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    Clinical Trial Results:
    A Phase 1 / 2 Study of HKI-272 in combination With Paclitaxel in Subjects With Solid Tumors and Breast Cancer

    Summary
    EudraCT number
    2006-006412-29
    Trial protocol
    BE  
    Global end of trial date
    07 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Feb 2019
    First version publication date
    24 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3144A1-203-WW
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00445458
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Puma Biotechnology, Inc.
    Sponsor organisation address
    10880 Wilshire Blvd, Los Angeles, United States, 90024
    Public contact
    Clinical Operations Senior Director, Puma Biotechnology, Inc., 1 4242486500, clinicaltrials@pumabiotechnology.com
    Scientific contact
    Clinical Operations Senior Director, 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
    07 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1: The primary objectives of part 1 are to assess the safety and tolerability, and to define the maximum tolerated dose (MTD) of HKI-272 in combination with paclitaxel in subjects with advanced solid tumors Part 2: The primary objective of part 2 of this study is to estimate the overall response rate (ORR) for subjects with HER2 positive breast cancer treated at the MTD of HKI-272 in combination with paclitaxel.
    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) if patient required more than 2 dose reductions of neratinib, or if 120 mg of neratinib was not tolerable, or if the subject had not recovered from treatment-related toxicity after >3 weeks; disease progression, pregnancy, or patient request.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Sep 2007
    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
    Ukraine: 11
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    China: 42
    Country: Number of subjects enrolled
    Hong Kong: 15
    Country: Number of subjects enrolled
    India: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Poland: 8
    Worldwide total number of subjects
    110
    EEA total number of subjects
    12
    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)
    105
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Informed consent was obtained before any protocol required assessments were performed. Subjects who signed informed consent, but fail to meet inclusion/exclusion criteria or withdrew consent prior to receiving any study medication were considered screen failures.

    Period 1
    Period 1 title
    Treatment Period (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
    Part 1 Ner160 + Paclitaxel
    Arm description
    Neratinib 160 mg orally once daily every day, in combination with paclitaxel 80 mg/m^2 intravenous infusion on days 1, 8 and 15 of a 28-day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 Neratinib 80-mg capsules or 4 40-mg tablets taken 1 daily, with food, preferably in the morning, during each 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Within each 28-day cycle, paclitaxel (80 mg/m2) was to be intravenously infused (over approximately 1 hour) on Days 1, 8, and 15 (Table 8).

    Arm title
    Part 1 Ner240 + Paclitaxel
    Arm description
    Neratinib 240 mg orally once daily every day, in combination with paclitaxel 80 mg/m^2 intravenous infusion on days 1, 8 and 15 of a 28-day cycle.
    Arm type
    Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib capsules or tablets (80 mg and/or 40 mg, as appropriate) were taken orally once daily, with food, preferably in the morning during each 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Within each 28-day cycle, paclitaxel (80 mg/m2) was to be intravenously infused (over approximately 1 hour) on Days 1, 8, and 15.

    Arm title
    Part 2 Ner240 + Paclitaxel ArmA
    Arm description
    Neratinib (MTD, 240 mg) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease.
    Arm type
    Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib capsules or tablets (80 mg and/or 40 mg, as appropriate) were taken orally once daily, with food, preferably in the morning during each 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Within each 28-day cycle, paclitaxel (80 mg/m2) was to be intravenously infused (over approximately 1 hour) on Days 1, 8, and 15.

    Arm title
    Part 2 Ner240 + Paclitaxel ArmB
    Arm description
    Neratinib (MTD, 240 mg) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 3 prior cytotoxic chemotherapy treatment regimen for metastatic disease.
    Arm type
    Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib capsules or tablets (80 mg and/or 40 mg, as appropriate) were taken orally once daily, with food, preferably in the morning during each 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Within each 28-day cycle, paclitaxel (80 mg/m2) was to be intravenously infused (over approximately 1 hour) on Days 1, 8, and 15.

    Number of subjects in period 1
    Part 1 Ner160 + Paclitaxel Part 1 Ner240 + Paclitaxel Part 2 Ner240 + Paclitaxel ArmA Part 2 Ner240 + Paclitaxel ArmB
    Started
    3
    5
    71
    31
    Completed
    0
    0
    0
    0
    Not completed
    3
    5
    71
    31
         Disease Progression
    3
    4
    54
    28
         Physician decision
    -
    -
    1
    1
         Adverse event, serious fatal
    -
    1
    2
    -
         Adverse event, non-fatal
    -
    -
    4
    -
         Surgical Procedure
    -
    -
    1
    -
         Study Discontinued by Sponsor
    -
    -
    1
    1
         Consent withdrawn by subject
    -
    -
    8
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period
    Reporting group description
    -

    Reporting group values
    Treatment Period Total
    Number of subjects
    110 110
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    105 105
        From 65-84 years
    5 5
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.6 ± 9.8 -
    Gender categorical
    Units: Subjects
        Female
    105 105
        Male
    5 5

    End points

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    End points reporting groups
    Reporting group title
    Part 1 Ner160 + Paclitaxel
    Reporting group description
    Neratinib 160 mg orally once daily every day, in combination with paclitaxel 80 mg/m^2 intravenous infusion on days 1, 8 and 15 of a 28-day cycle.

    Reporting group title
    Part 1 Ner240 + Paclitaxel
    Reporting group description
    Neratinib 240 mg orally once daily every day, in combination with paclitaxel 80 mg/m^2 intravenous infusion on days 1, 8 and 15 of a 28-day cycle.

    Reporting group title
    Part 2 Ner240 + Paclitaxel ArmA
    Reporting group description
    Neratinib (MTD, 240 mg) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 1 prior cytotoxic chemotherapy treatment regimen for metastatic disease.

    Reporting group title
    Part 2 Ner240 + Paclitaxel ArmB
    Reporting group description
    Neratinib (MTD, 240 mg) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than 3 prior cytotoxic chemotherapy treatment regimen for metastatic disease.

    Primary: Objective Response Rate. Part 2 of Study

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    End point title
    Objective Response Rate. Part 2 of Study [1]
    End point description
    Subjects with partial response (PR) or complete response (CR) with ERBB2 positive breast cancer treated at the maximum tolerated dose (MTD) of neratinib in combination with paclitaxel, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; PR, >=30% decrease in the sum of the longest diameter of target lesions; and no progressive disease (PD) for non-target lesions, and no new lesions.
    End point type
    Primary
    End point timeframe
    From first dose date to progression or last tumor assessment, up to 140 weeks
    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: There was no preplanned hypothesis testing. The objective of the study was to estimate the objective response rate within each arm.
    End point values
    Part 1 Ner160 + Paclitaxel Part 1 Ner240 + Paclitaxel Part 2 Ner240 + Paclitaxel ArmA Part 2 Ner240 + Paclitaxel ArmB
    Number of subjects analysed
    0 [2]
    0 [3]
    68
    31
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    ( to )
    70.6 (58.3 to 81.0)
    77.4 (58.9 to 90.4)
    Notes
    [2] - Objective Response Rate was measured and assessed in Part 2 of the study only.
    [3] - Objective Response Rate was measured and assessed in Part 2 of the study only.
    No statistical analyses for this end point

    Primary: Number of Subjects with Dose Limiting Toxicities Part 1

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    End point title
    Number of Subjects with Dose Limiting Toxicities Part 1 [4]
    End point description
    Dose Limiting Toxicity in subjects with solid tumors treated with neratinib, administered daily, in combination with paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle, for subjects in Part 1 of the study.
    End point type
    Primary
    End point timeframe
    From first dose date through day 28.
    Notes
    [4] - 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: The objective of this endpoint was to assess the maximum tolerated dose (MTD) of neratinib. There was no preplanned hypothesis testing.
    End point values
    Part 1 Ner160 + Paclitaxel Part 1 Ner240 + Paclitaxel Part 2 Ner240 + Paclitaxel ArmA Part 2 Ner240 + Paclitaxel ArmB
    Number of subjects analysed
    3
    5
    0 [5]
    0 [6]
    Units: Patients
    0
    0
    Notes
    [5] - DLTs were collected in Part 1 of the study only, in order to determine the Maximum Dose for Part 2.
    [6] - DLTs were collected in Part 1 of the study only, in order to determine the Maximum Dose for Part 2.
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve 0-24

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    End point title
    Area Under the Concentration-time Curve 0-24
    End point description
    Area under the concentration-time curve of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points.
    End point type
    Secondary
    End point timeframe
    Area under the concentration-time curve of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points.
    End point values
    Part 1 Ner160 + Paclitaxel Part 1 Ner240 + Paclitaxel Part 2 Ner240 + Paclitaxel ArmA Part 2 Ner240 + Paclitaxel ArmB
    Number of subjects analysed
    3
    4
    63
    27
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    684 ± 92
    1488 ± 29
    1239 ± 63
    1331 ± 61
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration of Neratinib

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    End point title
    Maximum Plasma Concentration of Neratinib
    End point description
    Maximum plasma concentration of neratinib; after each dosing of neratinib on Cycle 1 of Day 15, blood samples taken at regular time points.
    End point type
    Secondary
    End point timeframe
    Samples taken at 0 hour and at 1, 2, 4, 6, 8, and 24 hours postdose on Day 15 of Cycle 1, and 1 predose sample on Day 1 in Cycle 1.
    End point values
    Part 1 Ner160 + Paclitaxel Part 1 Ner240 + Paclitaxel Part 2 Ner240 + Paclitaxel ArmA Part 2 Ner240 + Paclitaxel ArmB
    Number of subjects analysed
    3
    4
    63
    27
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    66.78 ± 25
    91.74 ± 41
    80.31 ± 55
    79.13 ± 61
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose through 28 days after last dose
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Part 1 Ner160 + Paclitaxel
    Reporting group description
    Neratinib 160 mg orally once daily every day, in combination with paclitaxel 80 mg/m^2 intravenous infusion on days 1, 8 and 15 of a 28-day cycle.

    Reporting group title
    Part 1 Ner240 + Paclitaxel
    Reporting group description
    Neratinib 240 mg orally once daily every day, in combination with paclitaxel 80 mg/m^2 intravenous infusion on days 1, 8 and 15 of a 28-day cycle.

    Reporting group title
    Part 2 Ner240 + Paclitaxel ArmA
    Reporting group description
    Neratinib (MTD) qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than1 prior cytotoxic chemotherapy treatment regimen for metastatic disease

    Reporting group title
    Part 2 Ner240 + Paclitaxel ArmB
    Reporting group description
    Neratinib 240 mg qd + Paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28 day cycle for subjects with not more than3 prior cytotoxic chemotherapy treatment regimen for metastatic disease.

    Serious adverse events
    Part 1 Ner160 + Paclitaxel Part 1 Ner240 + Paclitaxel Part 2 Ner240 + Paclitaxel ArmA Part 2 Ner240 + Paclitaxel ArmB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 5 (80.00%)
    27 / 71 (38.03%)
    4 / 31 (12.90%)
         number of deaths (all causes)
    0
    1
    5
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    4 / 71 (5.63%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    2 / 71 (2.82%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    2 / 71 (2.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    0 / 71 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    6 / 71 (8.45%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    2 / 71 (2.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Ingrowing nail
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    2 / 71 (2.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    2 / 71 (2.82%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part 1 Ner160 + Paclitaxel Part 1 Ner240 + Paclitaxel Part 2 Ner240 + Paclitaxel ArmA Part 2 Ner240 + Paclitaxel ArmB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    5 / 5 (100.00%)
    70 / 71 (98.59%)
    31 / 31 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    1 / 71 (1.41%)
    1 / 31 (3.23%)
         occurrences all number
    0
    2
    1
    1
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    5 / 71 (7.04%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    6
    2
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 5 (40.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences all number
    2
    3
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    13 / 71 (18.31%)
    7 / 31 (22.58%)
         occurrences all number
    0
    0
    21
    13
    Axillary pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    16 / 71 (22.54%)
    6 / 31 (19.35%)
         occurrences all number
    2
    3
    36
    11
    Generalised oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    3
    Local swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    1
    4
    Malaise
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 5 (40.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    6 / 71 (8.45%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    30
    4
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    13 / 71 (18.31%)
    5 / 31 (16.13%)
         occurrences all number
    0
    2
    20
    7
    Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    2 / 71 (2.82%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    2
    1
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    18 / 71 (25.35%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    35
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    3
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    10 / 71 (14.08%)
    6 / 31 (19.35%)
         occurrences all number
    0
    0
    21
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    9 / 71 (12.68%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    18
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood urine present
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    10 / 71 (14.08%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    22
    2
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    4 / 71 (5.63%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    9
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    16 / 71 (22.54%)
    2 / 31 (6.45%)
         occurrences all number
    1
    1
    29
    2
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    9 / 71 (12.68%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    19
    1
    Epistaxis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    5 / 71 (7.04%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    5
    1
    Nasal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    4 / 71 (5.63%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    3 / 71 (4.23%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    6
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 5 (40.00%)
    24 / 71 (33.80%)
    12 / 31 (38.71%)
         occurrences all number
    5
    4
    69
    50
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    29 / 71 (40.85%)
    15 / 31 (48.39%)
         occurrences all number
    0
    0
    166
    104
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    37 / 71 (52.11%)
    17 / 31 (54.84%)
         occurrences all number
    0
    2
    143
    96
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    4 / 71 (5.63%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    6
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    7 / 71 (9.86%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    9
    5
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    10 / 71 (14.08%)
    5 / 31 (16.13%)
         occurrences all number
    0
    0
    15
    11
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 5 (20.00%)
    36 / 71 (50.70%)
    17 / 31 (54.84%)
         occurrences all number
    4
    1
    60
    27
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    3 / 71 (4.23%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    3
    4
    Abdominal distension
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 5 (20.00%)
    5 / 71 (7.04%)
    1 / 31 (3.23%)
         occurrences all number
    1
    1
    6
    2
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    8 / 71 (11.27%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    11
    7
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    10 / 71 (14.08%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    14
    4
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    3 / 71 (4.23%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    3
    1
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 5 (100.00%)
    65 / 71 (91.55%)
    29 / 31 (93.55%)
         occurrences all number
    12
    13
    389
    190
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    4 / 71 (5.63%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    4
    2
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    8 / 71 (11.27%)
    4 / 31 (12.90%)
         occurrences all number
    0
    2
    12
    4
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    5 / 71 (7.04%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    8
    3
    Gingival ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    2 / 71 (2.82%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    5
    5
    Mouth ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    5 / 71 (7.04%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    10
    0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 5 (80.00%)
    26 / 71 (36.62%)
    7 / 31 (22.58%)
         occurrences all number
    0
    6
    83
    9
    Rectal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    13 / 71 (18.31%)
    5 / 31 (16.13%)
         occurrences all number
    0
    1
    18
    10
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 5 (60.00%)
    20 / 71 (28.17%)
    4 / 31 (12.90%)
         occurrences all number
    0
    4
    86
    7
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    3 / 71 (4.23%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Hydronephrosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 5 (40.00%)
    37 / 71 (52.11%)
    12 / 31 (38.71%)
         occurrences all number
    0
    2
    40
    15
    Decubitus ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    1
    9
    Dry skin
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Nail disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    2 / 71 (2.82%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    4
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    2 / 71 (2.82%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    2
    5
    Pigmentation disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    2
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    7 / 71 (9.86%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    9
    5
    Rash
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 5 (40.00%)
    21 / 71 (29.58%)
    8 / 31 (25.81%)
         occurrences all number
    1
    2
    31
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    6 / 71 (8.45%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    13
    0
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    3 / 71 (4.23%)
    5 / 31 (16.13%)
         occurrences all number
    1
    0
    4
    6
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    5 / 71 (7.04%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    8
    1
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    3 / 71 (4.23%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    3
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    3 / 71 (4.23%)
    3 / 31 (9.68%)
         occurrences all number
    0
    2
    7
    5
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    8 / 71 (11.27%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    10
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 5 (60.00%)
    16 / 71 (22.54%)
    8 / 31 (25.81%)
         occurrences all number
    1
    4
    36
    17
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    6 / 71 (8.45%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    8
    3
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    7 / 71 (9.86%)
    3 / 31 (9.68%)
         occurrences all number
    0
    1
    33
    4
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    1 / 71 (1.41%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hypophagia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    2
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    4
    Gastroenteritis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 5 (0.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    4 / 71 (5.63%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    10
    1
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    6 / 71 (8.45%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    7
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    7 / 71 (9.86%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    27
    10
    Oral herpes
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 71 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    3 / 71 (4.23%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    3
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    9 / 71 (12.68%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    11
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    10 / 71 (14.08%)
    5 / 31 (16.13%)
         occurrences all number
    0
    2
    17
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jun 2007
    This protocol includes removal of lung and pancreatic cancer subjects and docetaxel treatment, addition of paclitaxel treatment, increased PK testing, additional secondary outcomes, expanded definition of dose limiting toxicity, change to number of subjects enrolled, eligibility criteria and other administrative updates.
    12 Dec 2007
    This protocol includes changes to exclusion criteria, study procedures, study drug administration, growth factor guidelines, PK testing, and other administrative updates.
    18 Mar 2008
    This protocol includes updates to study design, including addition of a second arm B (non-randomized) to Part 2, exclusion criterion changed to allow enrollment of subjects with prior lapatinib exposure in Arm B of Part 2. The sample size for Arm B of Part 2 included approximately 25 subjects, with a total number of 95 subjects enrolled in study. The number of sites increased to approximately 30. Temperature for storing PK samples was updated from -70°C to -20°C. Statistical considerations and study procedures and other administrative updates were also included.
    08 Feb 2010
    This protocol includes updates to the following sections: study rationale, length of treatment period, instructions for co-administration of neratinib and digoxin, additional blood chemistry and coagulation tests and other administrative updates.
    05 Apr 2011
    This protocol includes the addition of a treatment extension period and associated study procedures and other administrative updates.
    22 Mar 2012
    This protocol includes addition of a revised treatment extension period which decreases the efficacy assessments for those subjects that continue to receive clinical benefit, along with other administrative updates.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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