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    Clinical Trial Results:
    Effectiveness of first line treatment with lapatinib and ECF/X in histologically proven adenocarcinoma of the stomach or the esophagogastric junction (metastatic or not amenable to curative surgery) according to HER2 and EGFR status: a randomized phase II trial

    Summary
    EudraCT number
    		 2009-011580-36
    Trial protocol
    		 BE   DE   HU   PT  
    Global end of trial date
    04 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Aug 2016
    First version publication date
    13 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    40071
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01123473
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer
    Sponsor organisation address
    Avenue E. Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27441062, regulatory@eortc.be
    Scientific contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27441062, regulatory@eortc.be
    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
    11 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Mar 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To test the activity of lapatinib in patients HER2 positive by FISH and by IHC 2+ and 3+.
    Protection of trial subjects
    The responsible investigator ensured that this study was conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol had been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at http://www.ema.europa.eu/pdfs/human/ich/013595en.pdf). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 Reference therapy consists of ECF (epirubicin, cisplatin, infusional 5-FU) or the alternative ECX (epirubicin, cisplatin, capecitabine). The choice of 5-FU versus capecitabine is provided on an institutional basis. ECF/X (3-weekly cycles): Epirubicin 50 mg/m2 D1 Cisplatin 60 mg/m2 D1 FU 200 mg/m2 D1-D21 in continuous infusion with a pump (Electronic or Baxter type) through a port-a-cath or Capecitabine 1250 mg/m2 fractionnated into two daily oral doses D1-D21 The duration of chemotherapy (ECX/ECF) is six cycles (18 weeks) unless terminated by patient refusal, death, progressive disease or toxicity.
    Evidence for comparator
    		 ECF is the most widely accepted regime for gastric cancer, and the alternative ECX is considered equivalent (Ref. REAL2 study: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: LBA4017). The choice of 5-FU versus capecitabine is provided on an institutional basis because 1) capecitabine is not reimbursable in all countries, and 2) the trial should reflect present and future choices in order to have maximal impact on practice. Each center was free to choose between ECF and ECX before starting the trial. This choice had to be kept for all the subjects enrolled for the duration of the trial.
    Actual start date of recruitment
    16 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Hungary: 22
    Worldwide total number of subjects
    72
    EEA total number of subjects
    72
    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)
    47
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 16/02/2011 and 09/08/2013, patients with previously untreated adenocarcinoma of the stomach or the oesophagogastric junction that was metastatic or not amenable to curative surgery were recruited in 4 countries (Belgium, Germany, Hungary, Portugal). Patients were screened centrally for HER2 and EGFR status, both by FISH and IHC.

    Pre-assignment
    Screening details
    		 Eligibility criteria for HER2 and EGFR status (central testing): -HER2 positive status by IHC or EGFR positive status by FISH or IHC Protocol was amended on 03/02/2012 to exclude patients with HER2 FISH+ and IHC 2/3+ tumors. -Negative HER2 status by FISH or negative HER2 status by IHC

    Pre-assignment period milestones
    Number of subjects started
    		 72
    Intermediate milestone: Number of subjects
    Central testing for HER2 and EGFR status: 69
    Number of subjects completed
    		 29

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Tissue sample not delivered to central laboratory: 1
    Reason: Number of subjects
    		 Unknown: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 5
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 HER2+ by both IHC and FISH after amendment: 2
    Reason: Number of subjects
    		 Not eligible (HER2- and EGFR-): 30
    Reason: Number of subjects
    		 Not eligible (other reasons): 2
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Period 1
    Period 1 title
    From randomization (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Knowledge of the treatment was concealed from the people who organize and analyze the data of a study as well as from subjects and investigators (CDISC Clinical Research Glossary Version 8.0). After progression, the treatment was unblinded to the investigator. Subjects receiving lapatinib were treated at the investigator discretion. Subjects in the control arm were offered lapatinib to be taken alone or in combination with chemotherapy such as ECF/ECX or FOLFOX up to further progression.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ECF/X + Lapatinib
    Arm description
    		 ECF/X (3-weekly cycles) + Lapatinib. The duration of chemotherapy (ECX/ECF) is six cycles (18 weeks) unless terminated by patient refusal, death, progressive disease or toxicity. Lapatinib was to be continued until refusal, death, progression or toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    GW572016
    Other name
    Tykerb
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lapatinib: 1250mg/d po once daily continuously. Lapatinib tablets (250 mg) are oval, biconvex, orange, film-coated tablets with one side of the tablet plain and other side of the tablet debossed with FG HLS. The tablets contain 405 mg of GW572016 Ditosylate Monohydrate, equivalent to 250 mg GW572016 free base per tablet. Oral lapatinib was supplied as 250 mg tablets packaged as 90 tablets per bottle.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin 50 mg/m2 on day 1 (3-weekly cycles for 6 cycles)

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 60 mg/m2 on day 1 (3-weekly cycles for 6 cycles)

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    FU 200 mg/m2 from day 1 to day 21 (3-weekly cycles for 6 cycles) in continuous infusion with a pump (Electronic or Baxter type) through a port-a-cath.

    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
    Capecitabine 1250 mg/m2 fractionnated into two daily oral doses from day 1 to day 21 (3-weekly cycles for 6 cycles)

    Arm title
    		 ECF/X + Placebo
    Arm description
    		 ECF/X (3-weekly cycles) + Placebo. The duration of chemotherapy (ECX/ECF) is six cycles (18 weeks) unless terminated by patient refusal, death, progressive disease or toxicity. Placebo was to be continued until refusal, death, progression or toxicity. After progression, treatment was unblinded and subjects in the control arm were offered lapatinib to be taken alone or in combination with chemotherapy such as ECF/ECX or FOLFOX up to further progression.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo: 1250mg/d po once daily continuously Placebo tablets will be identical to active lapatinib oval, biconvex, orange, film-coated that are debossed on one side with FG HLS. The tablets contain microcrystallin cellulose and lactose. Placebo was supplied as 250 mg tablets packaged as 90 tablets per bottle.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin 50 mg/m2 on day 1 (3-weekly cycles for 6 cycles)

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 60 mg/m2 on day 1 (3-weekly cycles for 6 cycles)

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    FU 200 mg/m2 from day 1 to day 21 (3-weekly cycles for 6 cycles) in continuous infusion with a pump (Electronic or Baxter type) through a port-a-cath

    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
    Capecitabine 1250 mg/m2 fractionnated into two daily oral doses from day 1 to day 21 (3-weekly cycles for 6 cycles)

    Number of subjects in period 1 [1]
    		ECF/X + Lapatinib ECF/X + Placebo
    Started
    15
    14
    Completed
    10
    10
    Not completed
    5
    4
         Physician decision
    3
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 72 patients were registered and 29 patients were tested for their HER2 and EGFR status by the central laboratory. Patients without any tumor HER2 or EGFR overexpression or amplification were to be excluded per protocol. Protocol was amended on 03/02/2012 to further exclude patients with HER2 FISH+ and IHC 2/3+ tumors. A total of 29 patients were randomized.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ECF/X + Lapatinib
    Reporting group description
    		 ECF/X (3-weekly cycles) + Lapatinib. The duration of chemotherapy (ECX/ECF) is six cycles (18 weeks) unless terminated by patient refusal, death, progressive disease or toxicity. Lapatinib was to be continued until refusal, death, progression or toxicity.

    Reporting group title
    ECF/X + Placebo
    Reporting group description
    		 ECF/X (3-weekly cycles) + Placebo. The duration of chemotherapy (ECX/ECF) is six cycles (18 weeks) unless terminated by patient refusal, death, progressive disease or toxicity. Placebo was to be continued until refusal, death, progression or toxicity. After progression, treatment was unblinded and subjects in the control arm were offered lapatinib to be taken alone or in combination with chemotherapy such as ECF/ECX or FOLFOX up to further progression.

    Reporting group values
    		 ECF/X + Lapatinib ECF/X + Placebo Total
    Number of subjects
    		 15 14 29
    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)
    		 5 10 15
        From 65-84 years
    		 10 4 14
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 4 6
        Male
    		 13 10 23
    HER2 and EGFR status
    Result of the central testing for HER2 and EGFR status by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).
    Units: Subjects
        HER2 FISH+ and IHC 2/3+
    		 4 2 6
        HER2 FISH- and IHC 2/3+
    		 2 3 5
        HER2 IHC 0/1+ and EGFR FISH+ or IHC 2/3+
    		 9 9 18
    Histological grade
    Units: Subjects
        GI
    		 2 0 2
        GII
    		 5 7 12
        GIII
    		 4 3 7
        Unknown
    		 4 4 8
    Site of the tumor
    Units: Subjects
        Stomach
    		 11 5 16
        Esophagogastric junction
    		 3 5 8
        Both
    		 1 4 5
    T-stage
    Units: Subjects
        cT1
    		 0 1 1
        cT3
    		 4 2 6
        cT4
    		 0 3 3
        cTX
    		 10 8 18
        Unknown
    		 1 0 1
    N-stage
    Units: Subjects
        cN0
    		 1 0 1
        cN1
    		 3 2 5
        cN2
    		 2 3 5
        cN3
    		 2 2 4
        cNX
    		 6 7 13
        Unknown
    		 1 0 1
    M-stage
    Units: Subjects
        cM0
    		 1 0 1
        cM1
    		 14 14 28
    Subject analysis sets

    Subject analysis set title
    Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients HER2 IHC 0/1+ and EGFR FISH+ or IHC 2/3+ (EGFR+) in the ECF/X + Lapatinib Arm

    Subject analysis set title
    Patients HER2- by IHC and EGFR+ in ECF/X + Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients HER2 IHC 0/1+ and EGFR FISH+ or IHC 2/3+ (EGFR+) in the ECF/X + Placebo Arm

    Subject analysis sets values
    		 Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib Patients HER2- by IHC and EGFR+ in ECF/X + Placebo
    Number of subjects
    9
    9
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    1
    6
        From 65-84 years
    8
    3
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    1
    2
        Male
    8
    7
    HER2 and EGFR status
    Result of the central testing for HER2 and EGFR status by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).
    Units: Subjects
        HER2 FISH+ and IHC 2/3+
    0
    0
        HER2 FISH- and IHC 2/3+
    0
    0
        HER2 IHC 0/1+ and EGFR FISH+ or IHC 2/3+
    9
    9
    Histological grade
    Units: Subjects
        GI
    2
    0
        GII
    4
    4
        GIII
    1
    2
        Unknown
    2
    3
    Site of the tumor
    Units: Subjects
        Stomach
    7
    4
        Esophagogastric junction
    1
    3
        Both
    1
    2
    T-stage
    Units: Subjects
        cT1
    0
    1
        cT3
    3
    0
        cT4
    0
    2
        cTX
    5
    6
        Unknown
    1
    0
    N-stage
    Units: Subjects
        cN0
    0
    0
        cN1
    2
    1
        cN2
    1
    3
        cN3
    1
    0
        cNX
    4
    5
        Unknown
    1
    0
    M-stage
    Units: Subjects
        cM0
    0
    0
        cM1
    9
    9

    End points

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    End points reporting groups
    Reporting group title
    ECF/X + Lapatinib
    Reporting group description
    		 ECF/X (3-weekly cycles) + Lapatinib. The duration of chemotherapy (ECX/ECF) is six cycles (18 weeks) unless terminated by patient refusal, death, progressive disease or toxicity. Lapatinib was to be continued until refusal, death, progression or toxicity.

    Reporting group title
    ECF/X + Placebo
    Reporting group description
    		 ECF/X (3-weekly cycles) + Placebo. The duration of chemotherapy (ECX/ECF) is six cycles (18 weeks) unless terminated by patient refusal, death, progressive disease or toxicity. Placebo was to be continued until refusal, death, progression or toxicity. After progression, treatment was unblinded and subjects in the control arm were offered lapatinib to be taken alone or in combination with chemotherapy such as ECF/ECX or FOLFOX up to further progression.

    Subject analysis set title
    Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients HER2 IHC 0/1+ and EGFR FISH+ or IHC 2/3+ (EGFR+) in the ECF/X + Lapatinib Arm

    Subject analysis set title
    Patients HER2- by IHC and EGFR+ in ECF/X + Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients HER2 IHC 0/1+ and EGFR FISH+ or IHC 2/3+ (EGFR+) in the ECF/X + Placebo Arm

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Progression Free Survival was computed from the date of randomization to the date of first progression according to the RECIST criteria (version 1.1) or death, whatever comes first. Patients alive and free of progression prior to the analysis cut-off date are censored at the date of the most recent assessment.
    End point type
    Primary
    End point timeframe
    Tumor evaluation after start of treatment, CT scans or MRI were performed every 8 weeks during treatment. Patients who stopped treatment without progression were followed-up for progression every 3 months during the first 2 years and then every 6 months.
    End point values
    		 ECF/X + Lapatinib ECF/X + Placebo Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib Patients HER2- by IHC and EGFR+ in ECF/X + Placebo
    Number of subjects analysed
    14 [1]
    14
    9
    9
    Units: Months
        median (confidence interval 95%)
    7.95 (4.24 to 11.27)
    5.88 (4.14 to 9.92)
    7.95 (1.41 to 13.83)
    6.32 (1.84 to 12.19)
    Notes
    [1] - 1 patient not eligible (no evidence of metastases and amenable to surgery) was excluded.
    Statistical analysis title
    		 Primary analysis (per protocol population)
    Statistical analysis description
    Enrollment was curtailed after announcement of the LOGIC trial results (ASCO 2013). Therefore the original decision rule could not be applied. No formal statistical tests were carried out due to the low number of patients accrued. Efficacy analyses were done on the per protocol population (all patients eligible who started their allocated treatment). PFS curve was estimated using the Kaplan-Meier technique by treatment arm. Median PFS is reported with its 95% confidence interval.
    Comparison groups
    ECF/X + Lapatinib v ECF/X + Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.99
    Notes
    [2] - Due to the low number of patients accrued, only descriptive statistics are provided.
    Statistical analysis title
    		 Subgroup analysis (HER2- by IHC and EGFR+)
    Statistical analysis description
    The primary subgroup of interest in this trial was the population of patients HER2 by IHC 0/1+ / EGFR+ by FISH or EGFR+ by IHC 2/3+. PFS was estimated using the Kaplan-Meier technique by treatment arm in this subgroup. Median PFS is reported with its 95% confidence interval in this subgroup.
    Comparison groups
    Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib v Patients HER2- by IHC and EGFR+ in ECF/X + Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.46
    Notes
    [3] - Due to the low number of patients accrued, only descriptive statistics are provided.

    Secondary: Progression Free Survival (Sensitivity)

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    End point title
    		 Progression Free Survival (Sensitivity)
    End point description
    Progression Free Survival was computed from the date of randomization to the date of first progression counting clinical progressions/symptomatic deteriorations as events for PFS or death, whatever comes first. Patients alive and free of progression (clinical PD or PD according to RECIST v. 1.1) prior to the analysis cut-off date were censored at the date of the most recent assessment.
    End point type
    Secondary
    End point timeframe
    Tumor evaluation after start of treatment, CT scans or MRI were performed every 8 weeks during treatment. Patients who stopped treatment without progression were followed-up for progression every 3 months during the first 2 years and then every 6 months.
    End point values
    		 ECF/X + Lapatinib ECF/X + Placebo Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib Patients HER2- by IHC and EGFR+ in ECF/X + Placebo
    Number of subjects analysed
    14 [4]
    14
    9
    9
    Units: Months
        median (confidence interval 95%)
    7.1 (2.33 to 11.27)
    5.88 (4.14 to 9.92)
    6.21 (1.38 to 13.83)
    6.32 (1.84 to 12.19)
    Notes
    [4] - 1 patient not eligible (no evidence of metastases and amenable to surgery) was excluded.
    Statistical analysis title
    		 Sensitivity analysis
    Statistical analysis description
    The primary analysis on PFS was redone counting clinical progressions/symptomatic deteriorations as additional events for PFS and censoring patients alive and free of progression (clinical PD or PD according to RECIST v. 1.1) prior to the analysis cut-off date at the date of the most recent assessment.
    Comparison groups
    ECF/X + Lapatinib v ECF/X + Placebo
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 2.14
    Notes
    [5] - Sensitivity analysis
    Statistical analysis title
    		 Subgroup analysis (HER2- by IHC and EGFR+)
    Statistical analysis description
    The subgroup analysis of PFS in patients HER2 by IHC 0/1+ / EGFR+ by FISH or EGFR+ by IHC 2/3+ was redone counting clinical progressions/symptomatic deteriorations as additional events for PFS and censoring patients alive and free of progression (clinical PD or PD according to RECIST v. 1.1) prior to the analysis cut-off date at the date of the most recent assessment.
    Comparison groups
    Patients HER2- by IHC and EGFR+ in ECF/X + Placebo v Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Log hazard ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 2.75
    Notes
    [6] - Sensitivity analysis in the primary subgroup of interest

    Secondary: Best overall response

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    End point title
    		 Best overall response
    End point description
    Objective tumor response was measured according to the RECIST criteria version 1.1. All patients had their BEST RESPONSE from the start of study treatment until the end of treatment classified as: complete Response (CR), partial Response (PR), stable Disease (SD), progressive Disease (PD), early death or not evaluable.
    End point type
    Secondary
    End point timeframe
    Tumor evaluation after start of treatment, CT scans or MRI were performed every 8 weeks during treatment. Best overall response was assessed from the start of study treatment until the end of treatment.
    End point values
    		 ECF/X + Lapatinib ECF/X + Placebo Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib Patients HER2- by IHC and EGFR+ in ECF/X + Placebo
    Number of subjects analysed
    14 [7]
    14
    9
    9
    Units: Patient
        CR
    0
    0
    0
    0
        PR
    6
    3
    4
    2
        SD
    5
    6
    2
    3
        PD
    2
    3
    2
    2
        Early death from malignant disease
    1
    0
    1
    0
        Not evaluable
    0
    2
    0
    2
    Notes
    [7] - 1 patient not eligible (no evidence of metastases and amenable to surgery) was excluded.
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival was computed from the date of randomization to the date of death. Patients still alive at the analysis cut-off date were censored at the date of the most recent follow-up.
    End point type
    Secondary
    End point timeframe
    After end of treatment, patients were followed-up for survival every 3 months during the first 2 years and then every 6 months thereafter.
    End point values
    		 ECF/X + Lapatinib ECF/X + Placebo Patients HER2- by IHC and EGFR+ in ECF/X + Lapatinib Patients HER2- by IHC and EGFR+ in ECF/X + Placebo
    Number of subjects analysed
    14 [8]
    14
    9
    9
    Units: Months
        median (confidence interval 95%)
    13.83 (5.45 to 22.54)
    10.09 (4.37 to 22.54)
    9.92 (1.41 to 13.83)
    9.26 (2.33 to 20.73)
    Notes
    [8] - 1 patient not eligible (no evidence of metastases and amenable to surgery) was excluded.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected at baseline before starting treatment, at the end of each cycle during treatment and 8 weeks after last administration of treatment. In case of treatment-related toxicity, follow-up was until resolution of the AE.
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs has not been collected specifically, therefore all AEs will be reported in non-SAE section.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    ECF/X + Placebo
    Reporting group description
    		 Safety population: randomized patients who started placebo

    Reporting group title
    ECF/X + Lapatinib
    Reporting group description
    		 Safety population: randomized patients who started lapatinib

    Serious adverse events
    		 ECF/X + Placebo ECF/X + Lapatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 14 (42.86%)
    8 / 15 (53.33%)
         number of deaths (all causes)
    9
    9
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Urine output decreased
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukopenia
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
    Additional description: From pharmacovigilance database.
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ECF/X + Placebo ECF/X + Lapatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Phlebitis
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Flushing
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Thromboembolic event
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatique
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    13 / 14 (92.86%)
    11 / 15 (73.33%)
         occurrences all number
    13
    11
    Fever
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Other GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 14 (42.86%)
    5 / 15 (33.33%)
         occurrences all number
    6
    5
    Immune system disorders
    Allergic reaction
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Other REPRODUCTIVE SYSTEM AND BREAST DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 14 (21.43%)
    4 / 15 (26.67%)
         occurrences all number
    3
    4
    Cough
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    Other RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 14 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    4
    3
    Pleural effusion
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Other PSYCHIATRIC DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Investigations
    Other INVESTIGATIONS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 14 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    4
    3
    Cardiac disorders
    Other CARDIAC DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Sinus bradycardia
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 15 (20.00%)
         occurrences all number
    1
    3
    Other NERVOUS SYSTEM DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    7 / 14 (50.00%)
    4 / 15 (26.67%)
         occurrences all number
    7
    4
    Peripheral sensory neuropathy
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 14 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    4
    3
    Blood and lymphatic system disorders
    Febrile neutropenia
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Hearing impaired
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Eye disorders
    Other EYE DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Costipation
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    5 / 14 (35.71%)
    2 / 15 (13.33%)
         occurrences all number
    5
    2
    Diarrhea
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 14 (42.86%)
    12 / 15 (80.00%)
         occurrences all number
    6
    12
    Mucositis oral
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 14 (14.29%)
    4 / 15 (26.67%)
         occurrences all number
    2
    4
    Nausea
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    11 / 14 (78.57%)
    9 / 15 (60.00%)
         occurrences all number
    11
    9
    Other GASTROINTESTINAL DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    10 / 14 (71.43%)
    8 / 15 (53.33%)
         occurrences all number
    10
    8
    Vomiting
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    5 / 14 (35.71%)
    10 / 15 (66.67%)
         occurrences all number
    5
    10
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 14 (21.43%)
    4 / 15 (26.67%)
         occurrences all number
    3
    4
    Dry skin
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 14 (21.43%)
    5 / 15 (33.33%)
         occurrences all number
    3
    5
    Other SKIN AND SUBCUTANEOUS TISSUE DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Palma-plantar erythrodysesthesia syndrome
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    5 / 14 (35.71%)
    5 / 15 (33.33%)
         occurrences all number
    5
    5
    Rash maculo-papular
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pruritus
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Other RENAL AND URINARY DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Other MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 15 (20.00%)
         occurrences all number
    3
    3
    Infections and infestations
    Other INFECTIONS AND INFESTATIONS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Papulopustular rash
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Paronychia
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Anorexia
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 14 (28.57%)
    6 / 15 (40.00%)
         occurrences all number
    4
    6
    Other METABOLISM AND NUTRITION DISORDERS
    Additional description: From clinical database. All clinical adverse events (any grade) during treatment.
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2012
    Global Amendment number 1 (the only one): Modifications to the current protocol from version v2.0 dated 20JUL2010 to version 3.0 dated 03FEB2012. Description of the amendment: The main changes affecting the primary objective of the study&change in the patient eligibility criteria: The targeted patient populations for this study has been amended taking into account the indication for Herceptin. Initially, the trial was designed to assess in a randomized fashion the potential efficacy of lapatinib in both EGFR+/HER-2 and HER 2+ gastric tumors (weakly and strongly HER-2+) measured by IHC and FISH. Based on the indication of herceptin for HER-2+ patients, the strongly-positive HER-2 group (HER2+ by FISH/ HER2+ by IHC 2/3+) has been excluded from study entry. Accordingly, the eligibility criteria for the patient population have been amended and the randomization PIS/IC for the subject have been modified to reflect these changes.

    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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    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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