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    Clinical Trial Results:
    A Phase 1/2 Trial of Temsirolimus Plus Neratinib For Patients With Metastatic HER2-Amplified or Triple-Negative Breast Cancer

    Summary
    EudraCT number
    2012-005037-37
    Trial protocol
    GB   ES   DK  
    Global end of trial date
    20 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Dec 2017
    First version publication date
    16 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    10-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01111825
    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
    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
    29 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the trial are to determine the maximum tolerated dose of temsirolimus with daily neratinib, and to determine the safety and efficacy of this combination when given to patients with advanced breast carcinoma, specifically trastuzumab-refractory HER2-amplified disease or triple-negative disease.
    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 treatment for the following reasons: documented disease progression, unacceptable toxicity, withdrawal of consent, or death.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Apr 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 53
    Country: Number of subjects enrolled
    Hong Kong: 5
    Worldwide total number of subjects
    99
    EEA total number of subjects
    41
    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)
    85
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    One hundred and thirty four (134) subjects with metastatic HER2 amplified or triple-negative breast cancer were screened. Ninety-nine subjects were treated.

    Pre-assignment
    Screening details
    One hundred and thirty four (134) subjects with metastatic HER2 amplified or triple-negative breast cancer were screened. Ninety-nine subjects were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase I
    Arm description
    Patients with trastuzumab-refractory HER2-amplified disease. Patients were treated to determine the maximum tolerated dose (MTD) of temsirolimus.
    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
    Six 40 mg tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously until treatment discontinuation.

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ascending dose of temsirolimus in combination with neratinib 240 mg qd. Three cohorts of temsirolimus at 8 mg qw, 15 mg qw, or 25 mg qw intravenously (IV) on days 1, 8, 15 and 22 of a 28 day cycle.

    Arm title
    Phase II -ve
    Arm description
    Subjects with triple negative breast cancer. Invasive adenocarcinoma negative for estrogen receptor (< 5%), and progesterone receptor (< 5%) expression, and lack of HER2 overexpression and/or amplification as determined by IHC (<3+) or FISH (<2.0).
    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
    Six 40 mg tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously until treatment discontinuation.

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Temsirolimus administered by IV infusion at 8 mg QW on days 1, 8, 15, and 22 of a 28-day cycle. Treatment should continue until progression, unacceptable toxicity or withdrawal of consent.

    Arm title
    Phase II HER2+
    Arm description
    Subjects with HER2 overexpressed/amplified tumors, as determined by IHC (3+) or FISH (>= 2.0).
    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
    Six 40 mg tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously until treatment discontinuation.

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Temsirolimus administered by IV infusion at 8 mg QW on days 1, 8, 15, and 22 of a 28-day cycle. Treatment should continue until progression, unacceptable toxicity or withdrawal of consent.

    Arm title
    Phase II HER2+ Dose Esc
    Arm description
    Subjects with HER2 overexpressed/amplified tumors, as determined by IHC (3+) or FISH (>= 2.0), dose escalation of temsirolimus.
    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
    Six 40 mg tablets (240 mg) taken orally once daily with food, preferably in the morning, continuously until treatment discontinuation

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    8 mg (MTD established in Phase 1), administered IV QW on days 1, 8, 15, and 22 of a 28-day cycle; escalated to 15 mg temsirolimus, administered IV QW on days 1, 8, 15, and 22 of a 28-day cycle for subjects who tolerate 8 mg.

    Number of subjects in period 1
    Phase I Phase II -ve Phase II HER2+ Phase II HER2+ Dose Esc
    Started
    8
    6
    37
    48
    Completed
    5
    5
    29
    27
    Not completed
    3
    1
    8
    21
         Disease Progression
    1
    -
    -
    -
         Discontinuation by Sponsor
    -
    -
    -
    20
         Adverse event, non-fatal
    2
    1
    4
    -
         Consent withdrawn by subject
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I
    Reporting group description
    Patients with trastuzumab-refractory HER2-amplified disease. Patients were treated to determine the maximum tolerated dose (MTD) of temsirolimus.

    Reporting group title
    Phase II -ve
    Reporting group description
    Subjects with triple negative breast cancer. Invasive adenocarcinoma negative for estrogen receptor (< 5%), and progesterone receptor (< 5%) expression, and lack of HER2 overexpression and/or amplification as determined by IHC (<3+) or FISH (<2.0).

    Reporting group title
    Phase II HER2+
    Reporting group description
    Subjects with HER2 overexpressed/amplified tumors, as determined by IHC (3+) or FISH (>= 2.0).

    Reporting group title
    Phase II HER2+ Dose Esc
    Reporting group description
    Subjects with HER2 overexpressed/amplified tumors, as determined by IHC (3+) or FISH (>= 2.0), dose escalation of temsirolimus.

    Reporting group values
    Phase I Phase II -ve Phase II HER2+ Phase II HER2+ Dose Esc Total
    Number of subjects
    8 6 37 48 99
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    7 5 34 39 85
        From 65-84 years
    1 1 3 9 14
        85 years and over
    0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    47.5 ± 10.4 53.5 ± 13 52 ± 8.3 53.2 ± 11 -
    Gender categorical
    Units: Subjects
        Female
    8 6 37 47 98
        Male
    0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Phase I
    Reporting group description
    Patients with trastuzumab-refractory HER2-amplified disease. Patients were treated to determine the maximum tolerated dose (MTD) of temsirolimus.

    Reporting group title
    Phase II -ve
    Reporting group description
    Subjects with triple negative breast cancer. Invasive adenocarcinoma negative for estrogen receptor (< 5%), and progesterone receptor (< 5%) expression, and lack of HER2 overexpression and/or amplification as determined by IHC (<3+) or FISH (<2.0).

    Reporting group title
    Phase II HER2+
    Reporting group description
    Subjects with HER2 overexpressed/amplified tumors, as determined by IHC (3+) or FISH (>= 2.0).

    Reporting group title
    Phase II HER2+ Dose Esc
    Reporting group description
    Subjects with HER2 overexpressed/amplified tumors, as determined by IHC (3+) or FISH (>= 2.0), dose escalation of temsirolimus.

    Primary: Objective Response Rate

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    End point title
    Objective Response Rate [1] [2]
    End point description
    ORR is defined as proportion of subjects who achieved confirmed complete response (CR) or partial response (PR) per RECIST v1.1. A complete or partial response must be confirmed no less than 4-weeks after the criteria for response are initially met.
    End point type
    Primary
    End point timeframe
    From randomization to disease progression or last tumor assessment
    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: Per protocol no formal statistical comparison of cohorts was performed.
    [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: Per protocol no summary of endpoint data was planned for the Phase I group.
    End point values
    Phase II -ve Phase II HER2+ Phase II HER2+ Dose Esc
    Number of subjects analysed
    6
    37
    48
    Units: count of participants
        number (not applicable)
    0
    5
    14
    No statistical analyses for this end point

    Secondary: Progression Free Survival

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    End point title
    Progression Free Survival [3]
    End point description
    Defined as time from date of enrollment until the first disease recurrence or progression per RECIST V1.1 or death due to any cause; censored at the last assessable evaluation or at the initiation of new anti-cancer therapy. Disease assessment is based on investigator tumor assessments. If no post-baseline tumor assessment then censored at enrollment date.
    End point type
    Secondary
    End point timeframe
    From enrollment to disease progression or last tumor assessment
    Notes
    [3] - 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: Per protocol no summary of endpoint data was planned for the Phase I group.
    End point values
    Phase II -ve Phase II HER2+ Phase II HER2+ Dose Esc
    Number of subjects analysed
    6
    37
    48
    Units: months
        median (confidence interval 95%)
    1.8 (1.8 to 2)
    4.8 (2.7 to 8.4)
    6 (3.7 to 8.3)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    Duration of Response (DOR) [4]
    End point description
    Measured from the time at which measurement criteria were first met for CR or PR (whichever status was recorded first), until the date of first recurrence, PD, or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per RECIST (v1.1) criteria.
    End point type
    Secondary
    End point timeframe
    From first response to first progressive disease (PD) or death
    Notes
    [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: Per protocol no summary of endpoint data was planned for the Phase I group.
    End point values
    Phase II -ve Phase II HER2+ Phase II HER2+ Dose Esc
    Number of subjects analysed
    0 [5]
    5
    14
    Units: months
    number (not applicable)
        0 to <3 months
    1
    2
        3 to <6 months
    2
    1
        6 to <9 months
    0
    6
        9 to <12 months
    2
    2
        12+ months
    0
    3
    Notes
    [5] - There were no subjects in this arm who achieved a response.
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    Clinical Benefit Rate (CBR) [6]
    End point description
    Defined as the proportion of patients who achieved objective response (CR or PR) or SD for at least 24 weeks.
    End point type
    Secondary
    End point timeframe
    From enrollment to disease progression or death
    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: Per protocol no summary of endpoint data was planned for the Phase I group.
    End point values
    Phase II -ve Phase II HER2+ Phase II HER2+ Dose Esc
    Number of subjects analysed
    6
    37
    48
    Units: count of participants
        number (not applicable)
    0
    8
    19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose through 28 days after last dose
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Phase I
    Reporting group description
    Subjects with trastuzumab-refractory HER2-amplified disease. Patients were treated to determine themaximum tolerated dose (MTD) of temsirolimus.

    Reporting group title
    Phase II -ve
    Reporting group description
    Subjects with triple negative breast cancer. Invasive adenocarcinoma negative for estrogen receptor (< 5%), and progesterone receptor (< 5%) expression, and lack of HER2 overexpression and/or amplification as determined by IHC (< 3+) or FISH (< 2.0).

    Reporting group title
    Phase II HER2+
    Reporting group description
    Subjects with HER2 overexpressed/amplified tumors, as determined by IHC (3+) or FISH (>= 2.0).

    Reporting group title
    Phase II HER2+ Dose Esc
    Reporting group description
    Subjects with HER2 overexpressed/amplified tumors, as determined by IHC (3+) or FISH (>= 2.0), dose escalation of temsirolimus.

    Serious adverse events
    Phase I Phase II -ve Phase II HER2+ Phase II HER2+ Dose Esc
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    12 / 37 (32.43%)
    20 / 48 (41.67%)
         number of deaths (all causes)
    0
    0
    7
    27
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    0 / 48 (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
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Electrocardiogram ST segment depression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Haemoglobin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Transaminases increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    0 / 48 (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
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Polycythaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Neuropathy peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Spinal cord compression
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (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
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    3 / 37 (8.11%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    3 / 37 (8.11%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    3 / 48 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Muscular weakness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Failure to thrive
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Cellulitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         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
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Phase I Phase II -ve Phase II HER2+ Phase II HER2+ Dose Esc
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    6 / 6 (100.00%)
    37 / 37 (100.00%)
    48 / 48 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    1 / 48 (2.08%)
         occurrences all number
    4
    0
    1
    1
    Lymphoedema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    2 / 48 (4.17%)
         occurrences all number
    1
    0
    1
    2
    Post thrombotic syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    18 / 48 (37.50%)
         occurrences all number
    0
    0
    0
    27
    Chest discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    2
    1
    Fatigue
         subjects affected / exposed
    6 / 8 (75.00%)
    3 / 6 (50.00%)
    20 / 37 (54.05%)
    9 / 48 (18.75%)
         occurrences all number
    15
    5
    42
    30
    Oedema peripheral
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    2 / 37 (5.41%)
    9 / 48 (18.75%)
         occurrences all number
    3
    1
    2
    20
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    2
    0
    0
    5
    Pyrexia
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    6 / 37 (16.22%)
    4 / 48 (8.33%)
         occurrences all number
    2
    2
    6
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    1
    0
    7
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    2
    0
    0
    1
    Vulvovaginal dryness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    3 / 37 (8.11%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    0
    3
    Stoma site ulcer
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    2 / 48 (4.17%)
         occurrences all number
    0
    0
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    3
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    4 / 48 (8.33%)
         occurrences all number
    0
    0
    2
    6
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    0
    3
    Haemoglobin decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    0
    6
    Monocyte count increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    4 / 48 (8.33%)
         occurrences all number
    0
    0
    1
    6
    Weight decreased
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    5 / 37 (13.51%)
    6 / 48 (12.50%)
         occurrences all number
    4
    2
    5
    6
    Weight increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    4 / 37 (10.81%)
    9 / 48 (18.75%)
         occurrences all number
    5
    7
    5
    13
    Dysphonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    1
    3
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 6 (50.00%)
    3 / 37 (8.11%)
    9 / 48 (18.75%)
         occurrences all number
    3
    8
    3
    14
    Dyspnoea exertional
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    2
    2
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    3 / 37 (8.11%)
    10 / 48 (20.83%)
         occurrences all number
    0
    1
    4
    73
    Nasal dryness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 37 (2.70%)
    5 / 48 (10.42%)
         occurrences all number
    0
    1
    1
    6
    Pleural effusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    10 / 48 (20.83%)
         occurrences all number
    0
    0
    2
    14
    Neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    2
    5
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    4 / 48 (8.33%)
         occurrences all number
    0
    0
    1
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    6 / 37 (16.22%)
    4 / 48 (8.33%)
         occurrences all number
    1
    0
    7
    7
    Dysgeusia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    4 / 37 (10.81%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    4
    1
    Headache
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    2 / 37 (5.41%)
    11 / 48 (22.92%)
         occurrences all number
    5
    3
    2
    31
    Hypoaesthesia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 37 (2.70%)
    0 / 48 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    7 / 37 (18.92%)
    1 / 48 (2.08%)
         occurrences all number
    2
    0
    8
    2
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    5 / 37 (13.51%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    9
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    9
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    3 / 37 (8.11%)
    2 / 48 (4.17%)
         occurrences all number
    1
    0
    4
    2
    Vision blurred
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    5 / 37 (13.51%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    7
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    8 / 48 (16.67%)
         occurrences all number
    0
    0
    1
    13
    Cheilitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    1
    3
    Constipation
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    7 / 37 (18.92%)
    21 / 48 (43.75%)
         occurrences all number
    3
    2
    7
    44
    Diarrhoea
         subjects affected / exposed
    7 / 8 (87.50%)
    5 / 6 (83.33%)
    35 / 37 (94.59%)
    40 / 48 (83.33%)
         occurrences all number
    18
    13
    82
    673
    Dry mouth
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    6 / 48 (12.50%)
         occurrences all number
    1
    0
    2
    6
    Dyspepsia
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    2 / 48 (4.17%)
         occurrences all number
    3
    0
    1
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 37 (5.41%)
    2 / 48 (4.17%)
         occurrences all number
    0
    1
    2
    2
    Glossodynia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    9 / 48 (18.75%)
         occurrences all number
    0
    0
    0
    16
    Nausea
         subjects affected / exposed
    6 / 8 (75.00%)
    5 / 6 (83.33%)
    18 / 37 (48.65%)
    20 / 48 (41.67%)
         occurrences all number
    10
    8
    28
    45
    Stomatitis
         subjects affected / exposed
    5 / 8 (62.50%)
    4 / 6 (66.67%)
    25 / 37 (67.57%)
    29 / 48 (60.42%)
         occurrences all number
    15
    6
    58
    117
    Vomiting
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 6 (50.00%)
    9 / 37 (24.32%)
    23 / 48 (47.92%)
         occurrences all number
    6
    5
    11
    41
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 6 (50.00%)
    4 / 37 (10.81%)
    0 / 48 (0.00%)
         occurrences all number
    2
    5
    5
    0
    Dry skin
         subjects affected / exposed
    4 / 8 (50.00%)
    2 / 6 (33.33%)
    7 / 37 (18.92%)
    4 / 48 (8.33%)
         occurrences all number
    5
    4
    11
    4
    Hair texture abnormal
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nail disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    2 / 48 (4.17%)
         occurrences all number
    0
    0
    2
    2
    Nail dystrophy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    5 / 48 (10.42%)
         occurrences all number
    1
    0
    0
    7
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    4 / 37 (10.81%)
    7 / 48 (14.58%)
         occurrences all number
    2
    2
    4
    10
    Rash
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 6 (0.00%)
    17 / 37 (45.95%)
    21 / 48 (43.75%)
         occurrences all number
    9
    0
    25
    68
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Skin reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Swelling face
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 8 (50.00%)
    3 / 6 (50.00%)
    6 / 37 (16.22%)
    5 / 48 (10.42%)
         occurrences all number
    7
    3
    11
    10
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    6 / 37 (16.22%)
    4 / 48 (8.33%)
         occurrences all number
    1
    3
    7
    4
    Bone pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Joint stiffness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 37 (2.70%)
    4 / 48 (8.33%)
         occurrences all number
    0
    2
    2
    10
    Muscular weakness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    3 / 37 (8.11%)
    2 / 48 (4.17%)
         occurrences all number
    3
    0
    4
    3
    Musculoskeletal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    4 / 48 (8.33%)
         occurrences all number
    3
    0
    1
    5
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    2 / 37 (5.41%)
    2 / 48 (4.17%)
         occurrences all number
    0
    1
    2
    3
    Neck pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 37 (2.70%)
    0 / 48 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    2 / 37 (5.41%)
    6 / 48 (12.50%)
         occurrences all number
    3
    1
    2
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 8 (50.00%)
    1 / 6 (16.67%)
    6 / 37 (16.22%)
    19 / 48 (39.58%)
         occurrences all number
    4
    1
    7
    30
    Dehydration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    1
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 37 (5.41%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    5
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    0
    0
    4
    Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    3 / 37 (8.11%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    6
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    0
    3
    Localised infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    0
    4
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    5 / 48 (10.42%)
         occurrences all number
    0
    0
    0
    9
    Onychomycosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    4 / 37 (10.81%)
    4 / 48 (8.33%)
         occurrences all number
    0
    0
    5
    5
    Pharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 37 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    0
    0
    6
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 37 (2.70%)
    3 / 48 (6.25%)
         occurrences all number
    1
    0
    1
    4
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    3 / 37 (8.11%)
    4 / 48 (8.33%)
         occurrences all number
    0
    0
    3
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2010
    • Phase 1 eligibility criteria were changed to include no limit on the number of lines of prior therapy • Clarified that prior treatment and progression on lapatinib is not a requirement for eligibility • Definition of triple-negative disease in the eligibility criteria was changed to <5% estrogen receptor and progesterone receptor expression
    11 May 2010
    • Included Wyeth-Pfizer merger; Wyeth is now Wyeth Pharmaceuticals, Inc., a Pfizer Company • Changed drug supply; Wyeth will be providing neratinib in 240-mg and 80-mg capsules and 40-mg tablets.
    13 Jul 2010
    • A third dose cohort to Phase 1 (15 mg of temsirolimus and 240 mg of neratinib) was added. • The maximum number of patients needed to determine the MTD was increased to 18 patients.
    12 Sep 2010
    • Shari Goldfarb, MD, was added as an investigator; this amendment was not submitted to the IND.
    11 Jan 2011
    • The MTD from Phase 1 was determined to be 8 mg temsirolimus/240 mg neratinib. • Pathological nodes must be ≥15 mm by the short axis to be considered measurable.
    27 Sep 2011
    • Signed informed consent and medication list must be obtained within 1 month prior to starting therapy instead of 2 weeks. • If patients have received at least 6 months of therapy, they can be seen monthly (Day 1 of each cycle) by the MD instead of biweekly.
    13 Mar 2012
    • As of 2/10/12, the Triple-negative cohort was closed to accrual. This change in study design was not a result of safety concerns. After assessing the data of the Triple-negative patients, there was no indication that therapy with weekly temsirolimus (8 mg) and daily neratinib (240 mg) shows efficacy in terms of the ORR (CR + PR) as determined by RECIST 1.1 criteria. • Added that complete or partial responses will be confirmed with a repeat CT scan after 4 weeks. Radiographic assessments (CT and Bone or PET scan) may then be completed 8 weeks ±7 days from the confirmatory CT scan.
    29 May 2012
    • Study sponsorship was changed from Memorial Sloan Kettering Cancer Center (MSKCC) to Puma Biotechnology, Inc. (Puma); contact information was revised accordingly. • Subjects who were unable to complete 1 week of therapy will not be included in the analysis for toxicity or response; however, they will be followed for safety. Subjects not completing 1 week of therapy may be replaced by a new subject. • A new section “Follow-up Visits” was added stating that subjects will be followed for overall survival after the treatment phase is complete.
    16 Jan 2013
    • Two new sites in the US, in addition to MSKCC, were activated: Weill Cornell Medical College and University of Southern California. • Inclusion Criterion for Phase 2 HER2–Amplified Cohort was revised to allow enrollment of patients with no restriction on the number of prior chemotherapy regimens received. • The enrollment period was extended from 2 years to approximately 3 years. • To mitigate or reduce the incidence of diarrhea that generally occurs in the initial treatment cycle, a revised diarrhea management plan with mandatory prophylactic use of high-dose loperamide was implemented. This allowed for patients to take a maximum dose of 12 mg of loperamide for the first 3 days, followed by 6-8 mg of loperamide per day thereafter.
    17 Mar 2013
    • 16 patients added in Phase 2 HER2-positive cohort. If these patients tolerated the starting dose of neratinib 240 mg/day + temsirolimus 8 mg/week in the first cycle of therapy, intra-patient dose-escalation of temsirolimus to 15 mg/week was allowed. • Patient enrollment in Phase 2 portion of study revised to minimum of 19 patients and maximum of approximately 79 patients (50 HER2+ patients). • Study expanded to centers in Spain, United Kingdom, France, and Hong Kong. • Total duration of study increased to approximately 48 months with 10 centers. • Final analysis revised: “The final analysis of the primary endpoint will occur when disease progression is reported for all patients in the Phase 2 HER2-positive cohort (first 34 patients without dose-escalation).” • End of study (EOS) stated to occur when disease progression is reported for all patients on study, or when EOS is declared early once the primary endpoint has been met. • Phase 2 secondary objectives revised to determine progression-free survival, duration of response, clinical benefit rate, and overall survival, and estimate the efficacy and safety assessment of dose escalation to 240 mg neratinib plus 15 mg temsirolimus with revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients. • Inclusion and Exclusion criteria revisions regarding informed consent for procedures. • Inclusion criterion for contraception while on study revised. • Exclusion criterion removed: Unable to consent to biopsy of metastatic disease or for whom a biopsy would be medically unsafe. • Exclusion criterion added: Previous treatment with any strong inhibitor and/or inducer of CYP3A4 enzyme or sensitive P glycoprotein. • Section “10 Patient Withdrawal and Replacement” added to clarify conditions for discontinuing IP administration and reasons for study withdrawal. • Section “12 Statistical Methods” revised to clarify all statistical analyses and methods.
    14 Oct 2013
    • Number of patients in the HER2+ dose escalation cohort increased to approximately 100 and the number of centers to approximately 15 in order to expand the safety and efficacy data for the neratinib 240 mg/day plus temsirolimus 15 mg/week combination. • Minimum and maximum number of patients enrolled in Phase 2 increased from 19 to 119, and from 79 to 163, respectively. Maximum total sample size for study increased from 97 to 181 patients. • Statistical methods section and text throughout protocol revised to indicate that single-stage design was used to estimate sample size for HER2+ dose-escalation cohort. • Primary Phase 2 objective added to estimate the ORR for patients with dose escalation to 240 mg neratinib plus 15 mg, temsirolimus with a revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients. • Secondary Phase 2 objective revised to assess only safety (because the efficacy evaluation for this Phase 2 cohort was moved under primary objectives: to assess the safety of dose escalation to 240 mg neratinib plus 15 mg temsirolimus with a revised prophylactic diarrhea management regimen in pretreated HER2+ MBC patients. • Interim analysis for Phase 2 HER+ cohort added to determine if study continuation was warranted based on Simon 2-stage optimal design. • Text clarified, “final analysis of the primary endpoint will occur when disease progression is reported for all HER2-positive patients enrolled in the Phase 2 portion of study.” • Text added to clarify that efficacy analyses performed on the Efficacy Evaluable population, defined as “all patients who are enrolled into the study and have completed at least one week of treatment.” • Table added to clarify endpoints for laboratory assessments. • Definition of study termination clarified, “The end of study (EOS) is defined as the last visit of the last patient or the completion of any/all follow-up monitoring and data collection described in the protocol (ie, survival)."

    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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