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    Clinical Trial Results:
    Estudio de Fase I/II de HKI-272 en combinación con trastuzumab (Herceptin) en sujetos con cáncer de mama avanzado. A Phase I/II Study of HKI-272 in Combination With Trastuzumab (Herceptin) in Subjects With Advanced Breast Cancer.

    Summary
    EudraCT number
    		 2006-003215-52
    Trial protocol
    		 ES   FR  
    Global end of trial date
    23 May 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 May 2019
    First version publication date
    01 Jan 2017
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Update to reflect final study close out.
    Summary report(s)
    		 3144A1-202 PDS

    Trial information

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    Trial identification
    Sponsor protocol code
    3144A1-202-WW
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00398567
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Puma Biotechnology, Inc.
    Sponsor organisation address
    10880 Wilshire Blvd, Suite 2100, 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
    23 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives: Part 1: To assess the safety and tolerability, and to define the MTD of orally administered HKI-272 in combination with trastuzumab in subjects with advanced breast cancer. Part 2: To determine the 16 week progression free survival (PFS) rate for subjects with advanced breast cancer treated at the MTD with HKI-272 and trastuzumab.
    Protection of trial subjects
    Study commencement required prior written approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). Clinical trial data were monitored at regular intervals by the Sponsor or their representative throughout the study to verify compliance to study protocol, completeness, accuracy and consistency of the data and adherence to local regulations on the conduct of clinical research. Patients were discontinued from active treatment phase of the study for any of the following reasons, but not limited to: documented disease progression, adverse event, symptomatic deterioration, subject request, investigator request (with detailed documentation of reasoning), protocol violation, discontinuation of the study by the sponsor, lost to follow-up, or death. Subjects were discontinued or withdrawn from the study for any of the following reasons: subject request, lost to follow up, protocol violation, discontinuation of the study by the sponsor, or death.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    China: 20
    Worldwide total number of subjects
    45
    EEA total number of subjects
    5
    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)
    39
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All advertising, recruitment, and other written information provided to the subject had to have been approved by the IRB/IEC.

    Pre-assignment
    Screening details
    		 Patients were screened to evaluate any inclusion/exclusion criteria and were assigned to receive trastuzumab in combination Neratinib 160 mg or 240 mg in Part 1, and then the maximum tolerated dose, as determined in Part 1 of the study, in Part 2.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 Ner160 + Trastuzumab
    Arm description
    		 Part 1, dose-escalation phase. Neratinib 160 mg in combination with trastuzumab 4 mg/kg loading and then 2 mg/kg every week after.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib 160 mg was administered orally, preferably with a meal and in the morning. On the days when both neratinib and trastuzumab were administered, neratinib was taken within 30 minutes after the end of the trastuzumab infusion.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered as an IV infusion over 90 minutes at the dose of 4 mg/kg, followed by a weekly dose of 2 mg/kg administered over 30 minutes.

    Arm title
    		 Part 1 Ner240 + Trastuzumab
    Arm description
    		 Part 1, dose-escalation phase. Neratinib 240 mg in combination with trastuzumab 4 mg/kg loading and then 2 mg/kg every week after.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib 240 mg was administered orally, preferably with a meal and in the morning. On the days when both neratinib and trastuzumab were administered, neratinib was taken within 30 minutes after the end of the trastuzumab infusion.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered as an IV infusion over 90 minutes at the dose of 4 mg/kg, followed by a weekly dose of 2 mg/kg administered over 30 minutes.

    Arm title
    		 Part 2 Ner240 + Trastuzumab
    Arm description
    		 Part 2 of study. Neratinib 240 mg in combination with Trastuzumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib 240 mg was administered orally, preferably with a meal and in the morning. On the days when both neratinib and trastuzumab were administered, neratinib was taken within 30 minutes after the end of the trastuzumab infusion.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered as an IV infusion over 90 minutes at the dose of 4 mg/kg, followed by a weekly dose of 2 mg/kg administered over 30 minutes.

    Number of subjects in period 1
    		Part 1 Ner160 + Trastuzumab Part 1 Ner240 + Trastuzumab Part 2 Ner240 + Trastuzumab
    Started
    4
    4
    37
    Completed
    0
    0
    0
    Not completed
    4
    4
    37
         Consent withdrawn by subject
    1
    -
    4
         Adverse event, non-fatal
    -
    -
    2
         Study discontinuation by sponsor
    -
    -
    1
         Lost to follow-up
    -
    -
    2
         Disease Progression
    3
    4
    27
         Protocol deviation
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 Ner160 + Trastuzumab
    Reporting group description
    		 Part 1, dose-escalation phase. Neratinib 160 mg in combination with trastuzumab 4 mg/kg loading and then 2 mg/kg every week after.

    Reporting group title
    Part 1 Ner240 + Trastuzumab
    Reporting group description
    		 Part 1, dose-escalation phase. Neratinib 240 mg in combination with trastuzumab 4 mg/kg loading and then 2 mg/kg every week after.

    Reporting group title
    Part 2 Ner240 + Trastuzumab
    Reporting group description
    		 Part 2 of study. Neratinib 240 mg in combination with Trastuzumab.

    Reporting group values
    		 Part 1 Ner160 + Trastuzumab Part 1 Ner240 + Trastuzumab Part 2 Ner240 + Trastuzumab Total
    Number of subjects
    		 4 4 37 45
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 4 3 32 39
        From 65-84 years
    		 0 1 5 6
    Gender categorical
    Units: Subjects
        Female
    		 4 4 37 45

    End points

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    End points reporting groups
    Reporting group title
    Part 1 Ner160 + Trastuzumab
    Reporting group description
    		 Part 1, dose-escalation phase. Neratinib 160 mg in combination with trastuzumab 4 mg/kg loading and then 2 mg/kg every week after.

    Reporting group title
    Part 1 Ner240 + Trastuzumab
    Reporting group description
    		 Part 1, dose-escalation phase. Neratinib 240 mg in combination with trastuzumab 4 mg/kg loading and then 2 mg/kg every week after.

    Reporting group title
    Part 2 Ner240 + Trastuzumab
    Reporting group description
    		 Part 2 of study. Neratinib 240 mg in combination with Trastuzumab.

    Primary: Number of Patients with Dose Limiting Toxicity

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    End point title
    		 Number of Patients with Dose Limiting Toxicity [1] [2]
    End point description
    In part 1, the dose-escalation phase, 3 to 6 subjects were to be enrolled in each dose group. Enrollment at the next dose level began when all evaluable subjects at the first dose level were evaluated for 21 days after the first dose of test article. Additional subjects could be included at any dose level to further assess the safety and tolerability at that dose level. In part 1, subjects who withdrew from the study and were not considered evaluable could be replaced. DLTs were assessed from the administration of the first dose of test article through day 21, and were defined as any test article-related grade 2 or grade 3 diarrhea lasting >2 days despite optimal medical therapy, or diarrhea associated with fever or dehydration, grade 3 or grade 4 nonhematologic toxicity, grade 4 hematologic toxicity, or symptomatic congestive heart failure (CHF), confirmed by a cardiology assessment.
    End point type
    Primary
    End point timeframe
    From first dose date through 21 days after dose.
    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: The number of patients with Dose Limiting Toxicity were analyzed in each of the two arms in Part 1 of the study and they were analyzed separated. There were no comparisons or analyses to be made between the two arms.
    [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: Number of Patients with Dose Limiting Toxicity was analyzed only in Part 1 of the study.
    End point values
    		 Part 1 Ner160 + Trastuzumab Part 1 Ner240 + Trastuzumab
    Number of subjects analysed
    4
    4
    Units: Patients
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Primary: 16-Week Progression-Free Survival Rate

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    End point title
    		 16-Week Progression-Free Survival Rate [3] [4]
    End point description
    Sixteen (16) week PFS rate: the estimated proportion of evaluable subjects who are alive and progression-free 16 weeks after the first dose of test article. The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.
    End point type
    Primary
    End point timeframe
    From the date of first dose through Week 16.
    Notes
    [3] - 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: This 16-Week Progression-Free Survival Rate was computed for Part 2 of the study and there were no comparisons to be made. The rate and the corresponding 95% CI were estimated using the Kaplan-Meier method.
    [4] - 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: 16-Week Progression-Free Survival Rate was analyzed only in Part 2 of the study.
    End point values
    		 Part 2 Ner240 + Trastuzumab
    Number of subjects analysed
    28
    Units: percent
        number (confidence interval 95%)
    44.8 (25.9 to 62.1)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival [5]
    End point description
    The time to tumor progression is the interval from the date of the first dose of test article to the first date on which any of the following criteria are met: 1. Documented PD per modified RECIST criteria as described above. 2. Early determination of PD status in the opinion of the investigator, in the absence of measurement data. 3. Discontinuation of test article due to symptomatic deterioration, or death due to any cause. The date of the last dose of test article will be considered the date of progression. Subjects who do not meet the above criteria for progression will be censored at the last valid post-screening tumor assessment. Valid tumor assessment is defined as an assessment where overall response includes either CR or PR or SD. Subjects who do not have a post-screening tumor assessment will be censored at the date of first dose of test article. Median PFS estimated by Kaplan-Meier method is reported.
    End point type
    Secondary
    End point timeframe
    Interval from the first dose date of test article until the first date on which recurrence or progression, or death due to any cause, is documented, censored at the last tumor assessment date.
    Notes
    [5] - 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: Progression-Free Survival was analyzed only in Part 2 of the study.
    End point values
    		 Part 2 Ner240 + Trastuzumab
    Number of subjects analysed
    28
    Units: Weeks
        number (confidence interval 95%)
    15.9 (15.1 to 31.3)
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate [6]
    End point description
    Percent of subjects achieving a complete or partial response. Complete and partial responses must be confirmed by 2 observations not less than 4 weeks apart.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study through the last assessment.
    Notes
    [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: Objective Response Rate was analyzed only in Part 2 of the study.
    End point values
    		 Part 2 Ner240 + Trastuzumab
    Number of subjects analysed
    28
    Units: Percentage
        number (confidence interval 95%)
    28.6 (13.2 to 48.7)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate

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    End point title
    		 Clinical Benefit Rate [7]
    End point description
    Proportion of subjects demonstrating CR, PR, or duration of SD for at least 24 weeks
    End point type
    Secondary
    End point timeframe
    From first dose to last tumor assessment.
    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: Clinical Benefit Rate was analyzed only in Part 2 of the study.
    End point values
    		 Part 2 Ner240 + Trastuzumab
    Number of subjects analysed
    28
    Units: Percentage
        number (confidence interval 95%)
    35.7 (18.6 to 55.9)
    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
    NER160 + TRAST, PART 1
    Reporting group description
    		 Neratinib 160 mg qd + Trastuzumab IV weekly at 4 mg/kg or 2 mg/kg, Part 1

    Reporting group title
    NER240 + TRAST, PART 1
    Reporting group description
    		 Neratinib 240 mg qd + Trastuzumab IV weekly at 4 mg/kg or 2 mg/kg, Part 1

    Reporting group title
    NER240 + TRAST, PART 2
    Reporting group description
    		 Neratinib MTD (240) mg qd + Trastuzumab IV weekly at 4 mg/kg or 2 mg/kg, Part 2

    Serious adverse events
    		 NER160 + TRAST, PART 1 NER240 + TRAST, PART 1 NER240 + TRAST, PART 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    8 / 37 (21.62%)
         number of deaths (all causes)
    0
    0
    3
         number of deaths resulting from adverse events
    0
    0
    1
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NER160 + TRAST, PART 1 NER240 + TRAST, PART 1 NER240 + TRAST, PART 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    37 / 37 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphoedema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    14 / 37 (37.84%)
         occurrences all number
    0
    0
    27
    Catheter site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    Crying
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    6 / 37 (16.22%)
         occurrences all number
    1
    3
    8
    Irritability
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    2
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    1
    0
    8
    Reproductive system and breast disorders
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    1
    13
    Dry throat
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Dysphonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    0
    7
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    2
    1
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    0
    4
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    0
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    0
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    5 / 37 (13.51%)
         occurrences all number
    0
    0
    10
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    3
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    0
    4
    Haemoglobin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    3
    6
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    7 / 37 (18.92%)
         occurrences all number
    0
    3
    11
    Weight increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    5
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    5 / 37 (13.51%)
         occurrences all number
    0
    0
    5
    Dysgeusia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    2
    Headache
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    5 / 37 (13.51%)
         occurrences all number
    2
    1
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    2 / 37 (5.41%)
         occurrences all number
    2
    1
    3
    Leukopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    3
    Neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    4
    Neutrophilia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    3
    Thrombocytopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    0
    4
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    6 / 37 (16.22%)
         occurrences all number
    1
    1
    7
    Abdominal pain upper
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    2
    0
    2
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    34 / 37 (91.89%)
         occurrences all number
    27
    41
    135
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    0
    5
    Dysphagia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Nausea
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    17 / 37 (45.95%)
         occurrences all number
    5
    7
    32
    Stomatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Vomiting
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    14 / 37 (37.84%)
         occurrences all number
    2
    4
    28
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    3
    Alopecia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Dermatitis acneiform
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Dry skin
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    1
    0
    5
    Erythema
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    2 / 37 (5.41%)
         occurrences all number
    3
    1
    4
    Exfoliative rash
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    0
    Nail disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    4
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    6
    Rash
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    8 / 37 (21.62%)
         occurrences all number
    5
    1
    13
    Skin exfoliation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    3
    Skin lesion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    1
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    3
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    2
    Bone pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    0
    12
    Muscular weakness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    0
    5
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    3
    Lymphangitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    2
    Paronychia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    2
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    4 / 37 (10.81%)
         occurrences all number
    0
    1
    4
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    3
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    19 / 37 (51.35%)
         occurrences all number
    1
    2
    26
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    1
    3
    Hypocalcaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    1
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    0
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2007
    This amendment included a smaller part 2, with 30 subjects enrolled at maximum tolerated dose, and updates to the eligibility criteria.
    13 Sep 2007
    This amendment clarified that certain standard procedures do not need to be repeated for the purposes of determining eligibility if done within the screening window, and that for final visit, if LVEF was assessed within the previous 8 weeks, it does not need to be repeated at the final visit.
    19 May 2008
    This amendment specified that subjects may receive more than 12 months of treatment if treatment was well tolerated, if the disease has not progressed, if the subject is clinically stable, and if the subject has received the overall benefit from the treatment according to the investigator's judgement. Subject continuation will be discussed with the Sponsor. Study procedures for any visits beyond 12 months will be the same as months 3-12 with the exception of pharmacokinetics.
    22 Mar 2012
    This amendment changed the Sponsor to Puma and included a Treatment Extension Period, which allowed patients who still derived benefit from study participation to remain on the study and enabled the Sponsor to continue to provide investigational product (IP) to the patients after the primary objectives had been reached. During the Treatment Extension Period, the required procedures were limited to IP administration and monitoring for safety and tolerability; adverse events (AEs) and serious adverse events (SAEs) were documented, but no efficacy data were collected.

    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.
    Data reported in Addendum and Final Report for 3 patients followed after database lock are consistent with safety conclusions presented in iCSR and ISR and do not impact known safety profile of neratinib in combination with trastuzumab.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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