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    Clinical Trial Results:
    A Phase III Study for ErbB2 Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Junction Adenocarcinoma treated with Capecitabine plus Oxaliplatin with or without Lapatinib

    Summary
    EudraCT number
    		 2007-005725-29
    Trial protocol
    		 EE   IT   NL   HU  
    Global end of trial date
    03 Oct 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EGF110656
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00680901
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CLAP016C2301: Novartis
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Lichtstrasse 35, Basel, Switzerland, 4056
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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
    03 Oct 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was an international multi-center trial that enrolled patients with locally advanced, unresectable, or metastatic gastric, esophageal, or gastro-esophageal junction cancer whose tumors had amplification of the ErbB2 (HER2) gene. The trial investigated whether lapatinib, when added to the chemotherapy regimen, capecitabine plus oxaliplatin (CapeOx), extended the time to progression and overall survival. Tumor ErbB2 (HER2) status had to be known before trial entry. CapeOx was administered to all patients, and patients were randomly assigned to receive either lapatinib or placebo.
    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
    04 Jun 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 16
    Country: Number of subjects enrolled
    Brazil: 29
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    China: 120
    Country: Number of subjects enrolled
    Estonia: 10
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    India: 18
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 38
    Country: Number of subjects enrolled
    Korea, Republic of: 92
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Peru: 5
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Russian Federation: 62
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Türkiye: 1
    Country: Number of subjects enrolled
    Ukraine: 48
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    545
    EEA total number of subjects
    105
    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)
    368
    From 65 to 84 years
    176
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 186 centers in 21 countries in North America (Canada and US), Asia (China, Hong Kong, Korea and Taiwan), and Rest of World (ROW) (Argentina, Brazil, Chile, Estonia, Hungary, India, Israel, Italy, Mexico, Netherlands, Peru, Poland, Russian Federation, Turkey, and Ukraine).

    Pre-assignment
    Screening details
    		 Participants were randomized into one of two treatment arms: CapeOx plus lapatinib (the experimental arm) or CapeOx plus placebo (the control arm) using a 1:1 randomization.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CapeOx plus Lapatinib
    Arm description
    		 Participants received a combination therapy consisting of: 1) Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2) Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator’s discretion. 3) Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    5 pills at 250mg each once daily

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    130mg/m2 on day 1

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1700mg/m2/day in two daily doses

    Arm title
    		 CapeOx plus Placebo
    Arm description
    		 Participants received a combination therapy consisting of: 1) Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2) Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator’s discretion. 3) Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pillules
    Routes of administration
    Oral use
    Dosage and administration details
    5 pills each once daily

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion, Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    130mg/m2 on day 1

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1700mg/m2/day in two daily doses

    Number of subjects in period 1
    		CapeOx plus Lapatinib CapeOx plus Placebo
    Started
    272
    273
    Primary Efficacy (PE) population
    249
    238
    Safety population
    270
    267
    Ongoing: On Study Treatment
    1 [1]
    0 [2]
    Ongoing: In Follow Up
    1 [3]
    0 [4]
    Completed
    243
    233
    Not completed
    29
    40
         Physician decision
    -
    2
         Adverse event, non-fatal
    1
    1
         Ongoing: On Study Treatment
    1
    -
         Other protocol defined stopping criteria
    17
    17
         Ongoing: In Follow Up
    1
    -
         Lost to follow-up
    3
    5
         Sponsor decision
    1
    -
         Subject reached protocol defined stopping criteria
    1
    -
         Subject decided to withdraw from the study
    4
    15
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Due to local regulations in China, data from Chinese subjects dated from 01-Jul-2016 onward was excluded. As noted in the primary CSR, the subject had been withdrawn from the study on 05 Apr 2011 due to being lost to follow-up, and overall survival was unknown. However, a data transition issue from the previous database (TRIO) led to the subject being incorrectly reported as "ongoing" for study arm "CapeOx plus Lapatinib"
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Due to local regulations in China (HGRAC), data collection at all sites in China was immediately stopped as of 01-Jul-2016. No data from Chinese subjects was transferred or processed thereafter. Consequently, one subject was marked as "ongoing" in the database for study arm "CapeOx plus Lapatinib"
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Due to local regulations in China (HGRAC), data collection at all sites in China was immediately stopped as of 01-Jul-2016. No data from Chinese subjects was transferred or processed thereafter. Consequently, one subject was marked as "ongoing" in the database for study arm "CapeOx plus Lapatinib"
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Due to local regulations in China, data from Chinese subjects dated from 01-Jul-2016 onward was excluded. As noted in the primary CSR, the subject had been withdrawn from the study on 05 Apr 2011 due to being lost to follow-up, and overall survival was unknown. However, a data transition issue from the previous database (TRIO) led to the subject being incorrectly reported as "ongoing" for study arm "CapeOx plus Lapatinib"

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CapeOx plus Lapatinib
    Reporting group description
    		 Participants received a combination therapy consisting of: 1) Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2) Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator’s discretion. 3) Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    CapeOx plus Placebo
    Reporting group description
    		 Participants received a combination therapy consisting of: 1) Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2) Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator’s discretion. 3) Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group values
    		 CapeOx plus Lapatinib CapeOx plus Placebo Total
    Number of subjects
    		 272 273 545
    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)
    		 183 185 368
        From 65-84 years
    		 88 88 176
        85 years and over
    		 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 66 73 139
        Male
    		 206 200 406
    GenderNIH
    Units: Subjects
        Female
    		 66 73 139
        Male
    		 206 200 406
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage (Hrtg)
    		 2 3 5
        American Indian or Alaska Native
    		 3 3 6
        Central/South Asian Hrtg
    		 11 3 14
        Japanese/East Asian Hrtg/South East Asian Hrtg
    		 112 114 226
        White
    		 144 150 294
    AgeContinuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.4 ( 11.20 ) 58.5 ( 11.23 ) -

    End points

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    End points reporting groups
    Reporting group title
    CapeOx plus Lapatinib
    Reporting group description
    		 Participants received a combination therapy consisting of: 1) Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2) Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator’s discretion. 3) Lapatinib: 1250 mg orally once daily, starting on Day 1 and continued daily throughout the cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and lapatinib were continued until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    CapeOx plus Placebo
    Reporting group description
    		 Participants received a combination therapy consisting of: 1) Oxaliplatin (Ox): 130 mg/m² intravenously on Day 1 of each 21-day cycle, for up to 8 cycles. 2) Capecitabine (Cape): 1700 mg/m² per day, taken orally in two divided doses from the evening of Day 1 to the morning of Day 15 (28 doses per cycle), followed by a minimum 6.5-day rest period. The dose could be increased to 2000 mg/m²/day after the first cycle at the investigator’s discretion. 3) Lapatinib matching placebo: Taken orally once daily starting on Day 1 and continued throughout each cycle, including the rest period. After discontinuing oxaliplatin, capecitabine and the lapatinib placebo were continued until disease progression, unacceptable toxicity, or withdrawal of consent.

    Primary: Overall Survival in all randomized participants at the time of Primary Analysis

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    End point title
    		 Overall Survival in all randomized participants at the time of Primary Analysis
    End point description
    Overall Survival was defined as the time from randomization to death from any cause. Participants who had not died were censored at their follow-up visit, either because follow-up had ended or was still ongoing.
    End point type
    Primary
    End point timeframe
    From date of randomization till death due to any cause, assessed up the cut-off date for Primary Analysis (24-Sep-2012) (average of 4 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    272
    273
    Units: Months
        median (confidence interval 95%)
    11.9 (10.4 to 13.8)
    10.4 (9.1 to 11.3)
    Statistical analysis title
    		 Primary Analysis: OS (ITT population)
    Comparison groups
    CapeOx plus Lapatinib v CapeOx plus Placebo
    Number of subjects included in analysis
    545
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3244 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.1
    Notes
    [1] - Stratified log-rank test was conducted stratifying for prior adjuvant/neo-adjuvant treatment use and region.

    Primary: Overall Survival at the time of Primary Analysis

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    End point title
    		 Overall Survival at the time of Primary Analysis
    End point description
    Overall Survival was defined as the time from randomization to death from any cause. Participants who had not died were censored at their follow-up visit, either because follow-up had ended or was still ongoing.
    End point type
    Primary
    End point timeframe
    From date of randomization till death due to any cause, assessed up the cut-off date for Primary Analysis (24-Sep-2012) (average of 4 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    249
    238
    Units: Months
        median (confidence interval 95%)
    12.2 (10.6 to 14.2)
    10.5 (9.0 to 11.3)
    Statistical analysis title
    		 Primary Analysis: OS (PE population)
    Comparison groups
    CapeOx plus Lapatinib v CapeOx plus Placebo
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3492 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.12
    Notes
    [2] - Stratified log-rank test was conducted stratifying for prior adjuvant/neo-adjuvant treatment use and region.

    Secondary: Overall Survival at the time of Final Analysis

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    End point title
    		 Overall Survival at the time of Final Analysis
    End point description
    Overall Survival was defined as the time from randomization to death from any cause. Participants who had not died were censored at their follow-up visit, either because follow-up had ended or was still ongoing.
    End point type
    Secondary
    End point timeframe
    From date of randomization till death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    249
    238
    Units: Months
        median (confidence interval 95%)
    12.0 (10.4 to 13.8)
    10.4 (9.0 to 11.3)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression-Free Survival (PFS) was defined as the time from randomization to the earliest occurrence of disease progression or death from any cause. Per RECIST v1.0, progression was defined as at least a 20% increase in the sum of diameters of target lesions from the smallest recorded sum or the appearance of one or more new lesions. Participants with symptomatic progression, even without radiological confirmation, were also counted. Those who had neither progressed nor died were censored at their follow-up visit, either because follow-up had ended or was ongoing. Participants who received non-study anti-cancer therapies before progression were also censored.
    End point type
    Secondary
    End point timeframe
    From date of randomization till the earliest date of disease progression or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    249
    238
    Units: Months
        median (confidence interval 95%)
    6.2 (5.6 to 7.0)
    5.4 (4.4 to 5.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with a confirmed Complete Response (CR) or a Partial Response (PR)

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    End point title
    		 Percentage of Participants with a confirmed Complete Response (CR) or a Partial Response (PR)
    End point description
    A participant was considered a responder if they had achieved either a complete response (CR), defined as the disappearance of all target and non-target lesions, or a partial response (PR), defined as at least a 30% reduction in the sum of the longest diameters of target lesions from baseline, as assessed by the investigator and confirmed by radiographic imaging within four weeks of the initial observation.
    End point type
    Secondary
    End point timeframe
    From date of randomization till the date of the first documented response of CR or PR, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    249
    238
    Units: Participants
    131
    94
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Clinical Benefit (CB)

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    End point title
    		 Percentage of Participants with Clinical Benefit (CB)
    End point description
    Clinical Benefit (CB) was defined as evidence of a complete response (CR), partial response (PR), or stable disease (SD). CR referred to the disappearance of all target and non-target lesions, PR to at least a 30% reduction in the sum of the longest diameters of target lesions from baseline, and SD to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression, based on the smallest sum of diameters recorded since treatment initiation. All assessments were made by the investigator.
    End point type
    Secondary
    End point timeframe
    From date of randomization till date of disease progression (PD) or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    249
    238
    Units: Participants
    199
    188
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of Response (DOR) was defined as the time from the first documented evidence of a complete response (CR) or partial response (PR) until the first recorded sign of disease progression or death from any cause. According to RECIST, progression was defined as at least a 20% increase in the sum of diameters of target lesions from the smallest recorded sum or the appearance of one or more new lesions. Participants who had neither progressed nor died were censored at their follow-up visit, either because follow-up had ended or was ongoing. Those who received non-study anti-cancer therapies before progression were also censored.
    End point type
    Secondary
    End point timeframe
    From the time of the first documented evidence of a confirmed CR or PR until the earliest date of disease progression or death due to any cause, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    131
    94
    Units: Months
        median (confidence interval 95%)
    7.3 (6.4 to 8.5)
    5.6 (4.6 to 6.0)
    No statistical analyses for this end point

    Secondary: Time to response (TTR)

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    End point title
    		 Time to response (TTR)
    End point description
    Time to Response (TTR) was defined as the duration from randomization to the first documented evidence of either a complete response (CR) (the disappearance of all target and non-target lesions) or a partial response (PR) (at least a 30% reduction in the sum of the longest diameters of target lesions from baseline) as assessed by the investigator.
    End point type
    Secondary
    End point timeframe
    From date of randomization till the first documented evidence of confirmed CR or PR, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    131
    94
    Units: Months
        median (confidence interval 95%)
    1.4 (1.4 to 1.5)
    1.4 (1.4 to 1.6)
    No statistical analyses for this end point

    Secondary: Percentage of participants with any on-therapy Adverse Event (AE) and Serious Adverse Event (SAE)

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    End point title
    		 Percentage of participants with any on-therapy Adverse Event (AE) and Serious Adverse Event (SAE)
    End point description
    An Adverse Event (AE) was defined as any untoward medical occurrence in a participant that was temporally associated with the use of a medicinal product, regardless of its causal relationship. This included any unfavorable or unintended sign (such as abnormal lab findings), symptom, or disease, whether new or worsened. A Serious Adverse Event (SAE) was defined as any such occurrence that, at any dose, resulted in death, was life-threatening, required hospitalization or its prolongation, caused disability or incapacity, led to a congenital anomaly or birth defect, or was a potential case of drug-induced liver injury.
    End point type
    Secondary
    End point timeframe
    From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    270
    267
    Units: Participants
        On-Therapy AEs (All, regardless of seriousness)
    255
    237
        On-Therapy SAEs
    73
    54
    No statistical analyses for this end point

    Secondary: Percentage of participants with on-therapy Adverse Event (AE) by Maximum Grade

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    End point title
    		 Percentage of participants with on-therapy Adverse Event (AE) by Maximum Grade
    End point description
    An Adverse Event (AE) was defined as any untoward medical occurrence in a participant that was temporally associated with the use of a medicinal product, regardless of its relationship to the product. This included any unfavorable or unintended sign (such as abnormal lab results), symptom, or disease, whether new or worsened. The severity of AEs was graded according to NCI CTCAE version 3.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (death related to toxicity).
    End point type
    Secondary
    End point timeframe
    From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    255
    237
    Units: Participants
        Grade 1
    43
    56
        Grade 2
    85
    78
        Grade 3
    94
    69
        Grade 4
    17
    25
        Grade 5
    16
    9
    No statistical analyses for this end point

    Secondary: Percentage of participants with on-therapy Serious Adverse Event (SAE) by Maximum Grade

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    End point title
    		 Percentage of participants with on-therapy Serious Adverse Event (SAE) by Maximum Grade
    End point description
    A Serious Adverse Event (SAE) was defined as any such occurrence that resulted in death, was life-threatening, required hospitalization or its prolongation, caused disability or incapacity, led to a congenital anomaly or birth defect, or was a potential case of drug-induced liver injury. The severity of SAEs was graded according to NCI CTCAE version 3.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (death related to toxicity).
    End point type
    Secondary
    End point timeframe
    From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    73
    54
    Units: Participants
        Grade 1
    3
    3
        Grade 2
    6
    4
        Grade 3
    37
    21
        Grade 4
    13
    18
        Grade 5
    14
    8
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores

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    End point title
    		 Mean change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) Questionnaire Core 30 (QLQ-C30) Domain Scores
    End point description
    The EORTC QLQ-C30 is a comprehensive questionnaire developed for assessing the quality of life of cancer patients across different aspects including function scales namely physical, role, cognitive, emotional and social; symptom scales such as fatigue, pain, nausea and vomiting; and a global scale pronouncing overall health status. Its scoring method involves a 4-point Likert scale (ranging from 1 'Not at all' to 4 'Very Much'). Domain scores are calculated by averaging the items within the respective domain and then linearly transforming the score to fit within a 0-100 scale to finalize the scores. In terms of interpretation, a high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
    End point type
    Secondary
    End point timeframe
    From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    61
    61
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Global health status/QoL
    -6.6 ( 24.63 )
    -5.1 ( 23.97 )
        Physical functioning
    -9.4 ( 25.61 )
    -9.6 ( 22.33 )
        Role functioning
    -8.9 ( 34.64 )
    -11.7 ( 31.67 )
        Emotional functioning
    -3.8 ( 27.37 )
    -7.1 ( 23.61 )
        Cognitive functioning
    -7.4 ( 21.41 )
    -10.4 ( 21.98 )
        Social functioning
    -4.9 ( 32.54 )
    -0.5 ( 26.52 )
        Fatigue
    5.5 ( 26.42 )
    5.6 ( 25.30 )
        Nausea and vomiting
    3.3 ( 27.69 )
    4.4 ( 20.62 )
        Pain
    4.9 ( 30.48 )
    7.7 ( 30.06 )
        Dyspnoea
    6.7 ( 26.61 )
    7.8 ( 27.70 )
        Insomnia
    0.0 ( 33.33 )
    3.3 ( 35.09 )
        Appetite loss
    -0.5 ( 39.20 )
    5.5 ( 37.11 )
        Constipation
    -0.6 ( 32.18 )
    -3.8 ( 34.48 )
        Diarrhoea
    4.4 ( 29.49 )
    1.1 ( 23.95 )
        Financial difficulties
    0.0 ( 29.81 )
    0.6 ( 24.16 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale

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    End point title
    		 Mean change from Baseline in the EORTC Quality of Life (QOL) Questionnaire of Stomach 22 (QLQ-STO22) Scales/Items Score Scale
    End point description
    The QLQ-STO22 consists of 22 items divided into five subscales: dysphagia, pain, reflux, eating restrictions and anxiety, as well as single items addressing dry mouth, body image, taste, and hair loss. Each item is answered on a 4-point scale, ranging from 1 (not at all) to 4 (very much). Raw scores for each subscale or single item are calculated by averaging the scores of the individual items that make up the scale. These scores are then linearly transformed to range from 0 to 100. In terms of interpretation, a higher score indicates a worse quality of life concerning the specific symptoms assessed.
    End point type
    Secondary
    End point timeframe
    From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    60
    54
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Dysphagia scale
    3.4 ( 22.99 )
    -3.1 ( 16.92 )
        Pain scale
    -1.5 ( 22.20 )
    -0.6 ( 18.71 )
        Reflux scale
    -1.4 ( 21.86 )
    -4.1 ( 18.48 )
        Eating restrictions scale
    1.2 ( 27.83 )
    -3.2 ( 22.11 )
        Anxiety scale
    -2.9 ( 27.42 )
    -7.5 ( 24.38 )
        Dry mouth scale
    2.8 ( 31.13 )
    1.9 ( 32.00 )
        Taste scale
    4.5 ( 37.37 )
    9.2 ( 32.03 )
        Body image scale
    -3.3 ( 37.68 )
    -1.9 ( 30.66 )
        Hair loss scale
    -16.7 ( 23.57 )
    0.0 ( 33.33 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Utility Score (Health Utility Index) in the EuroQoL-5 Dimensions (EQ-5D) Questionnaire

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    End point title
    		 Mean change from Baseline in Utility Score (Health Utility Index) in the EuroQoL-5 Dimensions (EQ-5D) Questionnaire
    End point description
    The EQ-5D is a standardized instrument developed by the EuroQoL Group to measure health-related quality of life. It includes a descriptive system covering five dimensions and a Visual Analogue Scale (VAS), often referred to as the Thermometer Score. The Utility Score (Health Utility Index) is derived from the five dimensions of the EQ-5D descriptive system (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has levels indicating severity (e.g., 1 = no problems, 2 = some problems, 3 = extreme problems). These combinations form a health state, which is then converted into a single index value using a country-specific value set. In the UK-based value set, the possible EQ-5D index utility values range from –0.594 to 1.0, where: 1.0 = perfect health, 0 = death and < 0 = health states considered worse than death.
    End point type
    Secondary
    End point timeframe
    From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    59
    57
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.17 ( 0.347 )
    -0.07 ( 0.328 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Thermometer Score (EQ VAS) in the EuroQoL-5 Dimensions (EQ-5D) Questionnaire

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    End point title
    		 Mean change from Baseline in Thermometer Score (EQ VAS) in the EuroQoL-5 Dimensions (EQ-5D) Questionnaire
    End point description
    The EQ-5D is a standardized instrument developed by the EuroQol Group to measure health-related quality of life. It includes a descriptive system covering five dimensions and a Visual Analogue Scale (VAS), often referred to as the Thermometer Score. The Thermometer Score is a self-rated health score using a vertical visual analogue scale , where respondents rate their overall health on a scale from 0 (worst imaginable health) to 100 (best imaginable health).
    End point type
    Secondary
    End point timeframe
    From Baseline up to disease progression (PD), assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    61
    60
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -4.61 ( 23.054 )
    -7.90 ( 17.349 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with worst-case on-therapy Chemistry Toxicities

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    End point title
    		 Percentage of participants with worst-case on-therapy Chemistry Toxicities
    End point description
    The severity of chemistry parameters was graded according to NCI CTCAE version 3.0: Grade 0 (No adverse event or within normal limits), Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (life-threatening). Chemistry data included: Alanine aminotransferase (ALT), Albumin, Alkaline phosphatases (ALP), Aspartate aminotransferase (AST), Calcium (hypercalcemia), Calcium (hypocalcemia), Creatine Kinase (CK), Creatine, Glucose (hyperglycemia), Glucose (hypoglycemia), Magnesium (hypermagnesemia), Magnesium (hypomagnesemia), Potassium (hyperkalemia), Potassium (hypokalemia), Sodium (hypernatremia), Sodium (hyponatremia) and Total Bilirubin.
    End point type
    Secondary
    End point timeframe
    From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    260
    262
    Units: Participants
        Alanine aminotransferase (ALT)|Grade 0
    163
    153
        Albumin|Grade 0
    123
    140
        Alkaline phosphatases (ALP)|Grade 0
    120
    114
        Aspartate aminotransferase (AST)|Grade 0
    108
    93
        Calcium (hypercalcemia)|Grade 0
    237
    242
        Calcium (hypocalcemia)|Grade 0
    129
    134
        Creatine Kinase (CK)|Grade 0
    1
    3
        Creatinine|Grade 0
    230
    228
        Glucose (hyperglycemia)|Grade 0
    107
    119
        Glucose (hypoglycemia)|Grade 0
    223
    237
        Magnesium (hypermagnesemia)|Grade 0
    229
    234
        Magnesium (hypomagnesemia)|Grade 0
    189
    199
        Potassium (hyperkalemia)|Grade 0
    228
    234
        Potassium (hypokalemia)|Grade 0
    160
    195
        Sodium (hypernatremia)|Grade 0
    234
    234
        Sodium (hyponatremia)|Grade 0
    186
    199
        Total Bilirubin|Grade 0
    153
    178
        Alanine aminotransferase (ALT)|Grade 1
    87
    94
        Albumin|Grade 1
    72
    66
        Alkaline phosphatases (ALP)|Grade 1
    113
    109
        Aspartate aminotransferase (AST)|Grade 1
    133
    142
        Calcium (hypercalcemia)|Grade 1
    17
    19
        Calcium (hypocalcemia)|Grade 1
    74
    81
        Creatine Kinase (CK)|Grade 1
    0
    0
        Creatinine|Grade 1
    21
    33
        Glucose (hyperglycemia)|Grade 1
    115
    103
        Glucose (hypoglycemia)|Grade 1
    32
    20
        Magnesium (hypermagnesemia)|Grade 1
    20
    17
        Magnesium (hypomagnesemia)|Grade 1
    59
    52
        Potassium (hyperkalemia)|Grade 1
    20
    14
        Potassium (hypokalemia)|Grade 1
    75
    54
        Sodium (hypernatremia)|Grade 1
    18
    20
        Sodium (hyponatremia)|Grade 1
    52
    42
        Total Bilirubin|Grade 1
    55
    42
        Alanine aminotransferase (ALT)|Grade 2
    8
    11
        Albumin|Grade 2
    59
    48
        Alkaline phosphatases (ALP)|Grade 2
    22
    25
        Aspartate aminotransferase (AST)|Grade 2
    16
    21
        Calcium (hypercalcemia)|Grade 2
    2
    1
        Calcium (hypocalcemia)|Grade 2
    50
    43
        Creatine Kinase (CK)|Grade 2
    0
    0
        Creatinine|Grade 2
    7
    0
        Glucose (hyperglycemia)|Grade 2
    30
    32
        Glucose (hypoglycemia)|Grade 2
    3
    2
        Magnesium (hypermagnesemia)|Grade 2
    0
    0
        Magnesium (hypomagnesemia)|Grade 2
    5
    5
        Potassium (hyperkalemia)|Grade 2
    8
    11
        Potassium (hypokalemia)|Grade 2
    0
    0
        Sodium (hypernatremia)|Grade 2
    2
    5
        Sodium (hyponatremia)|Grade 2
    0
    0
        Total Bilirubin|Grade 2
    43
    33
        Alanine aminotransferase (ALT)|Grade 3
    2
    4
        Albumin|Grade 3
    3
    4
        Alkaline phosphatases (ALP)|Grade 3
    5
    12
        Aspartate aminotransferase (AST)|Grade 3
    3
    6
        Calcium (hypercalcemia)|Grade 3
    0
    0
        Calcium (hypocalcemia)|Grade 3
    3
    4
        Creatine Kinase (CK)|Grade 3
    0
    0
        Creatinine|Grade 3
    2
    1
        Glucose (hyperglycemia)|Grade 3
    6
    8
        Glucose (hypoglycemia)|Grade 3
    1
    1
        Magnesium (hypermagnesemia)|Grade 3
    5
    5
        Magnesium (hypomagnesemia)|Grade 3
    1
    0
        Potassium (hyperkalemia)|Grade 3
    2
    2
        Potassium (hypokalemia)|Grade 3
    21
    11
        Sodium (hypernatremia)|Grade 3
    3
    2
        Sodium (hyponatremia)|Grade 3
    19
    16
        Total Bilirubin|Grade 3
    7
    3
        Alanine aminotransferase (ALT)|Grade 4
    0
    0
        Albumin|Grade 4
    0
    0
        Alkaline phosphatases (ALP)|Grade 4
    0
    0
        Aspartate aminotransferase (AST)|Grade 4
    0
    0
        Calcium (hypercalcemia)|Grade 4
    0
    0
        Calcium (hypocalcemia)|Grade 4
    0
    0
        Creatine Kinase (CK)|Grade 4
    0
    0
        Creatinine|Grade 4
    0
    0
        Glucose (hyperglycemia)|Grade 4
    1
    0
        Glucose (hypoglycemia)|Grade 4
    0
    2
        Magnesium (hypermagnesemia)|Grade 4
    0
    0
        Magnesium (hypomagnesemia)|Grade 4
    0
    0
        Potassium (hyperkalemia)|Grade 4
    1
    0
        Potassium (hypokalemia)|Grade 4
    3
    1
        Sodium (hypernatremia)|Grade 4
    2
    0
        Sodium (hyponatremia)|Grade 4
    2
    4
        Total Bilirubin|Grade 4
    2
    5
    No statistical analyses for this end point

    Secondary: Percentage of participants with worst-case on-therapy Hematologic Toxicities

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    End point title
    		 Percentage of participants with worst-case on-therapy Hematologic Toxicities
    End point description
    The severity of hematologic parameters was graded according to NCI CTCAE version 3.0: Grade 0 (No adverse event or within normal limits), Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (life-threatening). Hematology data included: Hemoglobin, Platelet count, Total Neutrophils (Total ANC - Total Absolute Neutrophil Count) and White Blood Cell count.
    End point type
    Secondary
    End point timeframe
    From the first dose of study medication until 30 days after the last dose, assessed up the cut-off date for Final Analysis (03-Oct-2024) (average of 16 years)
    End point values
    		 CapeOx plus Lapatinib CapeOx plus Placebo
    Number of subjects analysed
    261
    263
    Units: Participants
        Hemoglobin|Grade 0
    18
    22
        Platelet count|Grade 0
    97
    116
        Total ANC (Absolute Neutrophil Count)|Grade 0
    112
    127
        White Blood Cell count|Grade 0
    126
    136
        Hemoglobin|Grade 1
    104
    121
        Platelet count|Grade 1
    95
    86
        Total ANC (Absolute Neutrophil Count)|Grade 1
    42
    45
        White Blood Cell count|Grade 1
    71
    74
        Hemoglobin|Grade 2
    104
    93
        Platelet count|Grade 2
    43
    27
        Total ANC (Absolute Neutrophil Count)|Grade 2
    58
    48
        White Blood Cell count|Grade 2
    50
    47
        Hemoglobin|Grade 3
    35
    27
        Platelet count|Grade 3
    21
    30
        Total ANC (Absolute Neutrophil Count)|Grade 3
    22
    27
        White Blood Cell count|Grade 3
    12
    4
        Hemoglobin|Grade 4
    0
    0
        Platelet count|Grade 4
    5
    2
        Total ANC (Absolute Neutrophil Count)|Grade 4
    6
    2
        White Blood Cell count|Grade 4
    2
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were documented from the first administration of the study medication through the end of the Long-Term Follow-up (LTFU) period, covering a duration of up to approximately 16 years.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    CapeOx + Lapatinib 1250 mg
    Reporting group description
    		 CapeOx + Lapatinib 1250 mg

    Reporting group title
    CapeOx + Placebo
    Reporting group description
    		 CapeOx + Placebo

    Serious adverse events
    		 CapeOx + Lapatinib 1250 mg CapeOx + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    73 / 270 (27.04%)
    54 / 267 (20.22%)
         number of deaths (all causes)
    42
    40
         number of deaths resulting from adverse events
    4
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 270 (0.74%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Drowning
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    3 / 270 (1.11%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 270 (1.48%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media reaction
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 270 (1.11%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord injury thoracic
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 270 (2.59%)
    4 / 267 (1.50%)
         occurrences causally related to treatment / all
    4 / 9
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 270 (1.11%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 270 (0.74%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 270 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gingival bleeding
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 270 (1.11%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric dilatation
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    16 / 270 (5.93%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    20 / 20
    1 / 1
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus spastic
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    6 / 270 (2.22%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    5 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 270 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 270 (2.59%)
    6 / 267 (2.25%)
         occurrences causally related to treatment / all
    4 / 7
    6 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice cholestatic
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lung abscess
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 270 (2.22%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 270 (1.48%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 270 (2.22%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CapeOx + Lapatinib 1250 mg CapeOx + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    243 / 270 (90.00%)
    214 / 267 (80.15%)
    Investigations
    Weight decreased
         subjects affected / exposed
    43 / 270 (15.93%)
    33 / 267 (12.36%)
         occurrences all number
    44
    33
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 270 (5.19%)
    14 / 267 (5.24%)
         occurrences all number
    17
    19
    Peripheral sensory neuropathy
         subjects affected / exposed
    34 / 270 (12.59%)
    29 / 267 (10.86%)
         occurrences all number
    69
    64
    Neuropathy peripheral
         subjects affected / exposed
    53 / 270 (19.63%)
    58 / 267 (21.72%)
         occurrences all number
    70
    81
    Headache
         subjects affected / exposed
    7 / 270 (2.59%)
    14 / 267 (5.24%)
         occurrences all number
    8
    18
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    30 / 270 (11.11%)
    26 / 267 (9.74%)
         occurrences all number
    46
    38
    Oedema peripheral
         subjects affected / exposed
    14 / 270 (5.19%)
    18 / 267 (6.74%)
         occurrences all number
    16
    20
    Fatigue
         subjects affected / exposed
    64 / 270 (23.70%)
    60 / 267 (22.47%)
         occurrences all number
    89
    100
    Asthenia
         subjects affected / exposed
    46 / 270 (17.04%)
    36 / 267 (13.48%)
         occurrences all number
    55
    43
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    16 / 270 (5.93%)
    9 / 267 (3.37%)
         occurrences all number
    23
    9
    Abdominal pain
         subjects affected / exposed
    27 / 270 (10.00%)
    32 / 267 (11.99%)
         occurrences all number
    34
    45
    Abdominal pain upper
         subjects affected / exposed
    20 / 270 (7.41%)
    27 / 267 (10.11%)
         occurrences all number
    22
    31
    Constipation
         subjects affected / exposed
    30 / 270 (11.11%)
    54 / 267 (20.22%)
         occurrences all number
    33
    72
    Diarrhoea
         subjects affected / exposed
    146 / 270 (54.07%)
    77 / 267 (28.84%)
         occurrences all number
    325
    157
    Dyspepsia
         subjects affected / exposed
    14 / 270 (5.19%)
    20 / 267 (7.49%)
         occurrences all number
    17
    24
    Nausea
         subjects affected / exposed
    128 / 270 (47.41%)
    113 / 267 (42.32%)
         occurrences all number
    270
    266
    Stomatitis
         subjects affected / exposed
    19 / 270 (7.04%)
    10 / 267 (3.75%)
         occurrences all number
    21
    12
    Vomiting
         subjects affected / exposed
    116 / 270 (42.96%)
    93 / 267 (34.83%)
         occurrences all number
    207
    204
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 270 (4.44%)
    19 / 267 (7.12%)
         occurrences all number
    15
    22
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    18 / 270 (6.67%)
    5 / 267 (1.87%)
         occurrences all number
    22
    7
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    57 / 270 (21.11%)
    40 / 267 (14.98%)
         occurrences all number
    71
    47
    Rash
         subjects affected / exposed
    46 / 270 (17.04%)
    16 / 267 (5.99%)
         occurrences all number
    51
    17
    Skin hyperpigmentation
         subjects affected / exposed
    16 / 270 (5.93%)
    7 / 267 (2.62%)
         occurrences all number
    16
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    9 / 270 (3.33%)
    16 / 267 (5.99%)
         occurrences all number
    10
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    107 / 270 (39.63%)
    85 / 267 (31.84%)
         occurrences all number
    163
    151

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2008
    Amendment 1: Update of the safety monitoring for hepatotoxicity; clarification of screening assessments; administrative changes.
    13 Aug 2008
    Amendment 2: Administrative update and pharmacokinetic sample was appended to the supplemental liver chemistry follow-up criteria sample panel to obtain serum levels of the study treatment (lapatinib).
    10 Sep 2009
    Amendment 3: Revision to statistical plan; administrative updates; clarification of operational elements and text
    28 Oct 2010
    Amendment 4: Clarification to prior use of oxaliplatin; updated prohibited medications table; elimination of collection of serum and RNA blood samples; administrative updates and clarifications to enhance consistency and quality of document, removal from the protocol of supportive care guidance (Appendix 5), to be placed in Study Procedures Manual
    22 Aug 2011
    Amendment 5: Statistical revisions: the definition of the primary efficacy population was revised to include all subjects centrally confirmed by FISH, whether or not the subject had taken study medication. The addition of per protocol population to support the sensitivity analysis of selective efficacy data in subjects who comply most closely with the intended protocol population and updated clarifications in prohibited medications table. Administration changes and clarification of operational procedures to enhance protocol uniformity
    28 Sep 2011
    Amendment 5: republished due to discrepancy in headers. No changes to the body of the protocol
    13 Dec 2011
    Amendment 6: Local amendment for sites in China to allow continuation of recruitment given the Chinese regulatory authority’s requirement for a minimum number of local subjects to participate in the study. Of note, no additional subjects were enrolled
    06 Mar 2014
    Amendment 7: This amendment is being implemented to discontinue collection of many studies specific assessments while allowing subjects currently on study treatment to have continued access to this treatment until the occurrence of unacceptable toxicity or disease progression (as determined by the Investigator) or withdrawal for any reasons. The aim is to continue to protect the safety of the subject, whilst removing the requirement for assessments intended to collect further efficacy data, unless clinically indicate; Amendment of study assessments: clinical assessments of safety and efficacy will be performed as directed by the Investigator judgment; Amendment to stop data collection for all subjects currently on follow –up; To ensure the safety of the subjects, Investigators will be asked to collect and report to the Sponsor all serious adverse events (SAEs) and pregnancies, and date and reasons for study treatment discontinuation (including adverse events (AEs) leading to discontinuation of study treatment and all other reasons for discontinuation of study treatment
    27 Apr 2015
    Amendment 8: Clarification to lapatinib drug supply, liver event data collection and interval of long-term follow-up period
    22 Mar 2016
    Amendment 9: Delete or replace references to GSK or its staff with that of Novartis/Novartis and its authorized agents. Make administrative changes to align with Novartis processes and procedures

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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