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    Clinical Trial Results:
    A Phase 1/2 Study of Neratinib (HKI-272) in Combination with Vinorelbine in Subjects with Solid Tumors and Metastatic Breast Cancer

    Summary
    EudraCT number
    2007-007885-39
    Trial protocol
    BE   PL   FR   NL   GB   SE  
    Global end of trial date
    07 Jun 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    06 Jul 2019
    First version publication date
    25 Dec 2016
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Update to reflect final study close out.
    Summary report(s)
    3144A1-2204 PDS

    Trial information

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    Trial identification
    Sponsor protocol code
    3144A1-2204-WW
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00706030
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Puma Biotechnology, Inc.
    Sponsor organisation address
    10880 Wilshire Blvd, Suite 2150, Los Angeles, United States, 90024
    Public contact
    Senior Director, Clinical Operations, Puma Biotechnology, Inc, 001 4242486550, clinicaltrials@pumabiotechnology.com
    Scientific contact
    Senior Director, Clinical Operations, Puma Biotechnology, Inc, 001 4242486550, 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 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 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 of the study are to assess the safety and tolerability and to define the maximum tolerated dose (MTD) of HKI-272 in combination with vinorelbine in subjects with advanced solid tumors. Part 2: The primary objective of part 2 of the study is to estimate the ORR for subjects with ErbB-2-positive breast cancer treated at the MTD of HKI-272 in combination with vinorelbine. Treatment Extension Period: The primary objective of the Treatment Extension Period is to provide continuous treatment to patients who continue to derive clinical benefit from study participation after the Part 2 objectives have been reached.
    Protection of trial subjects
    This study was designed and monitored in accordance with Sponsor procedures, which comply with the ethical principles of the International Council for Harmonisation (ICH) Good Clinical Practice (GCP), including the Declaration of Helsinki and the applicable laws and regulations. The protocol, the investigator’s brochure, and the informed consent form (ICF) for this clinical study were submitted to an institutional review board (IRB) or an independent ethics committee (IEC) for review and written approval. Any subsequent amendments to the protocol or any revisions to the ICF were submitted for IRB or IEC review and written approval. This study was conducted in accordance with the ICH Guideline for GCP and the ethical principles that have their origins in the Declaration of Helsinki. All investigators have provided written commitments to comply with GCP standards and the protocol. 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 may discontinued or were withdrawn from the study if any of the following occurred: documented disease progression; need for bisphosphonates during treatment period or palliative radiation therapy, if progressive disease was not ruled out, including whole-brain irradiation for documented central nervous system disease; required treatment with prohibited concomitant therapy; next dose was withheld for longer than 3 consecutive weeks due to test article-related toxicity; need for more than 2 dose reductions of neratinib and/or vinorelbine; any Grade 4 nonhematologic toxicity that was test article related; and pregnancy.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Apr 2008
    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
    Belgium: 16
    Country: Number of subjects enrolled
    China: 16
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    91
    EEA total number of subjects
    50
    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)
    79
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects had to meet all inclusion criteria and not meet any exclusion criteria to participate in this study. A signed and dated informed consent was required before any screen procedures were done.

    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 + Vinorelbine
    Arm description
    In Part 1, subjects with advanced solid tumors were to be enrolled in the dose group Ner160mg+Vinorelbine. AEs and DLTs were assessed from the first dose of test article through Day 21. A DLT was defined as any of the following related drug: 1) Grade 3 or 4 nonhematologic toxicity. 2) Grade 3 diarrhea lasting >2 days while the subject was on optimal medical therapy or that was associated with fever or dehydration. 3) Grade 4 neutropenia lasting 7 or more days or Grade 4 febrile neutropenia. 4) Grade 4 thrombocytopenia lasting 3 or more days or complicated with bleeding. 5) Delayed recovery (to NCI) Grade <=1 or Baseline) from 1 of of the above listed toxicities related to combo and delayed next dose by more than 3 weeks.
    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
    4 neratinib 40-mg tables, taken with food, preferably in the morning.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m2 intravenous on day 1 and day 8 of a 21-day cycle.

    Arm title
    Part 1 Ner240 + Vinorelbine
    Arm description
    In Part 1, subjects with advanced solid tumors were to be enrolled in the dose group Ner240mg+Vinorelbine. AEs and DLTs were assessed from the first dose of test article through Day 21. A DLT was defined as any of the following related drug: 1) Grade 3 or 4 nonhematologic toxicity. 2) Grade 3 diarrhea lasting >2 days while the subject was on optimal medical therapy or that was associated with fever or dehydration. 3) Grade 4 neutropenia lasting 7 or more days or Grade 4 febrile neutropenia. 4) Grade 4 thrombocytopenia lasting 3 or more days or complicated with bleeding. 5) Delayed recovery (to NCI) Grade <=1 or Baseline) from 1 of of the above listed toxicities related to combo and delayed next dose by more than 3 weeks.
    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
    1 neratinib 240-mg tables, taken with food, preferably in the morning.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m2 intravenous on day 1 and day 8 of a 21-day cycle.

    Arm title
    Part 2 Ner240 + Vinorelbine, no Prior Lap
    Arm description
    Neratinib 240 mg qd + Vinorelbine 25 mg/m2 IV on day 1 and 8 of a 21 day cycle; patients who had not received prior lapatinib.
    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
    1 neratinib 240-mg tables, taken with food, preferably in the morning.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m2 intravenous on day 1 and day 8 of a 21-day cycle.

    Arm title
    Part 2 Ner240 + Vinorelbine, Prior Lap
    Arm description
    Neratinib 240 mg qd + Vinorelbine 25 mg/m2 IV on day 1 and 8 of a 21 day cycle; patients who had received prior lapatinib.
    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
    1 neratinib 240-mg tables, taken with food, preferably in the morning.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m2 intravenous on day 1 and day 8 of a 21-day cycle.

    Number of subjects in period 1
    Part 1 Ner160 + Vinorelbine Part 1 Ner240 + Vinorelbine Part 2 Ner240 + Vinorelbine, no Prior Lap Part 2 Ner240 + Vinorelbine, Prior Lap
    Started
    6
    6
    64
    15
    Completed
    0
    0
    0
    0
    Not completed
    6
    6
    64
    15
         Protocol deviation
    -
    -
    2
    1
         Disease Progression
    4
    6
    46
    12
         Physician decision
    -
    -
    3
    -
         Symptomatic Deterioration
    -
    -
    1
    -
         Study discontinued by sponsor
    -
    -
    1
    -
         Adverse event, serious fatal
    -
    -
    1
    -
         Adverse event, non-fatal
    1
    -
    4
    2
         Consent withdrawn by subject
    1
    -
    5
    -
         Lost to follow-up
    -
    -
    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
    91 91
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.6 ± 10.8 -
    Gender categorical
    Units: Subjects
        Female
    89 89
        Male
    2 2

    End points

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    End points reporting groups
    Reporting group title
    Part 1 Ner160 + Vinorelbine
    Reporting group description
    In Part 1, subjects with advanced solid tumors were to be enrolled in the dose group Ner160mg+Vinorelbine. AEs and DLTs were assessed from the first dose of test article through Day 21. A DLT was defined as any of the following related drug: 1) Grade 3 or 4 nonhematologic toxicity. 2) Grade 3 diarrhea lasting >2 days while the subject was on optimal medical therapy or that was associated with fever or dehydration. 3) Grade 4 neutropenia lasting 7 or more days or Grade 4 febrile neutropenia. 4) Grade 4 thrombocytopenia lasting 3 or more days or complicated with bleeding. 5) Delayed recovery (to NCI) Grade <=1 or Baseline) from 1 of of the above listed toxicities related to combo and delayed next dose by more than 3 weeks.

    Reporting group title
    Part 1 Ner240 + Vinorelbine
    Reporting group description
    In Part 1, subjects with advanced solid tumors were to be enrolled in the dose group Ner240mg+Vinorelbine. AEs and DLTs were assessed from the first dose of test article through Day 21. A DLT was defined as any of the following related drug: 1) Grade 3 or 4 nonhematologic toxicity. 2) Grade 3 diarrhea lasting >2 days while the subject was on optimal medical therapy or that was associated with fever or dehydration. 3) Grade 4 neutropenia lasting 7 or more days or Grade 4 febrile neutropenia. 4) Grade 4 thrombocytopenia lasting 3 or more days or complicated with bleeding. 5) Delayed recovery (to NCI) Grade <=1 or Baseline) from 1 of of the above listed toxicities related to combo and delayed next dose by more than 3 weeks.

    Reporting group title
    Part 2 Ner240 + Vinorelbine, no Prior Lap
    Reporting group description
    Neratinib 240 mg qd + Vinorelbine 25 mg/m2 IV on day 1 and 8 of a 21 day cycle; patients who had not received prior lapatinib.

    Reporting group title
    Part 2 Ner240 + Vinorelbine, Prior Lap
    Reporting group description
    Neratinib 240 mg qd + Vinorelbine 25 mg/m2 IV on day 1 and 8 of a 21 day cycle; patients who had received prior lapatinib.

    Primary: Objective Response Rate - Part 2

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    End point title
    Objective Response Rate - Part 2 [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    hold
    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 comparisons between the 2 groups in Part 2 of the study were planned for the objective response rate.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy assessments to derive the objective response rate were collected only for subjects in Part 2.
    End point values
    Part 2 Ner240 + Vinorelbine, no Prior Lap Part 2 Ner240 + Vinorelbine, Prior Lap
    Number of subjects analysed
    56 [3]
    12 [4]
    Units: percentage
        number (confidence interval 95%)
    58.9 (45.0 to 71.9)
    50 (21.1 to 78.9)
    Notes
    [3] - Evaluable population.
    [4] - Evaluable Population
    No statistical analyses for this end point

    Primary: Number of Patients with Dose Limiting Toxicities

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    End point title
    Number of Patients with Dose Limiting Toxicities [5] [6]
    End point description
    End point type
    Primary
    End point timeframe
    From Day 1 of dose through Day 21
    Notes
    [5] - 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: Part 1 of the study was dose escalation and there were no comparisons planned between treatment groups.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Dose limiting toxicities only collected in Part 1 of the study.
    End point values
    Part 1 Ner160 + Vinorelbine Part 1 Ner240 + Vinorelbine
    Number of subjects analysed
    6
    6
    Units: Patients
    1
    0
    No statistical analyses for this end point

    Secondary: AUC at Day 21 Neratinib

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    End point title
    AUC at Day 21 Neratinib [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic samples were collected only for subjects in Part 2.
    End point values
    Part 2 Ner240 + Vinorelbine, no Prior Lap Part 2 Ner240 + Vinorelbine, Prior Lap
    Number of subjects analysed
    57
    13
    Units: ng*h/mL
        number (confidence interval 95%)
    1945 (1514 to 2374)
    2136 (794 to 3478)
    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
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    P1 N160+V25
    Reporting group description
    Part 1 Ner160 + Vinorelbine 25 mg/m2

    Reporting group title
    P1 N2400+V25
    Reporting group description
    Part 1 Ner240 + Vinorelbine 25 mg/m2

    Reporting group title
    P2 N2400+V25 NPL
    Reporting group description
    Neratinib 240 mg qd + Vinorelbine 25 mg/m2 IV on day 1 and 8 of a 21 day cycle; patients who had not received prior lapatinib

    Reporting group title
    P2 N2400+V25 PL
    Reporting group description
    Neratinib 240 mg qd + Vinorelbine 25 mg/m2 IV on day 1 and 8 of a 21 day cycle; patients who had received prior lapatinib

    Serious adverse events
    P1 N160+V25 P1 N2400+V25 P2 N2400+V25 NPL P2 N2400+V25 PL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    21 / 64 (32.81%)
    5 / 15 (33.33%)
         number of deaths (all causes)
    0
    2
    2
    1
         number of deaths resulting from adverse events
    0
    2
    1
    1
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Phlebitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (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
    Vena cava thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Surgical and medical procedures
    Mastectomy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Cardiac myxoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Malignant melanoma
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (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 / 1
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 64 (4.69%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (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 / 1
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         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 / 1
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Humerus fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Amylase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         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
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         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
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (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
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Brain oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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 / 1
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 64 (4.69%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Hepatic pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (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
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         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
    Ureteric haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    Erysipelas
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (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
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    0 / 15 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    P1 N160+V25 P1 N2400+V25 P2 N2400+V25 NPL P2 N2400+V25 PL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    64 / 64 (100.00%)
    15 / 15 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Hypotension
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 64 (4.69%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour associated fever
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tumour pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    16 / 64 (25.00%)
    5 / 15 (33.33%)
         occurrences all number
    0
    4
    48
    11
    Chest discomfort
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Fatigue
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    24 / 64 (37.50%)
    4 / 15 (26.67%)
         occurrences all number
    3
    4
    72
    6
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 64 (7.81%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    9
    1
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    6
    2
    Mucosal inflammation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    12 / 64 (18.75%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    26
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    7 / 64 (10.94%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    10
    3
    Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    3
    1
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    19 / 64 (29.69%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    33
    3
    Thrombosis in device
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    5 / 64 (7.81%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    6
    0
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 64 (4.69%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    3
    1
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 64 (7.81%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    15
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Menstruation irregular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Ovarian cyst
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Wound complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    12 / 64 (18.75%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    41
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    9 / 64 (14.06%)
    4 / 15 (26.67%)
         occurrences all number
    1
    0
    29
    7
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    4
    Blood magnesium decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    10
    4
    Haemoglobin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    15
    4
    High density lipoprotein decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    Red blood cells urine
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    4 / 64 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    4
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 64 (7.81%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    25
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 64 (7.81%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    13 / 64 (20.31%)
    3 / 15 (20.00%)
         occurrences all number
    1
    1
    23
    3
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    7 / 64 (10.94%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    8
    4
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    5 / 64 (7.81%)
    1 / 15 (6.67%)
         occurrences all number
    0
    4
    6
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    6
    1
    Pleural effusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    8
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    15 / 64 (23.44%)
    5 / 15 (33.33%)
         occurrences all number
    3
    2
    78
    9
    Leukopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    21 / 64 (32.81%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    130
    14
    Neutropenia
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    36 / 64 (56.25%)
    9 / 15 (60.00%)
         occurrences all number
    5
    1
    187
    36
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Balance disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    11 / 64 (17.19%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    15
    3
    Dysgeusia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    6 / 64 (9.38%)
    0 / 15 (0.00%)
         occurrences all number
    4
    1
    7
    0
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    18 / 64 (28.13%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    33
    6
    Hypoaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    6
    1
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    9 / 64 (14.06%)
    2 / 15 (13.33%)
         occurrences all number
    2
    0
    14
    4
    Paraesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 64 (7.81%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    9 / 64 (14.06%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    14
    0
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 64 (4.69%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    5
    3
    Eye irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Retinal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Scleral haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    5 / 64 (7.81%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    6
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    7
    0
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    22 / 64 (34.38%)
    4 / 15 (26.67%)
         occurrences all number
    1
    2
    35
    6
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    8 / 64 (12.50%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    9
    6
    Ascites
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 6 (83.33%)
    10 / 64 (15.63%)
    3 / 15 (20.00%)
         occurrences all number
    5
    6
    19
    3
    Diarrhoea
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    61 / 64 (95.31%)
    15 / 15 (100.00%)
         occurrences all number
    32
    12
    322
    87
    Dyspepsia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    5 / 64 (7.81%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    10
    0
    Gingival ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    6 / 64 (9.38%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    8
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    10 / 64 (15.63%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    14
    3
    Nausea
         subjects affected / exposed
    4 / 6 (66.67%)
    3 / 6 (50.00%)
    35 / 64 (54.69%)
    7 / 15 (46.67%)
         occurrences all number
    7
    3
    87
    17
    Stomatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    8 / 64 (12.50%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    12
    4
    Tongue discolouration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    23 / 64 (35.94%)
    10 / 15 (66.67%)
         occurrences all number
    4
    4
    46
    16
    Renal and urinary disorders
    Bladder prolapse
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chromaturia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Haemoglobinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Leukocyturia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    3
    Renal failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Ureteric haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    12 / 64 (18.75%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    14
    1
    Blister
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    2
    Dermatitis acneiform
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 64 (4.69%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    1
    Dry skin
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    7 / 64 (10.94%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    10
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nail disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    5
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    10 / 64 (15.63%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    19
    0
    Skin fissures
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 64 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    4
    2
    Skin toxicity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 6 (66.67%)
    0 / 6 (0.00%)
    6 / 64 (9.38%)
    2 / 15 (13.33%)
         occurrences all number
    4
    0
    6
    7
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    7 / 64 (10.94%)
    0 / 15 (0.00%)
         occurrences all number
    1
    3
    10
    0
    Bone pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 64 (4.69%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    4
    1
    Muscle spasms
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    12 / 64 (18.75%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    19
    0
    Muscular weakness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    6
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    3
    1
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    10 / 64 (15.63%)
    3 / 15 (20.00%)
         occurrences all number
    0
    1
    17
    8
    Neck pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 64 (3.13%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    4 / 64 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    5
    1
    4
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    20 / 64 (31.25%)
    7 / 15 (46.67%)
         occurrences all number
    2
    4
    33
    12
    Dehydration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    4 / 64 (6.25%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    6
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    5 / 64 (7.81%)
    5 / 15 (33.33%)
         occurrences all number
    0
    0
    10
    7
    Hyponatraemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    7
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 64 (1.56%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    1
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 64 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    9 / 64 (14.06%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    11
    1
    Oral herpes
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 64 (4.69%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    3
    Pharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    7 / 64 (10.94%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    8
    0
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 64 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    7 / 64 (10.94%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    8
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    6 / 64 (9.38%)
    3 / 15 (20.00%)
         occurrences all number
    1
    3
    8
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2008
    Amendment 1: Updated inclusion and exclusion criteria, dose limiting toxicity rules, dose adjustment rules, and the definition of the evaluable population.
    09 Dec 2008
    Amendment 2: Allowed enrollment of subjects who had relapsed under adjuvant treatment and those subjects who had skin disease (ie, as long as the skin lesions were measurable by CT/MRI). It was also amended to add CISH as an ErbB-2 testing method, extend the window for performing testing, to harmonize the reporting of medication errors, and to allow the use of neratinib 240 mg tablets. Conditions for destruction of test article on site were also revised.
    27 Jan 2010
    Amendment 3: Included additional unscheduled PK, chemistry, and coagulation testing for subjects with signs or symptoms of drug induced hepatic injury; to provide clarification regarding criteria for prior trastuzumab use; to provide clarification for the definition of evaluable population; to update the study contact information; and to remove the immunohistochemistry (IHC) testing methods specific to Part 1 of the protocol.
    22 Mar 2012
    Amendment 4: Updated the Sponsor to Puma and added a treatment extension period in order to allow subjects who continued to derive benefit from study participation to continue to receive test article with a reduced number of protocol required assessments. Amendment 4 enabled the Sponsor to continue to provide investigational product (IP) to these patients until disease progression, death or withdrawal from the study. During the treatment extension period, subject safety continued to be monitored through reporting of all adverse events (AEs), serious adverse events (SAEs), IP administration, and reasons for study withdrawal. Decision regarding laboratory assessments, monitoring for prohibited concomitant medications, and follow-up of disease progression were left to the investigators discretion to be performed as clinically indicated. No efficacy data were collected during the treatment extension period.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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