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    Clinical Trial Results:
    Randomized, Placebo-controlled, Double-blind Phase 1b/2 Study of U3-1287 (AMG 888) in Combination with Erlotinib in EGFR Treatment Naive Subjects with Advanced Non-Small Cell Lung Cancer (NSCLC) Who Have Progressed on at Least One Prior Chemotherapy

    Summary
    EudraCT number
    		 2010-021082-74
    Trial protocol
    		 DE   BE   LT   HU   GB   BG   AT   SI   IT  
    Global end of trial date
    06 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2016
    First version publication date
    09 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    U31287-A-U201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01211483
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo Development Limited
    Sponsor organisation address
    Chiltern Place, Chalfont Park, Gerrards Cross, United Kingdom, SL90BG
    Public contact
    Clinical Trial Information , Daiichi Sankyo Development Limited, +44 1753482800, info@dsd-eu.com
    Scientific contact
    Clinical Trial Information , Daiichi Sankyo Development Limited, +44 1753482800, info@dsd-eu.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
    22 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 1b Portion - To evaluate the safety and tolerability of the combination of patritumab and erlotinib in subjects with advanced or metastatic NSCLC. - To determine the recommended dose of patritumab for Phase 2 study (RP2D) in combination with erlotinib. Phase II Portion - To evaluate progression-free survival (PFS) among all randomized subjects treated with erlotinib in combination with high and low doses of patritumab compared to erlotinib plus placebo. - To evaluate the safety profile of the combination of patritumab and erlotinib.
    Protection of trial subjects
    The study was conducted in compliance with ethical principles that have their origin in the Declarations of Helsinki, the International Conference on Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s): • European Commission Directive (2001/20/EC Apr 2001) and/or • European Commission Directive (2005/28/EC Apr 2005) and/or • United States (US) Food and Drug Administration (FDA) GCP Regulations: Code of Federal Regulations (CFR) Title 21, parts 11, 50, 54, 56, and 312 as appropriate and/or • Other applicable local regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Sep 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
    Israel: 7
    Country: Number of subjects enrolled
    Slovenia: 1
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Germany: 92
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Ukraine: 18
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Romania: 21
    Worldwide total number of subjects
    222
    EEA total number of subjects
    166
    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)
    133
    From 65 to 84 years
    88
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects, after having the study explained to them by the Investigator or designee, gave voluntary and signed informed consent before participating in any study procedures.

    Period 1
    Period 1 title
    Baseline and Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Erlotinib
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered IV every 3 weeks

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg/day erlotinib taken in the morning, at the same time of each day, 1 hour before or 2 hours after a meal.

    Arm title
    		 Patritumab 18 mg/kg + Erlotinib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patritumab
    Investigational medicinal product code
    U3-1287
    Other name
    AMG 888
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patritumab infusions were administered every 3 weeks. Patritumab was administered as a continuous intravenous infusion over 60 minutes (± 10 minutes). Infusion times could be extended to a maximum of 120 minutes for subjects unable to tolerate the 60 minute infusion.

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg/day erlotinib taken in the morning, at the same time of each day, 1 hour before or 2 hours after a meal.

    Arm title
    		 Patritumab 9 mg/kg + Erlotinib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patritumab
    Investigational medicinal product code
    U3-1287
    Other name
    AMG 888
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patritumab infusions were administered every 3 weeks. Patritumab was administered as a continuous intravenous infusion over 60 minutes (± 10 minutes). Infusion times could be extended to a maximum of 120 minutes for subjects unable to tolerate the 60 minute infusion.

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg/day erlotinib taken in the morning, at the same time of each day, 1 hour before or 2 hours after a meal.

    Arm title
    		 Patritumab 18 mg/kg + Erlotinib Phase Ib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Patritumab
    Investigational medicinal product code
    U3-1287
    Other name
    AMG 888
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patritumab infusions were administered every 3 weeks. Patritumab was administered as a continuous intravenous infusion over 60 minutes (± 10 minutes). Infusion times could be extended to a maximum of 120 minutes for subjects unable to tolerate the 60 minute infusion.

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg/day erlotinib taken in the morning, at the same time of each day, 1 hour before or 2 hours after a meal.

    Number of subjects in period 1
    		Placebo + Erlotinib Patritumab 18 mg/kg + Erlotinib Patritumab 9 mg/kg + Erlotinib Patritumab 18 mg/kg + Erlotinib Phase Ib
    Started
    71
    72
    72
    7
    Phase Ib
    0
    0
    0
    7
    Phase II
    71
    72
    72
    0
    Completed
    0
    0
    0
    0
    Not completed
    71
    72
    72
    7
         Adverse event, serious fatal
    4
    8
    2
    -
         Enrolled/randomized but Not Dosed
    -
    2
    1
    -
         Consent withdrawn by subject
    3
    1
    3
    -
         Adverse event, non-fatal
    7
    11
    8
    -
         Other
    3
    4
    7
    -
         Progressive Disease
    53
    46
    48
    7
         Ongoing on the treatment
    1
    -
    3
    -

    Baseline characteristics

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

    Reporting group values
    		 Baseline and Treatment Total
    Number of subjects
    		 222 222
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 133 133
        From 65-84 years
    		 88 88
        85 years and over
    		 1 1
    Gender categorical
    Units: Subjects
        Female
    		 87 87
        Male
    		 135 135

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Erlotinib
    Reporting group description
    		 -

    Reporting group title
    Patritumab 18 mg/kg + Erlotinib
    Reporting group description
    		 -

    Reporting group title
    Patritumab 9 mg/kg + Erlotinib
    Reporting group description
    		 -

    Reporting group title
    Patritumab 18 mg/kg + Erlotinib Phase Ib
    Reporting group description
    		 -

    Primary: Progression Free Survival - Time to event (months)

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    End point title
    		 Progression Free Survival - Time to event (months) [1]
    End point description
    End point type
    Primary
    End point timeframe
    16 months
    Notes
    [1] - 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 not assessed in the Phase IB portion of the study, the objective of this portion being to evaluate the safety and tolerability of the combination of patritumab and erlotinib in subjects with advanced or metastatic NSCLC and determine the recommended dose of patritumab for the Phase 2 in combination with erlotinib.
    End point values
    		 Placebo + Erlotinib Patritumab 18 mg/kg + Erlotinib Patritumab 9 mg/kg + Erlotinib
    Number of subjects analysed
    71 [2]
    70 [3]
    71 [4]
    Units: Months
        median (confidence interval 95%)
    1.6 (1.4 to 2.6)
    1.4 (1.3 to 2.7)
    2.5 (1.5 to 3)
    Notes
    [2] - 59 subjects had an event
    [3] - 58 subjects had an event
    [4] - 52 subjects had an event
    Statistical analysis title
    		 Stratified log-rank linear trend test for the dose
    Comparison groups
    Placebo + Erlotinib v Patritumab 18 mg/kg + Erlotinib v Patritumab 9 mg/kg + Erlotinib
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9166
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Progression-Free Survival Pairwise Comparisons
    Comparison groups
    Placebo + Erlotinib v Patritumab 18 mg/kg + Erlotinib
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.978
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.674
         upper limit
    		 1.42
    Statistical analysis title
    		 Progression-Free Survival Pairwise Comparisons
    Comparison groups
    Placebo + Erlotinib v Patritumab 9 mg/kg + Erlotinib
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.523
         upper limit
    		 1.131

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reported from time of Informed Consent to EOT visit assessment and up to 53 days after the last dose of U3-1287, or, if U3-1287 was discontinued earlier or if subject received erlotinib alone, up to 30 days after the last dose of erlotinib
    Adverse event reporting additional description
    AEs may have been directly observed, reported spontaneously by the subject or by questioning the subject at each study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Placebo + Erlotinib
    Reporting group description
    		 -

    Reporting group title
    U3-1287 9 mg/kg + Erlotinib
    Reporting group description
    		 -

    Reporting group title
    U3-1287 18 mg/kg + Erlotinib
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo + Erlotinib U3-1287 9 mg/kg + Erlotinib U3-1287 18 mg/kg + Erlotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 71 (33.80%)
    24 / 71 (33.80%)
    35 / 70 (50.00%)
         number of deaths (all causes)
    53
    53
    62
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 71 (2.82%)
    4 / 70 (5.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Puncture site pain
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    5 / 70 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
    Dyspnoea
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 71 (2.82%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    3 / 71 (4.23%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Alveolitis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skeletal injury
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia of malignant disease
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Panophthalmitis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         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
    Diarrhoea
         subjects affected / exposed
    1 / 71 (1.41%)
    5 / 71 (7.04%)
    4 / 70 (5.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Dysphagia
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         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 upper
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 71 (4.23%)
    3 / 71 (4.23%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 71 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         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
    		 Placebo + Erlotinib U3-1287 9 mg/kg + Erlotinib U3-1287 18 mg/kg + Erlotinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 71 (97.18%)
    70 / 71 (98.59%)
    69 / 70 (98.57%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 71 (18.31%)
    22 / 71 (30.99%)
    18 / 70 (25.71%)
         occurrences all number
    18
    27
    24
    General physical health deterioration
         subjects affected / exposed
    7 / 71 (9.86%)
    10 / 71 (14.08%)
    11 / 70 (15.71%)
         occurrences all number
    8
    10
    14
    Oedema peripheral
         subjects affected / exposed
    4 / 71 (5.63%)
    9 / 71 (12.68%)
    9 / 70 (12.86%)
         occurrences all number
    4
    10
    9
    Pyrexia
         subjects affected / exposed
    4 / 71 (5.63%)
    6 / 71 (8.45%)
    8 / 70 (11.43%)
         occurrences all number
    4
    7
    9
    Asthenia
         subjects affected / exposed
    6 / 71 (8.45%)
    4 / 71 (5.63%)
    7 / 70 (10.00%)
         occurrences all number
    9
    4
    8
    Mucosal inflammation
         subjects affected / exposed
    2 / 71 (2.82%)
    6 / 71 (8.45%)
    4 / 70 (5.71%)
         occurrences all number
    2
    7
    4
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 71 (7.04%)
    1 / 71 (1.41%)
    5 / 70 (7.14%)
         occurrences all number
    5
    1
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 71 (16.90%)
    17 / 71 (23.94%)
    12 / 70 (17.14%)
         occurrences all number
    14
    19
    14
    Cough
         subjects affected / exposed
    11 / 71 (15.49%)
    11 / 71 (15.49%)
    5 / 70 (7.14%)
         occurrences all number
    16
    13
    5
    Dysphonia
         subjects affected / exposed
    1 / 71 (1.41%)
    7 / 71 (9.86%)
    2 / 70 (2.86%)
         occurrences all number
    1
    7
    2
    Respiratory failure
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
    6 / 70 (8.57%)
         occurrences all number
    2
    0
    6
    Epistaxis
         subjects affected / exposed
    2 / 71 (2.82%)
    6 / 71 (8.45%)
    6 / 70 (8.57%)
         occurrences all number
    2
    6
    8
    Productive cough
         subjects affected / exposed
    4 / 71 (5.63%)
    6 / 71 (8.45%)
    3 / 70 (4.29%)
         occurrences all number
    5
    7
    3
    Haemoptysis
         subjects affected / exposed
    5 / 71 (7.04%)
    3 / 71 (4.23%)
    5 / 70 (7.14%)
         occurrences all number
    5
    3
    5
    Oropharyngeal pain
         subjects affected / exposed
    3 / 71 (4.23%)
    4 / 71 (5.63%)
    0 / 70 (0.00%)
         occurrences all number
    4
    4
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 71 (1.41%)
    0 / 70 (0.00%)
         occurrences all number
    5
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 71 (1.41%)
    4 / 71 (5.63%)
    2 / 70 (2.86%)
         occurrences all number
    1
    4
    2
    Investigations
    Weight decreased
         subjects affected / exposed
    8 / 71 (11.27%)
    16 / 71 (22.54%)
    10 / 70 (14.29%)
         occurrences all number
    11
    17
    14
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    2
    0
    4
    Dizziness
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 71 (5.63%)
    1 / 70 (1.43%)
         occurrences all number
    2
    4
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 71 (7.04%)
    6 / 71 (8.45%)
    7 / 70 (10.00%)
         occurrences all number
    7
    10
    11
    Anaemia of malignant disease
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
    5 / 70 (7.14%)
         occurrences all number
    1
    1
    5
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 71 (5.63%)
    5 / 70 (7.14%)
         occurrences all number
    3
    4
    5
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 71 (2.82%)
    5 / 71 (7.04%)
    4 / 70 (5.71%)
         occurrences all number
    6
    7
    4
    Lacrimation increased
         subjects affected / exposed
    0 / 71 (0.00%)
    5 / 71 (7.04%)
    0 / 70 (0.00%)
         occurrences all number
    0
    5
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    23 / 71 (32.39%)
    50 / 71 (70.42%)
    47 / 70 (67.14%)
         occurrences all number
    40
    65
    66
    Nausea
         subjects affected / exposed
    14 / 71 (19.72%)
    17 / 71 (23.94%)
    26 / 70 (37.14%)
         occurrences all number
    14
    24
    29
    Vomiting
         subjects affected / exposed
    5 / 71 (7.04%)
    7 / 71 (9.86%)
    18 / 70 (25.71%)
         occurrences all number
    12
    7
    22
    Constipation
         subjects affected / exposed
    4 / 71 (5.63%)
    10 / 71 (14.08%)
    9 / 70 (12.86%)
         occurrences all number
    4
    12
    9
    Abdominal pain
         subjects affected / exposed
    3 / 71 (4.23%)
    9 / 71 (12.68%)
    9 / 70 (12.86%)
         occurrences all number
    4
    10
    10
    Abdominal pain upper
         subjects affected / exposed
    8 / 71 (11.27%)
    5 / 71 (7.04%)
    5 / 70 (7.14%)
         occurrences all number
    9
    5
    5
    Dysphagia
         subjects affected / exposed
    2 / 71 (2.82%)
    7 / 71 (9.86%)
    0 / 70 (0.00%)
         occurrences all number
    2
    7
    0
    Stomatitis
         subjects affected / exposed
    0 / 71 (0.00%)
    3 / 71 (4.23%)
    6 / 70 (8.57%)
         occurrences all number
    0
    3
    6
    Dyspepsia
         subjects affected / exposed
    1 / 71 (1.41%)
    5 / 71 (7.04%)
    3 / 70 (4.29%)
         occurrences all number
    1
    6
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    28 / 71 (39.44%)
    38 / 71 (53.52%)
    35 / 70 (50.00%)
         occurrences all number
    55
    60
    58
    Dry skin
         subjects affected / exposed
    6 / 71 (8.45%)
    12 / 71 (16.90%)
    5 / 70 (7.14%)
         occurrences all number
    9
    14
    5
    Rash generalised
         subjects affected / exposed
    4 / 71 (5.63%)
    8 / 71 (11.27%)
    8 / 70 (11.43%)
         occurrences all number
    4
    16
    11
    Dermatitis acneiform
         subjects affected / exposed
    7 / 71 (9.86%)
    6 / 71 (8.45%)
    4 / 70 (5.71%)
         occurrences all number
    12
    9
    6
    Alopecia
         subjects affected / exposed
    4 / 71 (5.63%)
    4 / 71 (5.63%)
    6 / 70 (8.57%)
         occurrences all number
    4
    5
    6
    Pruritus
         subjects affected / exposed
    4 / 71 (5.63%)
    6 / 71 (8.45%)
    3 / 70 (4.29%)
         occurrences all number
    5
    6
    3
    Decubitus ulcer
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
    5 / 70 (7.14%)
         occurrences all number
    0
    1
    6
    Skin fissures
         subjects affected / exposed
    1 / 71 (1.41%)
    3 / 71 (4.23%)
    5 / 70 (7.14%)
         occurrences all number
    1
    3
    5
    Night sweats
         subjects affected / exposed
    4 / 71 (5.63%)
    2 / 71 (2.82%)
    1 / 70 (1.43%)
         occurrences all number
    4
    3
    1
    Pruritus generalised
         subjects affected / exposed
    0 / 71 (0.00%)
    4 / 71 (5.63%)
    2 / 70 (2.86%)
         occurrences all number
    0
    5
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 71 (5.63%)
    3 / 71 (4.23%)
    6 / 70 (8.57%)
         occurrences all number
    4
    3
    6
    Pain in extremity
         subjects affected / exposed
    1 / 71 (1.41%)
    6 / 71 (8.45%)
    4 / 70 (5.71%)
         occurrences all number
    1
    10
    5
    Musculoskeletal pain
         subjects affected / exposed
    4 / 71 (5.63%)
    3 / 71 (4.23%)
    4 / 70 (5.71%)
         occurrences all number
    6
    3
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 71 (4.23%)
    4 / 71 (5.63%)
    3 / 70 (4.29%)
         occurrences all number
    3
    7
    3
    Infections and infestations
    Paronychia
         subjects affected / exposed
    1 / 71 (1.41%)
    5 / 71 (7.04%)
    8 / 70 (11.43%)
         occurrences all number
    1
    5
    8
    Oral candidiasis
         subjects affected / exposed
    0 / 71 (0.00%)
    6 / 71 (8.45%)
    3 / 70 (4.29%)
         occurrences all number
    0
    6
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 71 (5.63%)
    5 / 70 (7.14%)
         occurrences all number
    2
    8
    6
    Nasopharyngitis
         subjects affected / exposed
    2 / 71 (2.82%)
    5 / 71 (7.04%)
    0 / 70 (0.00%)
         occurrences all number
    3
    8
    0
    Pneumonia
         subjects affected / exposed
    5 / 71 (7.04%)
    4 / 71 (5.63%)
    4 / 70 (5.71%)
         occurrences all number
    5
    10
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 71 (19.72%)
    17 / 71 (23.94%)
    18 / 70 (25.71%)
         occurrences all number
    17
    21
    19
    Hypokalaemia
         subjects affected / exposed
    3 / 71 (4.23%)
    11 / 71 (15.49%)
    12 / 70 (17.14%)
         occurrences all number
    3
    14
    17
    Dehydration
         subjects affected / exposed
    1 / 71 (1.41%)
    4 / 71 (5.63%)
    5 / 70 (7.14%)
         occurrences all number
    4
    4
    6
    Hyponatraemia
         subjects affected / exposed
    3 / 71 (4.23%)
    1 / 71 (1.41%)
    4 / 70 (5.71%)
         occurrences all number
    3
    1
    5
    Hypomagnesaemia
         subjects affected / exposed
    0 / 71 (0.00%)
    4 / 71 (5.63%)
    0 / 70 (0.00%)
         occurrences all number
    0
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2011
    1. An exclusion criterion to exclude subjects with a history of hypersensitivity to any of the study drugs or any excipients was added. 2. The window for the end-of-treatment visit was revised to 53 to 60 days after the last dose of study drug to ensure safety follow-up for at least 5 times the elimination half-life of U3-1287. 3. The extension phase of the protocol was deleted. 4. An independent Data Monitoring Committee (DMC) was to be established prior to the last subject in the Phase 1b portion of the study completing 1 cycle of treatment.

    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.
    Results released at ASCO: J Clin Oncol 32:5s, 2014 (suppl; abstr 8045)

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26137564
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    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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