRN (as needed) basis, from the start of neratinib dosing with a goal of titrating to 1-2 bowel movements a day (not to exceed 16 mg per day).

    Investigational medicinal product name
    neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients enrolled starting with Amendment 7 will receive neratinib 160 mg neratinib for the first 2 weeks (Cycle 1, Day 1 through – Cycle 1 Day 14), followed by 200 mg neratinib for the next 2 weeks (Cycle 1 Day 15 through Cycle 1 Day 28), followed by 240 mg neratinib thereafter (Cycle 2 Day 1 to End of Treatment, up to 364 days). Daily dosing should continue until a criterion for treatment withdrawal is met.

    Number of subjects in period 1
    		Loperamide Budesonide Colestipol Colestipol + Loperamide PRN Neratinib Dose Escalation Neratinib Dose Escalation Scheme 2
    Started
    137
    64
    136
    104
    60
    62
    Completed
    76
    52
    97
    75
    47
    46
    Not completed
    61
    12
    39
    29
    13
    16
         Consent withdrawn by subject
    2
    -
    11
    7
    5
    4
         Physician decision
    -
    -
    1
    1
    -
    1
         Adverse event, non-fatal
    55
    11
    21
    19
    5
    8
         Disease relapse
    1
    1
    1
    1
    2
    1
         Non-compliance with study drug
    -
    -
    1
    -
    -
    -
         Other reasons
    3
    -
    4
    1
    -
    2
         Lost to follow-up
    -
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Loperamide
    Reporting group description
    		 Patients in the Loperamide Arm were enrolled under the original protocol as well as patients enrolled under amendments 1 and 2. Patients enrolled under Original Protocol received mandatory low dose loperamide prophylaxis for 2 cycles + neratinib 240 mg/day for all thirteen (13) 28-day cycles. Patients enrolled under Amendment 1 or 2 received mandatory high dose loperamide prophylaxis for 2 cycles + neratinib 240 mg/day for all thirteen (13) 28-day cycles.

    Reporting group title
    Budesonide
    Reporting group description
    		 Patients enrolled in the Budesonide Arm (under Amendment 3) received mandatory high dose loperamide prophylaxis for two (2) cycles + budesonide for one (1) cycle + neratinib 240 mg/day for all thirteen (13) 28-day cycles.

    Reporting group title
    Colestipol
    Reporting group description
    		 Patients enrolled in the Colestipol Arm (under amendment 4) received mandatory high dose loperamide prophylaxis + colestipol for one (1) cycle + neratinib 240 mg/day for all thirteen (13) 28-day cycles.

    Reporting group title
    Colestipol + Loperamide PRN
    Reporting group description
    		 Patients enrolled in the Colestipol + Loperamide PRN Arm (under amendment 5) received loperamide as needed + colestipol for 1 cycle + neratinib 240 mg/day all 13 cycles.

    Reporting group title
    Neratinib Dose Escalation
    Reporting group description
    		 Patients enrolled in the Neratinib Dose Escalation Arm (under Amendments 6 and 6.1) received 120 mg neratinib daily for Week 1 (C1D1 – C1D7), followed by 160 mg neratinib daily for Week 2 (C1D8 – C1D14), followed by 240 mg neratinib daily starting at Week 3 and thereafter (C1D15 to EOT). Loperamide was administered on an as-needed basis only.

    Reporting group title
    Neratinib Dose Escalation Scheme 2
    Reporting group description
    		 Patients enrolled in the Neratinib Dose Escalation Scheme 2 Arm (under Amendments 7 and 7.1) received 160 mg neratinib daily for Weeks 1 and 2 (C1D1 – C1D14), followed by 200 mg neratinib daily for Weeks 3 and 4 (C1D15 – C1D28), followed by 240 mg neratinib daily starting at Week 5 and thereafter (C2D1 to EOT). Loperamide was administered on an as-needed basis only.

    Reporting group values
    		 Loperamide Budesonide Colestipol Colestipol + Loperamide PRN Neratinib Dose Escalation Neratinib Dose Escalation Scheme 2 Total
    Number of subjects
    		 137 64 136 104 60 62 563
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 116 58 117 93 51 52 487
        65 years and older
    		 21 6 19 11 9 10 76
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.4 ( 11.1 ) 49.1 ( 10.6 ) 52.5 ( 11.1 ) 52.0 ( 10.2 ) 51.9 ( 10.7 ) 53.8 ( 10.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 137 64 133 104 60 62 560
        Male
    		 0 0 3 0 0 0 3

    End points

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    End points reporting groups
    Reporting group title
    Loperamide
    Reporting group description
    		 Patients in the Loperamide Arm were enrolled under the original protocol as well as patients enrolled under amendments 1 and 2. Patients enrolled under Original Protocol received mandatory low dose loperamide prophylaxis for 2 cycles + neratinib 240 mg/day for all thirteen (13) 28-day cycles. Patients enrolled under Amendment 1 or 2 received mandatory high dose loperamide prophylaxis for 2 cycles + neratinib 240 mg/day for all thirteen (13) 28-day cycles.

    Reporting group title
    Budesonide
    Reporting group description
    		 Patients enrolled in the Budesonide Arm (under Amendment 3) received mandatory high dose loperamide prophylaxis for two (2) cycles + budesonide for one (1) cycle + neratinib 240 mg/day for all thirteen (13) 28-day cycles.

    Reporting group title
    Colestipol
    Reporting group description
    		 Patients enrolled in the Colestipol Arm (under amendment 4) received mandatory high dose loperamide prophylaxis + colestipol for one (1) cycle + neratinib 240 mg/day for all thirteen (13) 28-day cycles.

    Reporting group title
    Colestipol + Loperamide PRN
    Reporting group description
    		 Patients enrolled in the Colestipol + Loperamide PRN Arm (under amendment 5) received loperamide as needed + colestipol for 1 cycle + neratinib 240 mg/day all 13 cycles.

    Reporting group title
    Neratinib Dose Escalation
    Reporting group description
    		 Patients enrolled in the Neratinib Dose Escalation Arm (under Amendments 6 and 6.1) received 120 mg neratinib daily for Week 1 (C1D1 – C1D7), followed by 160 mg neratinib daily for Week 2 (C1D8 – C1D14), followed by 240 mg neratinib daily starting at Week 3 and thereafter (C1D15 to EOT). Loperamide was administered on an as-needed basis only.

    Reporting group title
    Neratinib Dose Escalation Scheme 2
    Reporting group description
    		 Patients enrolled in the Neratinib Dose Escalation Scheme 2 Arm (under Amendments 7 and 7.1) received 160 mg neratinib daily for Weeks 1 and 2 (C1D1 – C1D14), followed by 200 mg neratinib daily for Weeks 3 and 4 (C1D15 – C1D28), followed by 240 mg neratinib daily starting at Week 5 and thereafter (C2D1 to EOT). Loperamide was administered on an as-needed basis only.

    Primary: Percentage of Patients with Grade 3 or Higher Diarrhoea

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    End point title
    		 Percentage of Patients with Grade 3 or Higher Diarrhoea [1]
    End point description
    The primary objective of this study is to characterize the percentage of patients with Grade 3 or higher diarrhoea in patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.
    End point type
    Primary
    End point timeframe
    From first dose through 28 days after last dose, up to 15.5 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: No formal comparisons between treatment groups were specified by the protocol. Descriptive statistics only are provided.
    End point values
    		 Loperamide Budesonide Colestipol Colestipol + Loperamide PRN Neratinib Dose Escalation Neratinib Dose Escalation Scheme 2
    Number of subjects analysed
    137
    64
    136
    104
    60
    62
    Units: percentage of patients
        number (confidence interval 95%)
    30.7 (23.1 to 39.1)
    28.1 (17.6 to 40.8)
    20.6 (14.1 to 28.4)
    32.7 (23.8 to 42.6)
    13.3 (5.9 to 24.6)
    27.4 (16.9 to 40.2)
    No statistical analyses for this end point

    Secondary: Percentage of Patients With Diarrhoea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0.

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    End point title
    		 Percentage of Patients With Diarrhoea by Grade, According to the National Cancer Institute Common Terminology Criteria (NCI CTCAE), Version 4.0.
    End point description
    Assess the percentage of patients with diarrhoea after the administration of an anti-inflammatory agent, a bile acid sequestrant, or following two different dose-escalation regimens of neratinib, by maximum CTC grade. Grade 1: an increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline. Grade 2: Increase of 4 -6 stools per day over baseline; moderate increase in ostomy output compared to baseline. Grade 3: Increase of >=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.
    End point type
    Secondary
    End point timeframe
    From first dose through 28 days after last dose, up to 15.5 months.
    End point values
    		 Loperamide Budesonide Colestipol Colestipol + Loperamide PRN Neratinib Dose Escalation Neratinib Dose Escalation Scheme 2
    Number of subjects analysed
    137
    64
    136
    104
    60
    62
    Units: percentage of patients
    number (not applicable)
        Grade 1
    24.1
    23.4
    27.9
    32.7
    40.0
    37.1
        Grade 2
    24.8
    34.4
    34.6
    29.8
    45.0
    33.9
        Grade 3
    30.7
    28.1
    20.6
    32.7
    13.3
    27.4
    No statistical analyses for this end point

    Secondary: Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest

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    End point title
    		 Percentage of Patients With Serious Adverse Events and Other Adverse Events of Special Interest
    End point description
    Assess the percentage of patients with serious adverse events (SAEs) and other adverse events of special interest (AESI). AESIs were selected based on the known safety profile of neratinib as well as typical key body system toxicity concerns generally reviewed for any new drug. These AESIs were grouped into the following categories: gastrointestinal toxicity (diarrhea and stomatitis), hepatotoxicity, pulmonary toxicity (interstitial lung disease), cardiac toxicity (LVEF decreased), and dermatologic toxicity (rash and nail disorders). The AESIs were analyzed by searching the clinical database for all TEAEs and SAEs using either Standardized MedDRA Queries(SMQs) or, if an applicable SMQ did not exist, a Sponsor-defined list of MedDRA Preferred Terms.
    End point type
    Secondary
    End point timeframe
    From first dose of investigational product through 28 days after last dose, up to 15.5 months.
    End point values
    		 Loperamide Budesonide Colestipol Colestipol + Loperamide PRN Neratinib Dose Escalation Neratinib Dose Escalation Scheme 2
    Number of subjects analysed
    137
    64
    136
    104
    60
    62
    Units: percentage of patients
    number (not applicable)
        % of patients with SAEs
    6.57
    6.25
    6.62
    2.88
    8.33
    8.06
        % of patients with GI toxicities (broad)
    81.75
    87.5
    83.82
    96.15
    98.33
    98.39
        % of patients with hepatotoxicities (broad)
    12.41
    7.81
    4.41
    4.81
    8.33
    4.84
        % of patients with ILD (broad)
    0
    0
    0
    0
    0
    0
        % of patients with cardiac toxicities (broad)
    5.84
    6.25
    10.29
    7.69
    10.00
    4.84
        % of patients with dermatologic toxicities
    12.41
    37.5
    23.53
    18.27
    11.67
    30.65
        % of patients with GI toxicities (narrow)
    80.29
    85.94
    83.09
    95.19
    98.33
    98.39
        % of patients with hepatotoxicities (narrow)
    10.95
    7.81
    3.68
    3.85
    8.33
    4.84
        % of patients with ILD (narrow)
    0
    0
    0
    0
    0
    0
        % of patients with cardiac toxicites (narrow)
    2.92
    0
    1.47
    0.96
    1.67
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1st dose through 28 days after last dose up to 15.5 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Loperamide
    Reporting group description
    		 Loperamide

    Reporting group title
    Budesonide
    Reporting group description
    		 Budesonide

    Reporting group title
    Colestipol
    Reporting group description
    		 Colestipol

    Reporting group title
    Colestipol+Loperamide PRN
    Reporting group description
    		 Colestipol+Loperamide PRN

    Reporting group title
    Neratinib Dose Escalation
    Reporting group description
    		 Neratinib Dose Escalation

    Reporting group title
    Neratinib Dose Escalation Scheme 2
    Reporting group description
    		 Neratinib Dose Escalation Scheme 2

    Serious adverse events
    		 Loperamide Budesonide Colestipol Colestipol+Loperamide PRN Neratinib Dose Escalation Neratinib Dose Escalation Scheme 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 137 (6.57%)
    4 / 64 (6.25%)
    9 / 136 (6.62%)
    3 / 104 (2.88%)
    5 / 60 (8.33%)
    5 / 62 (8.06%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fat necrosis
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 64 (1.56%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 64 (1.56%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    2 / 136 (1.47%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 137 (1.46%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 64 (1.56%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 64 (1.56%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    1 / 104 (0.96%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 64 (1.56%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    1 / 104 (0.96%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    1 / 104 (0.96%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    1 / 104 (0.96%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 64 (0.00%)
    1 / 136 (0.74%)
    0 / 104 (0.00%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Loperamide Budesonide Colestipol Colestipol+Loperamide PRN Neratinib Dose Escalation Neratinib Dose Escalation Scheme 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 137 (100.00%)
    64 / 64 (100.00%)
    136 / 136 (100.00%)
    104 / 104 (100.00%)
    60 / 60 (100.00%)
    62 / 62 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    8 / 137 (5.84%)
    6 / 64 (9.38%)
    17 / 136 (12.50%)
    7 / 104 (6.73%)
    7 / 60 (11.67%)
    4 / 62 (6.45%)
         occurrences all number
    8
    7
    17
    7
    7
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 137 (4.38%)
    1 / 64 (1.56%)
    1 / 136 (0.74%)
    4 / 104 (3.85%)
    3 / 60 (5.00%)
    2 / 62 (3.23%)
         occurrences all number
    6
    1
    1
    4
    5
    2
    Fatigue
         subjects affected / exposed
    73 / 137 (53.28%)
    34 / 64 (53.13%)
    65 / 136 (47.79%)
    41 / 104 (39.42%)
    28 / 60 (46.67%)
    19 / 62 (30.65%)
         occurrences all number
    92
    53
    85
    62
    35
    30
    Pyrexia
         subjects affected / exposed
    6 / 137 (4.38%)
    2 / 64 (3.13%)
    10 / 136 (7.35%)
    3 / 104 (2.88%)
    2 / 60 (3.33%)
    1 / 62 (1.61%)
         occurrences all number
    6
    4
    11
    4
    2
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    4 / 137 (2.92%)
    7 / 64 (10.94%)
    8 / 136 (5.88%)
    6 / 104 (5.77%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences all number
    4
    7
    9
    6
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 137 (5.11%)
    7 / 64 (10.94%)
    9 / 136 (6.62%)
    8 / 104 (7.69%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences all number
    8
    9
    9
    10
    1
    0
    Dyspnoea
         subjects affected / exposed
    9 / 137 (6.57%)
    4 / 64 (6.25%)
    4 / 136 (2.94%)
    4 / 104 (3.85%)
    3 / 60 (5.00%)
    1 / 62 (1.61%)
         occurrences all number
    10
    4
    5
    4
    3
    1
    Epistaxis
         subjects affected / exposed
    2 / 137 (1.46%)
    2 / 64 (3.13%)
    9 / 136 (6.62%)
    4 / 104 (3.85%)
    3 / 60 (5.00%)
    4 / 62 (6.45%)
         occurrences all number
    2
    4
    10
    5
    3
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 137 (4.38%)
    8 / 64 (12.50%)
    10 / 136 (7.35%)
    8 / 104 (7.69%)
    3 / 60 (5.00%)
    4 / 62 (6.45%)
         occurrences all number
    6
    9
    10
    8
    3
    4
    Anxiety
         subjects affected / exposed
    5 / 137 (3.65%)
    4 / 64 (6.25%)
    3 / 136 (2.21%)
    3 / 104 (2.88%)
    3 / 60 (5.00%)
    2 / 62 (3.23%)
         occurrences all number
    5
    4
    4
    3
    3
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 137 (6.57%)
    4 / 64 (6.25%)
    4 / 136 (2.94%)
    3 / 104 (2.88%)
    4 / 60 (6.67%)
    2 / 62 (3.23%)
         occurrences all number
    12
    6
    4
    3
    5
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 137 (2.92%)
    1 / 64 (1.56%)
    3 / 136 (2.21%)
    2 / 104 (1.92%)
    3 / 60 (5.00%)
    2 / 62 (3.23%)
         occurrences all number
    7
    1
    3
    6
    3
    3
    Weight decreased
         subjects affected / exposed
    10 / 137 (7.30%)
    4 / 64 (6.25%)
    11 / 136 (8.09%)
    4 / 104 (3.85%)
    1 / 60 (1.67%)
    3 / 62 (4.84%)
         occurrences all number
    13
    5
    11
    4
    1
    3
    Blood glucose increased
         subjects affected / exposed
    0 / 137 (0.00%)
    0 / 64 (0.00%)
    0 / 136 (0.00%)
    0 / 104 (0.00%)
    3 / 60 (5.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 137 (13.87%)
    6 / 64 (9.38%)
    21 / 136 (15.44%)
    20 / 104 (19.23%)
    9 / 60 (15.00%)
    8 / 62 (12.90%)
         occurrences all number
    21
    8
    26
    24
    10
    9
    Headache
         subjects affected / exposed
    26 / 137 (18.98%)
    12 / 64 (18.75%)
    20 / 136 (14.71%)
    24 / 104 (23.08%)
    13 / 60 (21.67%)
    8 / 62 (12.90%)
         occurrences all number
    31
    18
    40
    27
    15
    10
    Neuropathy peripheral
         subjects affected / exposed
    4 / 137 (2.92%)
    3 / 64 (4.69%)
    3 / 136 (2.21%)
    6 / 104 (5.77%)
    0 / 60 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    4
    4
    3
    7
    0
    1
    Paraesthesia
         subjects affected / exposed
    3 / 137 (2.19%)
    1 / 64 (1.56%)
    3 / 136 (2.21%)
    0 / 104 (0.00%)
    5 / 60 (8.33%)
    0 / 62 (0.00%)
         occurrences all number
    4
    1
    3
    0
    5
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 137 (5.84%)
    5 / 64 (7.81%)
    1 / 136 (0.74%)
    5 / 104 (4.81%)
    0 / 60 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    9
    5
    1
    7
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 137 (0.00%)
    4 / 64 (6.25%)
    3 / 136 (2.21%)
    0 / 104 (0.00%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences all number
    0
    5
    3
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    7 / 137 (5.11%)
    2 / 64 (3.13%)
    7 / 136 (5.15%)
    5 / 104 (4.81%)
    2 / 60 (3.33%)
    0 / 62 (0.00%)
         occurrences all number
    7
    2
    8
    6
    2
    0
    Abdominal distension
         subjects affected / exposed
    21 / 137 (15.33%)
    5 / 64 (7.81%)
    22 / 136 (16.18%)
    15 / 104 (14.42%)
    6 / 60 (10.00%)
    10 / 62 (16.13%)
         occurrences all number
    27
    7
    28
    16
    7
    10
    Abdominal pain
         subjects affected / exposed
    36 / 137 (26.28%)
    12 / 64 (18.75%)
    26 / 136 (19.12%)
    27 / 104 (25.96%)
    13 / 60 (21.67%)
    15 / 62 (24.19%)
         occurrences all number
    55
    21
    36
    31
    16
    24
    Constipation
         subjects affected / exposed
    78 / 137 (56.93%)
    48 / 64 (75.00%)
    93 / 136 (68.38%)
    39 / 104 (37.50%)
    22 / 60 (36.67%)
    15 / 62 (24.19%)
         occurrences all number
    180
    391
    773
    392
    271
    126
    Abdominal pain upper
         subjects affected / exposed
    5 / 137 (3.65%)
    7 / 64 (10.94%)
    16 / 136 (11.76%)
    7 / 104 (6.73%)
    3 / 60 (5.00%)
    8 / 62 (12.90%)
         occurrences all number
    5
    8
    20
    8
    3
    9
    Dry mouth
         subjects affected / exposed
    18 / 137 (13.14%)
    6 / 64 (9.38%)
    12 / 136 (8.82%)
    5 / 104 (4.81%)
    4 / 60 (6.67%)
    3 / 62 (4.84%)
         occurrences all number
    23
    6
    14
    5
    4
    3
    Diarrhoea
         subjects affected / exposed
    109 / 137 (79.56%)
    55 / 64 (85.94%)
    113 / 136 (83.09%)
    99 / 104 (95.19%)
    59 / 60 (98.33%)
    61 / 62 (98.39%)
         occurrences all number
    802
    1159
    2174
    2843
    1640
    1821
    Dyspepsia
         subjects affected / exposed
    12 / 137 (8.76%)
    10 / 64 (15.63%)
    16 / 136 (11.76%)
    13 / 104 (12.50%)
    7 / 60 (11.67%)
    6 / 62 (9.68%)
         occurrences all number
    17
    12
    20
    16
    16
    6
    Flatulence
         subjects affected / exposed
    5 / 137 (3.65%)
    6 / 64 (9.38%)
    5 / 136 (3.68%)
    2 / 104 (1.92%)
    1 / 60 (1.67%)
    3 / 62 (4.84%)
         occurrences all number
    5
    8
    5
    2
    1
    4
    Nausea
         subjects affected / exposed
    78 / 137 (56.93%)
    32 / 64 (50.00%)
    83 / 136 (61.03%)
    64 / 104 (61.54%)
    27 / 60 (45.00%)
    28 / 62 (45.16%)
         occurrences all number
    115
    52
    130
    103
    48
    40
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 137 (7.30%)
    5 / 64 (7.81%)
    10 / 136 (7.35%)
    6 / 104 (5.77%)
    2 / 60 (3.33%)
    4 / 62 (6.45%)
         occurrences all number
    11
    7
    12
    6
    2
    4
    Stomatitis
         subjects affected / exposed
    7 / 137 (5.11%)
    4 / 64 (6.25%)
    14 / 136 (10.29%)
    13 / 104 (12.50%)
    6 / 60 (10.00%)
    6 / 62 (9.68%)
         occurrences all number
    9
    13
    15
    27
    6
    7
    Vomiting
         subjects affected / exposed
    36 / 137 (26.28%)
    16 / 64 (25.00%)
    43 / 136 (31.62%)
    25 / 104 (24.04%)
    9 / 60 (15.00%)
    5 / 62 (8.06%)
         occurrences all number
    47
    21
    55
    43
    10
    6
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    2 / 137 (1.46%)
    4 / 64 (6.25%)
    5 / 136 (3.68%)
    1 / 104 (0.96%)
    1 / 60 (1.67%)
    4 / 62 (6.45%)
         occurrences all number
    3
    4
    5
    1
    1
    5
    Dry skin
         subjects affected / exposed
    6 / 137 (4.38%)
    8 / 64 (12.50%)
    7 / 136 (5.15%)
    10 / 104 (9.62%)
    4 / 60 (6.67%)
    9 / 62 (14.52%)
         occurrences all number
    6
    8
    7
    10
    4
    9
    Onychoclasis
         subjects affected / exposed
    5 / 137 (3.65%)
    3 / 64 (4.69%)
    6 / 136 (4.41%)
    4 / 104 (3.85%)
    3 / 60 (5.00%)
    6 / 62 (9.68%)
         occurrences all number
    5
    3
    6
    4
    3
    6
    Rash
         subjects affected / exposed
    7 / 137 (5.11%)
    12 / 64 (18.75%)
    15 / 136 (11.03%)
    10 / 104 (9.62%)
    1 / 60 (1.67%)
    8 / 62 (12.90%)
         occurrences all number
    9
    28
    20
    16
    2
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 137 (7.30%)
    14 / 64 (21.88%)
    15 / 136 (11.03%)
    13 / 104 (12.50%)
    9 / 60 (15.00%)
    4 / 62 (6.45%)
         occurrences all number
    11
    17
    18
    15
    12
    4
    Back pain
         subjects affected / exposed
    10 / 137 (7.30%)
    5 / 64 (7.81%)
    9 / 136 (6.62%)
    10 / 104 (9.62%)
    4 / 60 (6.67%)
    2 / 62 (3.23%)
         occurrences all number
    11
    5
    10
    11
    5
    2
    Muscle spasms
         subjects affected / exposed
    15 / 137 (10.95%)
    8 / 64 (12.50%)
    14 / 136 (10.29%)
    15 / 104 (14.42%)
    12 / 60 (20.00%)
    8 / 62 (12.90%)
         occurrences all number
    18
    10
    17
    17
    17
    9
    Myalgia
         subjects affected / exposed
    3 / 137 (2.19%)
    4 / 64 (6.25%)
    6 / 136 (4.41%)
    5 / 104 (4.81%)
    2 / 60 (3.33%)
    3 / 62 (4.84%)
         occurrences all number
    3
    4
    7
    6
    2
    4
    Pain in extremity
         subjects affected / exposed
    7 / 137 (5.11%)
    3 / 64 (4.69%)
    7 / 136 (5.15%)
    5 / 104 (4.81%)
    2 / 60 (3.33%)
    3 / 62 (4.84%)
         occurrences all number
    9
    3
    7
    6
    2
    3
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 137 (1.46%)
    0 / 64 (0.00%)
    3 / 136 (2.21%)
    4 / 104 (3.85%)
    3 / 60 (5.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    3
    4
    3
    0
    Cellulitis
         subjects affected / exposed
    3 / 137 (2.19%)
    1 / 64 (1.56%)
    0 / 136 (0.00%)
    2 / 104 (1.92%)
    3 / 60 (5.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    1
    0
    3
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 137 (3.65%)
    4 / 64 (6.25%)
    2 / 136 (1.47%)
    3 / 104 (2.88%)
    1 / 60 (1.67%)
    1 / 62 (1.61%)
         occurrences all number
    6
    5
    2
    3
    1
    1
    Urinary tract infection
         subjects affected / exposed
    10 / 137 (7.30%)
    2 / 64 (3.13%)
    8 / 136 (5.88%)
    9 / 104 (8.65%)
    6 / 60 (10.00%)
    5 / 62 (8.06%)
         occurrences all number
    10
    2
    9
    12
    9
    6
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 137 (3.65%)
    7 / 64 (10.94%)
    7 / 136 (5.15%)
    5 / 104 (4.81%)
    6 / 60 (10.00%)
    2 / 62 (3.23%)
         occurrences all number
    6
    9
    7
    5
    6
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 137 (18.98%)
    11 / 64 (17.19%)
    24 / 136 (17.65%)
    26 / 104 (25.00%)
    8 / 60 (13.33%)
    8 / 62 (12.90%)
         occurrences all number
    26
    11
    29
    30
    9
    8
    Hypokalaemia
         subjects affected / exposed
    4 / 137 (2.92%)
    1 / 64 (1.56%)
    8 / 136 (5.88%)
    2 / 104 (1.92%)
    1 / 60 (1.67%)
    0 / 62 (0.00%)
         occurrences all number
    5
    1
    9
    2
    1
    0
    Dehydration
         subjects affected / exposed
    7 / 137 (5.11%)
    6 / 64 (9.38%)
    5 / 136 (3.68%)
    4 / 104 (3.85%)
    2 / 60 (3.33%)
    2 / 62 (3.23%)
         occurrences all number
    9
    7
    6
    4
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2015
    Amendment 1 changed the loperamide dosing schedule to regular daytime intervals of three times a day, with the intent of improving patient compliance.
    06 Nov 2015
    Amendment 2 added patient reported outcomes to the data collection performed. The number of assessments of left ventricular ejection fraction (LVEF) with ECHO or MUGA evaluations was also decreased from 6 to 2 (Screening Visit and End of Treatment Visit), based on echocardiogram results from study 3144A2-3004-WW, A Randomized, Double-Blind, Placebo-Controlled Trial of Neratinib (HKI-272) after Trastuzumab in Women with Early-Stage HER-2/neu Overexpressed/Amplified Breast Cancer, showing no LVEF change from baseline to Month 12. Patients enrolled under the Original Protocol, Amendment 1, and Amendment 2 comprised the Loperamide (L) cohort.
    24 Mar 2016
    Amendment 3 added anti-inflammatory treatment to neratinib and loperamide prophylaxis. Budesonide XR 9 mg tablets administered once daily for 1 cycle was added to the 2 cycles of loperamide prophylaxis during neratinib therapy. Two additional anti-inflammatory medication cohorts, mesalamine and bismuth subsalicylate, were also added by Amendment 3, but these cohorts were subsequently terminated in Amendment 5 without enrollment (new information was reviewed by the Sponsor, in addition to the availability of results from recent sets of preclinical data which were discussed with external expert consultants, which indicated that the bile acid sequestrant colestipol would be more effective in mitigating diarrhea than either bismuth subsalicylate or mesalamine). Patients enrolled under Amendment 3 comprised the Budesonide+Loperamide (BL) cohort.
    19 Aug 2016
    Amendment 4 added colestipol (a bile acid sequestrant), using a regimen of two 1 g tablets administered twice daily to neratinib and intensive loperamide prophylaxis for 1 cycle based on the results of preclinical rat model studies, which suggested the possible implication of bile acid malabsorption. Patients enrolled under Amendment 4 comprised the Colestipol+Loperamide (CL) cohort.
    19 Sep 2017
    Amendment 5 used the same colestipol treatment regimen as Amendment 4, but loperamide was to be taken on a PRN basis only. Patients enrolled under Amendment 5 comprised the Colestipol+Loperamide PRN (CL-PRN) cohort.
    26 Oct 2017
    Amendment 6 introduced a design to evaluate the effects of a more gradual neratinib titration regimen (ie, 120 mg daily from C1D1-C1D7, to 160 mg daily from C1D8-C1D14, then 240 mg daily on C1D15 thereafter) on the incidence of severe diarrhea. Amendment 6.1 (30-APR-2018) added another patient reported outcome to the data collection. Patients enrolled under Amendment 6 and 6.1 comprised the Dose Escalation (DE) cohort.
    08 Oct 2018
    Amendment 7 was designed to investigate the effect of a second dose escalation scheme on the incidence and severity of diarrhea. Patients in this cohort were started at 160 mg daily neratinib for the first 2 weeks of treatment followed by 200 mg daily neratinib for the subsequent 2 weeks of dosing, then reaching the full 240 mg daily dose of neratinib from Cycle 2 onwards. An inclusion criteria requirement was also added by this amendment to require documented hormone receptor (HR)-positive disease, defined as estrogen receptor (ER) positive and/or progesterone receptor (PR) positive disease; however, this requirement was later removed for North America and Australia in regional Amendment 7.1 (25-JUL-2019). Patients enrolled under Amendment 7 and 7.1 comprised the Dose Escalation 2 (DE2) cohort.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Mar 2020
    The study indefinitely paused screening and enrollment of new patients on 23-Mar-2020 in response to the global COVID-19 pandemic. In September 2020, enrollment was formally closed due to the study having achieved its scientific objective. There were sufficient data to analyze the primary endpoint of the study and other key variables. All remaining active ongoing patients continued to receive per protocol treatment and care according to study protocol, and relevant country and/or institutional COVID-19 pandemic guidelines.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32464281
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