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    Clinical Trial Results:
    A Phase II, Randomised, Multi-Centre Study Evaluating Lapatinib in Combination with Vinorelbine or Capecitabine in Women with ErbB2-Overexpressing Metastatic Breast Cancer Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2009-009885-15
    Trial protocol
    		 DE   FR   ES   IT   GR   BG  
    Global end of trial date
    01 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jul 2018
    First version publication date
    21 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LAP016A2205 (NVS)/LAP112620 (GSK)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01013740
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    01 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the progression-free survival in women with HER2-overexpressing metastatic breast cancer treated with lapatinib in combination with vinorelbine or capecitabine, who had received no more than 1 prior chemotherapeutic regimen in the metastatic setting;
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Nov 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Greece: 18
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Spain: 9
    Worldwide total number of subjects
    112
    EEA total number of subjects
    104
    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)
    84
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In the Randomized Phase (RP), participants were treated until disease progression (PD) or discontinuation of treatment due to unacceptable toxicity, withdrawal of consent, lost to follow-up, or death. After PD in the RP, participants were given the option of crossing over to the alternative treatment arm in a post-progression Cross-over Phase (CP).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lapatinib + capecitabine in RP; lapatinib + vinorelbine in CP
    Arm description
    		 Participants received a daily dose of 5 tablets of lapatinib (1250 milligrams [mg]) continuously at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received capecitabine 2000 mg per meters squared (mg/m^2) per day, divided and administered orally twice daily, 12 hours apart, for 14 days, every 21 days. Capecitabine was taken with food or within 30 minutes after food with approximately 200 milliliters (mL) of water. After disease progression in the Randomized Phase (in which participants received lapatinib plus vinorelbine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus capecitabine), and continuing in a post-progression Cross-over Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    LAP016
    Other name
    LAP112620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LAPATINIB 1250 mg orally once daily

    Investigational medicinal product name
    capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2000 mg/m2/day orally in 2 doses 12 hours apart on Days 1 to 14 every third week

    Arm title
    		 Lapatinib + vinorelbine in RP; lapatinib + capecitabine in CP
    Arm description
    		 Participants received a daily dose of 5 tablets of lapatinib (1250 mg) at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received an intravenous (IV) infusion of vinorelbine 20 mg/m^2 over the course of 5 to 10 minutes on Days 1 and 8 of a 21-day treatment cycle. After disease progression in the Randomized Phase (in which participants received lapatinib plus capecitabine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus vinorelbine), and continuing in a post-progression Cross-over Phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/m2 IV on Day 1 and 8, every third week

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    LAP016
    Other name
    LAP112620
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LAPATINIB 1250 mg orally once daily

    Number of subjects in period 1
    		Lapatinib + capecitabine in RP; lapatinib + vinorelbine in CP Lapatinib + vinorelbine in RP; lapatinib + capecitabine in CP
    Started
    37
    75
    Completed
    26
    56
    Not completed
    11
    19
         Consent withdrawn by subject
    2
    10
         Physician decision
    2
    -
         Ongoing: Study records not completed
    -
    2
         study close / terminated : done in error
    2
    1
         Lost to follow-up
    3
    5
         Missing
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lapatinib + capecitabine in RP; lapatinib + vinorelbine in CP
    Reporting group description
    		 Participants received a daily dose of 5 tablets of lapatinib (1250 milligrams [mg]) continuously at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received capecitabine 2000 mg per meters squared (mg/m^2) per day, divided and administered orally twice daily, 12 hours apart, for 14 days, every 21 days. Capecitabine was taken with food or within 30 minutes after food with approximately 200 milliliters (mL) of water. After disease progression in the Randomized Phase (in which participants received lapatinib plus vinorelbine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus capecitabine), and continuing in a post-progression Cross-over Phase.

    Reporting group title
    Lapatinib + vinorelbine in RP; lapatinib + capecitabine in CP
    Reporting group description
    		 Participants received a daily dose of 5 tablets of lapatinib (1250 mg) at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received an intravenous (IV) infusion of vinorelbine 20 mg/m^2 over the course of 5 to 10 minutes on Days 1 and 8 of a 21-day treatment cycle. After disease progression in the Randomized Phase (in which participants received lapatinib plus capecitabine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus vinorelbine), and continuing in a post-progression Cross-over Phase.

    Reporting group values
    		 Lapatinib + capecitabine in RP; lapatinib + vinorelbine in CP Lapatinib + vinorelbine in RP; lapatinib + capecitabine in CP Total
    Number of subjects
    		 37 75 112
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 27 57 84
        From 65-84 years
    		 10 18 28
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 37 75 112
        Male
    		 0 0 0
    AgeContinuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 57.5 ± 10.9 57.7 ± 10.23 -

    End points

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    End points reporting groups
    Reporting group title
    Lapatinib + capecitabine in RP; lapatinib + vinorelbine in CP
    Reporting group description
    		 Participants received a daily dose of 5 tablets of lapatinib (1250 milligrams [mg]) continuously at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received capecitabine 2000 mg per meters squared (mg/m^2) per day, divided and administered orally twice daily, 12 hours apart, for 14 days, every 21 days. Capecitabine was taken with food or within 30 minutes after food with approximately 200 milliliters (mL) of water. After disease progression in the Randomized Phase (in which participants received lapatinib plus vinorelbine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus capecitabine), and continuing in a post-progression Cross-over Phase.

    Reporting group title
    Lapatinib + vinorelbine in RP; lapatinib + capecitabine in CP
    Reporting group description
    		 Participants received a daily dose of 5 tablets of lapatinib (1250 mg) at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received an intravenous (IV) infusion of vinorelbine 20 mg/m^2 over the course of 5 to 10 minutes on Days 1 and 8 of a 21-day treatment cycle. After disease progression in the Randomized Phase (in which participants received lapatinib plus capecitabine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus vinorelbine), and continuing in a post-progression Cross-over Phase.

    Subject analysis set title
    Lapatinib plus capecitabine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a daily dose of 5 tablets of lapatinib (1250 milligrams [mg]) continuously at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received capecitabine 2000 mg per meters squared (mg/m^2) per day, divided and administered orally twice daily, 12 hours apart, for 14 days, every 21 days. Capecitabine was taken with food or within 30 minutes after food with approximately 200 milliliters (mL) of water.

    Subject analysis set title
    Lapatinib plus vinorelbine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a daily dose of 5 tablets of lapatinib (1250 mg) at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received an intravenous (IV) infusion of vinorelbine 20 mg/m^2 over the course of 5 to 10 minutes on Days 1 and 8 of a 21-day treatment cycle.

    Subject analysis set title
    Lapatinib plus Capecitabine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a daily dose of 5 tablets of lapatinib (1250 milligrams [mg]) continuously at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received capecitabine 2000 mg per meters squared (mg/m^2) per day, divided and administered orally twice daily, 12 hours apart, for 14 days, every 21 days. Capecitabine was taken with food or within 30 minutes after food with approximately 200 milliliters (mL) of water.

    Subject analysis set title
    Lapatinib plus Vinorelbine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a daily dose of 5 tablets of lapatinib (1250 mg) at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received an intravenous (IV) infusion of vinorelbine 20 mg/m^2 over the course of 5 to 10 minutes on Days 1 and 8 of a 21-day treatment cycle.

    Subject analysis set title
    Lapatinib plus Capecitabine
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received a daily dose of 5 tablets of lapatinib (1250 milligrams [mg]) continuously at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received capecitabine 2000 mg per meters squared (mg/m^2) per day, divided and administered orally twice daily, 12 hours apart, for 14 days, every 21 days. Capecitabine was taken with food or within 30 minutes after food with approximately 200 milliliters (mL) of water.

    Subject analysis set title
    Lapatinib plus Vinorelbine
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received a daily dose of 5 tablets of lapatinib (1250 mg) at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received an intravenous (IV) infusion of vinorelbine 20 mg/m^2 over the course of 5 to 10 minutes on Days 1 and 8 of a 21-day treatment cycle.

    Subject analysis set title
    Lapatinib plus Capecitabine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a daily dose of 5 tablets of lapatinib (1250 milligrams [mg]) continuously at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received capecitabine 2000 mg per meters squared (mg/m^2) per day, divided and administered orally twice daily, 12 hours apart, for 14 days, every 21 days. Capecitabine was taken with food or within 30 minutes after food with approximately 200 milliliters (mL) of water.

    Subject analysis set title
    Lapatinib plus Vinorelbine
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received a daily dose of 5 tablets of lapatinib (1250 mg) at approximately the same time every day, either 1 hour (or more) before food or 1 hour (or more) after food. Participants also received an intravenous (IV) infusion of vinorelbine 20 mg/m^2 over the course of 5 to 10 minutes on Days 1 and 8 of a 21-day treatment cycle.

    Primary: Progression Free Survival (PFS) in the Randomized Phase

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    End point title
    		 Progression Free Survival (PFS) in the Randomized Phase
    End point description
    PFS is defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause, if sooner. PD is defined as at least a 20 % increase in the sum of the longest diameter (LD) of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesion.
    End point type
    Primary
    End point timeframe
    From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
    End point values
    		 Lapatinib plus capecitabine Lapatinib plus vinorelbine
    Number of subjects analysed
    37
    75
    Units: months
        median (confidence interval 95%)
    6.2 (4.4 to 8.3)
    6.2 (4.2 to 8.8)
    Statistical analysis title
    		 Analysis of PFS L+C vs L+ V
    Comparison groups
    Lapatinib plus capecitabine v Lapatinib plus vinorelbine
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.35

    Secondary: Number of participants with Overall Response (OR), as assessed by the investigator in the Randomized Phase

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    End point title
    		 Number of participants with Overall Response (OR), as assessed by the investigator in the Randomized Phase
    End point description
    OR is defined as the number of participants achieving either a confirmed complete response (CR: the disappearance of all target lesions [TLs]) or partial response (PR: a >=30% decrease in the sum of the longest diameter [LD] of the TLs, taking as reference the baseline sum LD) as assessed by the investigator as the best OR.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
    End point values
    		 Lapatinib plus Capecitabine Lapatinib plus Vinorelbine
    Number of subjects analysed
    37
    75
    Units: participants
    13
    15
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from randomization to the date of death due to any cause. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until death (average of 55 study weeks)
    End point values
    		 Lapatinib plus Capecitabine Lapatinib plus Vinorelbine
    Number of subjects analysed
    37
    75
    Units: months
        median (confidence interval 95%)
    19.4 (16.4 to 27.2)
    24.3 (16.4 to 9999999)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) in the Randomized Phase

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    End point title
    		 Duration of response (DOR) in the Randomized Phase
    End point description
    DOR is defined as the time from the first documented evidence of response (CR or PR) until the first documented sign of disease progression (a >=20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesion) or death, if sooner. CR=the disappearance of all TLs. PR=a >=30% decrease in the sum of the LD of target lesions, taking as a reference the Baseline sum LD.
    End point type
    Secondary
    End point timeframe
    From the time of the first documented confirmed complete or partial response until disease progression or death, if sooner (average of 27 study weeks)
    End point values
    		 Lapatinib plus Capecitabine Lapatinib plus Vinorelbine
    Number of subjects analysed
    13
    15
    Units: months
        median (confidence interval 95%)
    10.8 (4.3 to 9999)
    6.7 (4.6 to 8.3)
    No statistical analyses for this end point

    Secondary: Time to response in the Randomized Phase

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    End point title
    		 Time to response in the Randomized Phase
    End point description
    Time to response is defined as the time from randomization until the first documented evidence of CR (the disappearance of all TLs) or PR (a >=30% decrease in the sum of the LD of the TLs, taking as a reference the basline sum LD) (whichever status is recorded first). When tumor response was confirmed at a repeat assessment, the time to response was taken to be the first time that the response was observed.
    End point type
    Secondary
    End point timeframe
    From randomization until the time of the first documented confirmed CR or PR (average of 27 study weeks)
    End point values
    		 Lapatinib plus Capecitabine Lapatinib plus Vinorelbine
    Number of subjects analysed
    13
    15
    Units: weeks
        median (confidence interval 95%)
    9.3 (9.1 to 10)
    9.4 (9 to 10.1)
    No statistical analyses for this end point

    Secondary: Number of participants with clinical benefit (CB) in the Randomized Phase

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    End point title
    		 Number of participants with clinical benefit (CB) in the Randomized Phase
    End point description
    CB is defined as the the number of participants achieving either a confirmed CR or PR or having stable disease (SD) for at least 24 weeks (i.e., approximately 6 months). CR=the disappearance of all TLs. PR=a >=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD=at least a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesion). Participants with unknown or missing responses were treated as non-responders.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks)
    End point values
    		 Lapatinib plus Capecitabine Lapatinib plus Vinorelbine
    Number of subjects analysed
    37
    75
    Units: participants
    18
    29
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve over the dosing interval (AUC-tau) for vinorelbine

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    End point title
    		 Area under the concentration-time curve over the dosing interval (AUC-tau) for vinorelbine
    End point description
    AUC-tau is defined as the area under the concentration-time curve over a dosing interval at steady state, where tau is the length of the dosing interval. The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. Pharmacokinetic (PK) parameters were to be assessed in an optional sub-study. No participants were enrolled in this optional sub-study; thus, no PK data are available.
    End point type
    Secondary
    End point timeframe
    Days 1 and 8; 0 to 24 hours post-dose
    End point values
    		 Lapatinib plus Capecitabine Lapatinib plus Vinorelbine
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: nanograms*hour/milliliter
    Notes
    [1] - No participants were enrolled in this optional sub-study; thus, no PK data are available.
    [2] - No participants were enrolled in this optional sub-study; thus, no PK data are available.
    No statistical analyses for this end point

    Secondary: Maximum concentration (Cmax) for vinorelbine

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    End point title
    		 Maximum concentration (Cmax) for vinorelbine
    End point description
    Cmax is defined as the maximum observed plasma or serum concentration after administration of the drug. PK parameters were to be assessed in an optional sub-study. No participants were enrolled in this optional sub-study; thus, no PK data are available.
    End point type
    Secondary
    End point timeframe
    Days 1 and 8; 0 to 24 hours post-dose
    End point values
    		 Lapatinib plus Capecitabine Lapatinib plus Vinorelbine
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: nanograms per milliliter
        number (not applicable)
    Notes
    [3] - No participants were enrolled in this optional sub-study; thus, no PK data are available.
    [4] - No participants were enrolled in this optional sub-study; thus, no PK data are available.
    No statistical analyses for this end point

    Secondary: Number of participants with Grade 4 and Grade 5 adverse events (AE)

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    End point title
    		 Number of participants with Grade 4 and Grade 5 adverse events (AE)
    End point description
    An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grades: 0 = no AE or within normal limits; 1 = mild AE; 2 = moderate AE; 3 = severe and undesirable AE; 4 = life-threatening or disabling AE; 5 = death related to AE.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression, death, or discontinuation from the study (average of 55 study weeks)
    End point values
    		 Lapatinib plus Capecitabine Lapatinib plus Vinorelbine
    Number of subjects analysed
    37
    75
    Units: participants
        Helicobacter gastritis, Grade 4
    1
    0
        Neutropenia, Grade 4
    0
    9
        Leukopenia, Grade 4
    0
    1
        Febrile neutropenia, Grade 4
    0
    1
        Mucosal inflammation, Grade 4
    0
    1
        Pulmonary embolism, Grade 4
    0
    1
        Intestinal obstruction, Grade 5
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All other adverse events are monitored from First Subject First Treatment until LSLV.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Randomized phase Lapatinib 1250mg QD + Capecitabine 2000mg/m2
    Reporting group description
    		 Randomized phase Lapatinib 1250mg QD + Capecitabine 2000mg/m2

    Reporting group title
    Randomized phase Lapatinib 1250mg QD + Vinorelbine 20mg/m2
    Reporting group description
    		 Randomized phase Lapatinib 1250mg QD + Vinorelbine 20mg/m2

    Reporting group title
    Crossover phase Lapatinib 1250mg QD + Capecitabine 2000mg/m2
    Reporting group description
    		 Crossover phase Lapatinib 1250mg QD + Capecitabine 2000mg/m2

    Reporting group title
    Crossover phase Lapatinib 1250mg QD + Vinorelbine 20mg/m2
    Reporting group description
    		 Crossover phase Lapatinib 1250mg QD + Vinorelbine 20mg/m2

    Serious adverse events
    		 Randomized phase Lapatinib 1250mg QD + Capecitabine 2000mg/m2 Randomized phase Lapatinib 1250mg QD + Vinorelbine 20mg/m2 Crossover phase Lapatinib 1250mg QD + Capecitabine 2000mg/m2 Crossover phase Lapatinib 1250mg QD + Vinorelbine 20mg/m2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 37 (10.81%)
    25 / 75 (33.33%)
    3 / 37 (8.11%)
    4 / 17 (23.53%)
         number of deaths (all causes)
    1
    3
    4
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    0 / 17 (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
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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 / 37 (0.00%)
    2 / 75 (2.67%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Product issues
    Device leakage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Nervous system disorders
    Paraplegia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 75 (2.67%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 75 (2.67%)
    0 / 37 (0.00%)
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 37 (0.00%)
    10 / 75 (13.33%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    11 / 11
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    0 / 17 (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
    Diarrhoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Cholestasis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Infections and infestations
    Helicobacter gastritis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    0 / 17 (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
    Herpes zoster
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Lymphangitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomized phase Lapatinib 1250mg QD + Capecitabine 2000mg/m2 Randomized phase Lapatinib 1250mg QD + Vinorelbine 20mg/m2 Crossover phase Lapatinib 1250mg QD + Capecitabine 2000mg/m2 Crossover phase Lapatinib 1250mg QD + Vinorelbine 20mg/m2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 37 (86.49%)
    72 / 75 (96.00%)
    27 / 37 (72.97%)
    15 / 17 (88.24%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 75 (2.67%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    3
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 37 (13.51%)
    10 / 75 (13.33%)
    3 / 37 (8.11%)
    0 / 17 (0.00%)
         occurrences all number
    5
    12
    3
    0
    Axillary pain
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 37 (8.11%)
    17 / 75 (22.67%)
    1 / 37 (2.70%)
    2 / 17 (11.76%)
         occurrences all number
    4
    19
    1
    2
    Inflammation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 75 (2.67%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    0
    1
    Injection site reaction
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 37 (0.00%)
    9 / 75 (12.00%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    0
    11
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 37 (2.70%)
    7 / 75 (9.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    7
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    1 / 37 (2.70%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 37 (2.70%)
    10 / 75 (13.33%)
    2 / 37 (5.41%)
    2 / 17 (11.76%)
         occurrences all number
    1
    12
    2
    5
    Reproductive system and breast disorders
    Vaginal inflammation
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 37 (2.70%)
    9 / 75 (12.00%)
    0 / 37 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    1
    10
    0
    3
    Dyspnoea
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 75 (5.33%)
    2 / 37 (5.41%)
    1 / 17 (5.88%)
         occurrences all number
    3
    5
    2
    1
    Epistaxis
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 75 (4.00%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    2
    8
    2
    0
    Haemoptysis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    1 / 37 (2.70%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    3
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 75 (5.33%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    4
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 37 (8.11%)
    8 / 75 (10.67%)
    4 / 37 (10.81%)
    2 / 17 (11.76%)
         occurrences all number
    4
    12
    5
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 37 (10.81%)
    8 / 75 (10.67%)
    5 / 37 (13.51%)
    2 / 17 (11.76%)
         occurrences all number
    4
    12
    6
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 75 (5.33%)
    3 / 37 (8.11%)
    1 / 17 (5.88%)
         occurrences all number
    1
    6
    3
    1
    Blood bilirubin increased
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 75 (0.00%)
    1 / 37 (2.70%)
    1 / 17 (5.88%)
         occurrences all number
    7
    0
    1
    1
    Blood calcium increased
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 75 (6.67%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Weight decreased
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 75 (5.33%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    3
    9
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 75 (6.67%)
    2 / 37 (5.41%)
    0 / 17 (0.00%)
         occurrences all number
    0
    5
    2
    0
    Headache
         subjects affected / exposed
    2 / 37 (5.41%)
    8 / 75 (10.67%)
    2 / 37 (5.41%)
    2 / 17 (11.76%)
         occurrences all number
    2
    10
    4
    2
    Neuropathy peripheral
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 75 (6.67%)
    2 / 37 (5.41%)
    0 / 17 (0.00%)
         occurrences all number
    0
    5
    3
    0
    Paraesthesia
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 75 (2.67%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 37 (0.00%)
    8 / 75 (10.67%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    13
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 37 (5.41%)
    13 / 75 (17.33%)
    2 / 37 (5.41%)
    2 / 17 (11.76%)
         occurrences all number
    4
    19
    2
    2
    Febrile neutropenia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    3 / 37 (8.11%)
    11 / 75 (14.67%)
    1 / 37 (2.70%)
    2 / 17 (11.76%)
         occurrences all number
    3
    40
    1
    2
    Neutropenia
         subjects affected / exposed
    3 / 37 (8.11%)
    34 / 75 (45.33%)
    2 / 37 (5.41%)
    7 / 17 (41.18%)
         occurrences all number
    4
    117
    4
    29
    Thrombocytopenia
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 75 (4.00%)
    2 / 37 (5.41%)
    1 / 17 (5.88%)
         occurrences all number
    0
    3
    2
    3
    Eye disorders
    Ophthalmoplegia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 37 (5.41%)
    7 / 75 (9.33%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    3
    7
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 75 (8.00%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    6
    0
    0
    Constipation
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 75 (8.00%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    3
    6
    0
    0
    Diarrhoea
         subjects affected / exposed
    21 / 37 (56.76%)
    35 / 75 (46.67%)
    7 / 37 (18.92%)
    1 / 17 (5.88%)
         occurrences all number
    39
    65
    11
    1
    Dyspepsia
         subjects affected / exposed
    0 / 37 (0.00%)
    6 / 75 (8.00%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    0
    6
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    3 / 37 (8.11%)
    20 / 75 (26.67%)
    6 / 37 (16.22%)
    0 / 17 (0.00%)
         occurrences all number
    3
    31
    9
    0
    Stomatitis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    1 / 37 (2.70%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    1
    1
    Vomiting
         subjects affected / exposed
    4 / 37 (10.81%)
    13 / 75 (17.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    4
    20
    0
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    1 / 37 (2.70%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    5
    Hyperbilirubinaemia
         subjects affected / exposed
    6 / 37 (16.22%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    49
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 75 (8.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    6
    0
    1
    Erythema
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 75 (1.33%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Nail disorder
         subjects affected / exposed
    4 / 37 (10.81%)
    2 / 75 (2.67%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    4
    2
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    24 / 37 (64.86%)
    6 / 75 (8.00%)
    18 / 37 (48.65%)
    0 / 17 (0.00%)
         occurrences all number
    32
    6
    23
    0
    Rash
         subjects affected / exposed
    5 / 37 (13.51%)
    15 / 75 (20.00%)
    2 / 37 (5.41%)
    1 / 17 (5.88%)
         occurrences all number
    6
    19
    2
    1
    Skin fissures
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 75 (2.67%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 37 (8.11%)
    9 / 75 (12.00%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    3
    16
    3
    0
    Back pain
         subjects affected / exposed
    1 / 37 (2.70%)
    7 / 75 (9.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    11
    0
    0
    Bone pain
         subjects affected / exposed
    2 / 37 (5.41%)
    7 / 75 (9.33%)
    0 / 37 (0.00%)
    3 / 17 (17.65%)
         occurrences all number
    2
    7
    0
    3
    Myalgia
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 75 (6.67%)
    2 / 37 (5.41%)
    0 / 17 (0.00%)
         occurrences all number
    0
    8
    4
    0
    Neck pain
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 37 (8.11%)
    8 / 75 (10.67%)
    4 / 37 (10.81%)
    2 / 17 (11.76%)
         occurrences all number
    3
    8
    4
    2
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 75 (5.33%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    4
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 75 (2.67%)
    1 / 37 (2.70%)
    1 / 17 (5.88%)
         occurrences all number
    1
    3
    1
    1
    Herpes zoster
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 75 (5.33%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    1
    7
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Paronychia
         subjects affected / exposed
    5 / 37 (13.51%)
    2 / 75 (2.67%)
    2 / 37 (5.41%)
    0 / 17 (0.00%)
         occurrences all number
    7
    2
    3
    0
    Pharyngitis
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 37 (5.41%)
    5 / 75 (6.67%)
    1 / 37 (2.70%)
    0 / 17 (0.00%)
         occurrences all number
    2
    6
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 37 (5.41%)
    12 / 75 (16.00%)
    2 / 37 (5.41%)
    0 / 17 (0.00%)
         occurrences all number
    2
    14
    2
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    0
    6
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 75 (5.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 75 (1.33%)
    0 / 37 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Hypochloraemia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 75 (0.00%)
    0 / 37 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2015
    Following analysis and reporting of the study primary efficacy and safety data and of updated overall survival rates, further collection and analysis of study efficacy and safety data is unlikely to change the overall outcome of the study or interpretation of the primary analysis of the study data. This amendment will discontinue collection of many study-specific assessments while allowing subjects currently on active study treatment to have continued access to treatment until the occurrence of unacceptable toxicity or disease progression (as determined by the investigator) or permanent withdrawal from treatment for any reason. Subjects who have completed study treatment and are in the follow up phase will be withdrawn from the study with no further follow up.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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