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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multicentre, Phase II Study of Oral Lapatinib in combination with Concurrent Radiotherapy and Cisplatin versus Radiotherapy and Cisplatin alone, in Subjects with Stage III and IVA,B Squamous Cell Carcinoma of the Head and Neck (SCCHN)

    Summary
    EudraCT number
    		 2005-003767-23
    Trial protocol
    		 GB   HU   ES   NL  
    Global end of trial date
    21 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    03 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EGF105884
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate and explore the activity of lapatinib or placebo in the two treatment groups with respect to the complete response rate (per RECIST) at six months (24 weeks) from chemoradiation completion in subjects with locally advanced SCCHN.
    Protection of trial subjects
    Independent Data Monitoring Committee to review safety data (6-monthly). Monitoring and management of potential treatment-specific adverse events (liver toxicity, cardiac dysfunction, pneumonitis). Study drug interruptions reported to medical monitor if related to an adverse event, to provide ‘real time’ awareness of any unexpected issues. Protocol amendment after analysis of primary endpoint data to minimize study-specific procedures. Thorough screening and inclusion/exclusion criteria to ensure an appropriate patient population is enrolled. A radiotherapy (RT) quality assurance program was included: in order to standardize RT practice an independent vendor qualified each site, provided RT guidelines, and reviewed the RT plan for every subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Nov 2006
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    India: 12
    Country: Number of subjects enrolled
    Peru: 4
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    67
    EEA total number of subjects
    47
    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)
    62
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Study completion was not well defined by the protocol. However, participants were to be followed up until death, unless withdrawn from the study. Therefore the number of participants completing the study is equal to the number of participants who died whilst on-study.

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Chemoradiotherapy + Placebo, followed by Placebo
    Arm description
    		 Participants received radiotherapy once daily (OD), with a dose/fraction <2.5 Gray (Gy) to a total dose of 70 Gy (using two-dimensional [2D] or 3D techniques) or 65 Gy (using Intensity Modulated Radiation Therapy [IMRT]) to the gross site of disease. Concurrent chemotherapy of cisplatin 100 milligrams per meters squared (mg/m^2) was administered intravenously (IV) on Days 1, 22, and 43 of the course of radiotherapy (Study Days 8, 29, and 50). Matching placebo administration commenced 1 week (or less than or equal to 3 days) prior to the concurrent administration with chemoradiation for a duration of up to 6 to 7 weeks. After the completion of chemoradiotherapy, placebo monotherapy was administered until disease progression or withdrawal.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Six tablets once daily as monotherapy for one week, then concurrently with chemoradiation for 6 to 7 weeks, then as monotherapy until disease progression or withdrawal from the study. Tablets were to be taken whole at least one hour before or one hour after the morning meal. Tablets could be crushed and taken as a suspension in water by subjects who were unable to swallow tablets.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered intravenously at a dose of 100 mg/m^2 on days 1, 22 and 43 of radiotherapy.

    Arm title
    		 Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Arm description
    		 Participants received radiotherapy once daily (OD), with a dose/fraction <2.5 Gy to a total dose of 70 Gy (using 2D or 3D techniques) or 65 Gy (using IMRT) to the gross site of disease. Concurrent chemotherapy of cisplatin 100 mg/m^2 was administered IV on Days 1, 22, and 43 of the course of radiotherapy (Study Days 8, 29, and 50). Lapatinib 1500 mg OD administration commenced 1 week (or less than or equal to 3 days) prior to the concurrent administration with chemoradiation for a duration of up to 6 to 7 weeks. After the completion of chemoradiotherapy, lapatinib 1500 mg OD monotherapy was administered until disease progression or withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1500 mg once daily as monotherapy for one week, then concurrently with chemoradiation for 6 to 7 weeks, then as monotherapy until disease progression or withdrawal from the study. Lapatinib was provided as 250 mg tablets, to be taken whole at least one hour before or one hour after the morning meal. Tablets could be crushed and taken as a suspension in water by subjects who were unable to swallow tablets.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered intravenously at a dose of 100 mg/m^2 on days 1, 22 and 43 of radiotherapy.

    Number of subjects in period 1
    		Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Started
    33
    34
    Completed
    16
    16
    Not completed
    17
    18
         Consent withdrawn by subject
    3
    2
         Physician decision
    -
    1
         Sponsor Unblinded
    1
    -
         Required by Protocol Amendment #4
    12
    10
         Lost to follow-up
    -
    4
         Serious Adverse Event
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chemoradiotherapy + Placebo, followed by Placebo
    Reporting group description
    		 Participants received radiotherapy once daily (OD), with a dose/fraction <2.5 Gray (Gy) to a total dose of 70 Gy (using two-dimensional [2D] or 3D techniques) or 65 Gy (using Intensity Modulated Radiation Therapy [IMRT]) to the gross site of disease. Concurrent chemotherapy of cisplatin 100 milligrams per meters squared (mg/m^2) was administered intravenously (IV) on Days 1, 22, and 43 of the course of radiotherapy (Study Days 8, 29, and 50). Matching placebo administration commenced 1 week (or less than or equal to 3 days) prior to the concurrent administration with chemoradiation for a duration of up to 6 to 7 weeks. After the completion of chemoradiotherapy, placebo monotherapy was administered until disease progression or withdrawal.

    Reporting group title
    Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Reporting group description
    		 Participants received radiotherapy once daily (OD), with a dose/fraction <2.5 Gy to a total dose of 70 Gy (using 2D or 3D techniques) or 65 Gy (using IMRT) to the gross site of disease. Concurrent chemotherapy of cisplatin 100 mg/m^2 was administered IV on Days 1, 22, and 43 of the course of radiotherapy (Study Days 8, 29, and 50). Lapatinib 1500 mg OD administration commenced 1 week (or less than or equal to 3 days) prior to the concurrent administration with chemoradiation for a duration of up to 6 to 7 weeks. After the completion of chemoradiotherapy, lapatinib 1500 mg OD monotherapy was administered until disease progression or withdrawal.

    Reporting group values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib Total
    Number of subjects
    		 33 34 67
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ± 6.61 55.8 ± 5.73 -
    Gender categorical
    Units: Subjects
        Female
    		 2 5 7
        Male
    		 31 29 60
    Race
    Units: Subjects
        African American/African Heritage
    		 0 1 1
        American Indian or Alaska Native
    		 2 2 4
        Asian - Central/South Asian Heritage
    		 3 6 9
        Asian - South East Asian Heritage
    		 2 1 3
        White - White/Caucasian/European Heritage
    		 26 24 50

    End points

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    End points reporting groups
    Reporting group title
    Chemoradiotherapy + Placebo, followed by Placebo
    Reporting group description
    		 Participants received radiotherapy once daily (OD), with a dose/fraction <2.5 Gray (Gy) to a total dose of 70 Gy (using two-dimensional [2D] or 3D techniques) or 65 Gy (using Intensity Modulated Radiation Therapy [IMRT]) to the gross site of disease. Concurrent chemotherapy of cisplatin 100 milligrams per meters squared (mg/m^2) was administered intravenously (IV) on Days 1, 22, and 43 of the course of radiotherapy (Study Days 8, 29, and 50). Matching placebo administration commenced 1 week (or less than or equal to 3 days) prior to the concurrent administration with chemoradiation for a duration of up to 6 to 7 weeks. After the completion of chemoradiotherapy, placebo monotherapy was administered until disease progression or withdrawal.

    Reporting group title
    Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Reporting group description
    		 Participants received radiotherapy once daily (OD), with a dose/fraction <2.5 Gy to a total dose of 70 Gy (using 2D or 3D techniques) or 65 Gy (using IMRT) to the gross site of disease. Concurrent chemotherapy of cisplatin 100 mg/m^2 was administered IV on Days 1, 22, and 43 of the course of radiotherapy (Study Days 8, 29, and 50). Lapatinib 1500 mg OD administration commenced 1 week (or less than or equal to 3 days) prior to the concurrent administration with chemoradiation for a duration of up to 6 to 7 weeks. After the completion of chemoradiotherapy, lapatinib 1500 mg OD monotherapy was administered until disease progression or withdrawal.

    Primary: Number of participants (par.) with Complete Response (CR), as assessed by independent radiological review

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    End point title
    		 Number of participants (par.) with Complete Response (CR), as assessed by independent radiological review
    End point description
    Participants with CR are defined as those who achieved a complete tumor response at 6 months after the completion of the chemoradiation treatment (CRT), as assessed by independent radiological review. Tumor response was assessed using modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Per RECIST, CR is defined as the disappearance of all target and non-target lesions. Data are based on Week 24 scans from participants receiving study treatment at that time and on those in follow-up. Intent-to-Treat (ITT) Population: all participants who were randomized to study treatment, regardless of whether they actually received study medication.
    End point type
    Primary
    End point timeframe
    From the date of randomization until 6 months post chemoradiation treatment, assessed for a median time of 13 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [1]
    34 [2]
    Units: Participants
    12
    18
    Notes
    [1] - ITT Population
    [2] - ITT Population
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Chemoradiotherapy + Placebo, followed by Placebo v Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.3658 [4]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentage of par. with CR
    Point estimate
    10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 37.3
    Notes
    [3] - Complete response was defined as the percentage of participants achieving a CR as determined by an independent radiological review.
    [4] - From exact test that common odds ratio equals 1

    Secondary: Number of participants with CR, as assessed by the investigator

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    End point title
    		 Number of participants with CR, as assessed by the investigator
    End point description
    Participants with CR are defined as those who achieved a complete tumor response at 6 months after the completion of the CRT, as determined by the investigator. Tumor response was assessed using modified RECIST criteria. Per RECIST, CR is defined as the disappearance of all target and non-target lesions. Data are based on Week 24 scans from participants receiving study treatment at that time and on those in follow-up.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until 6 months post chemoradiation treatment, assessed after a median time of 13 months of follow-up
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [5]
    34 [6]
    Units: Participants
    7
    17
    Notes
    [5] - ITT Population
    [6] - ITT Population
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Chemoradiotherapy + Placebo, followed by Placebo v Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.013 [8]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentage of par. with CR
    Point estimate
    28.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.7
         upper limit
    		 53.6
    Notes
    [7] - Complete response was defined as the percentage of participants achieving a CR as determined by the investigator.
    [8] - From exact test that common odds ratio equals 1

    Secondary: Progression-Free Survival (PFS), as assessed by the investigator

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    End point title
    		 Progression-Free Survival (PFS), as assessed by the investigator
    End point description
    PFS=the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. Per RECIST, progressive disease=a >=20% increase in the sum of the longest diameter of target lesions (TLs), or the appearance of >=1 new L, symptomatic progression and/or unequivocal progression of existing non-TLs. For participants who did not progress or die at the time of reporting (data cut-off 1-Aug-2014), PFS data were censored at the time of the last investigator assessed radiological scan preceding the initiation of any alternative anti-cancer therapy. There were too few events to allow for the calculation of the upper limit of the confidence interval; therefore, 99999 was entered which represents NA.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of disease progression or death due to any cause, assessed after a median of 22 months of follow-up
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [9]
    34 [10]
    Units: Months
        median (confidence interval 95%)
    12.1 (7.3 to 99999)
    20.4 (10.8 to 99999)
    Notes
    [9] - ITT Population
    [10] - ITT Population
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from randomization until death due to any cause. Time to death (data cut-off 1-Aug-2014) was censored at the time of last contact for participants who did not die. There were too few events to allow for the calculation of the upper limit of the confidence interval; therefore, 99999 was entered which indicates NA.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of death due to any cause, assessed after a median of 30.9 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [11]
    34 [12]
    Units: Months
        median (confidence interval 95%)
    23 (14.2 to 99999)
    48.4 (18.8 to 99999)
    Notes
    [11] - ITT Population
    [12] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants who died due to progressive disease

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    End point title
    		 Number of participants who died due to progressive disease
    End point description
    The number of participants who died due to progressive disease (a >=20% increase in the sum of the longest diameter of target lesions, or the appearance of >=1 new lesion, symptomatic progression and/or unequivocal progression of existing non-target lesions), or died due to head and neck cancer without evidence of disease progression, after randomization in the study is presented, using a data cut of 1 August 2014.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of death due to disease under study, assessed after a median of 30.9 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [13]
    34 [14]
    Units: Participants
    11
    8
    Notes
    [13] - ITT Population
    [14] - ITT Population
    No statistical analyses for this end point

    Secondary: Disease-specific Survival

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    End point title
    		 Disease-specific Survival
    End point description
    Disease-specific survival is defined as the time from randomization until death due to head and neck cancer. The cumulative incidence remained lower than 25% in the lapatinib arm, so neither the median nor the inter-quartile range were observed; therefore, 99999 was entered which represents NA. The cumulative incidence in the placebo arm remained lower than 50%, so the median and upper quartile were not observed; therefore, 99999 was entered which represents NA.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of death due to disease, assessed after a median of 13 months of follow-up
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [15]
    34 [16]
    Units: Months
        arithmetic mean (inter-quartile range (Q1-Q3))
    99999 (15.6 to 99999)
    99999 (99999 to 99999)
    Notes
    [15] - ITT Population. For par. who did not die, time to death was censored at the time of last contact.
    [16] - ITT Population. For par. who did not die, time to death was censored at the time of last contact.
    No statistical analyses for this end point

    Secondary: Number of participants with loco-regional recurrence of initial disease

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    End point title
    		 Number of participants with loco-regional recurrence of initial disease
    End point description
    Participants with loco-regional recurrence were those who had progression of disease in the T and N sites. Per the Tumor, Node, and Metastases (TNM) staging of tumors: T describes the size of the tumor and whether it has invaded nearby tissue, and N describes regional lymph nodes that are involved. If a participant had progression in the T or N sites, then the participant was counted as having had an event of interest.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until progression in the T or N site or death due to any cause, assessed after a median of 30.9 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [17]
    34 [18]
    Units: Participants
    7
    4
    Notes
    [17] - ITT Population
    [18] - ITT Population
    No statistical analyses for this end point

    Secondary: Loco-regional control

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    End point title
    		 Loco-regional control
    End point description
    Loco-regional control is defined as the time from the date of randomization until progression in the T or N site. Participants who died or had secondary primary malignancies in the head and neck region outside of the T and N site or distant metastasis were not counted as an event and were instead treated as competing risks. Per the TNM staging of tumors: T describes the size of the tumor and whether it has invaded nearby tissue, and N describes regional lymph nodes that are involved. Due to the minimal events reported (data cut-off 30-Sep-2010), valid analysis could not be performed for loco-regional control rate.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until progression in the T or N site or death due to any cause, assessed after a median of 30.9 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: Months
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [19] - ITT Population
    [20] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with distant recurrence of initial disease

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    End point title
    		 Number of participants with distant recurrence of initial disease
    End point description
    Participants were analyzed for the occurrence of distant metastasis (spread of a disease from one organ or part to another non-adjacent organ or part) after randomization in the study until data cut-off date 1-Aug-2014. Participants who died or had recurrence of disease in the T or N sites or secondary primary malignancies in the head and neck region outside of the original T and N site were not counted as an event and were instead treated as competing risks.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the first occurrence of distant metastasis, assessed after a median of 30.9 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [21]
    34 [22]
    Units: Participants
    5
    8
    Notes
    [21] - ITT Population
    [22] - ITT Population
    No statistical analyses for this end point

    Secondary: Distant Relapse

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    End point title
    		 Distant Relapse
    End point description
    Distant relapse is defined as the time from the date of randomization until the first occurrence of distant metastasis (spread of a disease from one organ or part to another non-adjacent organ of part). Participants who died or had recurrence of disease in the T or N sites or secondary primary malignancies in the head and neck region outside of the original T and N site were not counted as an event and were instead treated as competing risks. If a participant had a distant metastasis and then died, then the participant was counted as having had an event of interest. The cumulative incidence in the lapatinib arm did not reach 50% (most participants had not relapsed), so the median and the upper limit of the interquartile range were not observed; therefore, 99999 was entered which represents NA. The cumulative incidence remained below 25% in the placebo arm, so neither the median nor the inter-quartile range were observed; therefore, 99999 was entered which represents NA.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the first occurrence of distant metastasis, assessed after a median of 30.9 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [23]
    34 [24]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (56.8 to 99999)
    Notes
    [23] - ITT Population
    [24] - ITT Population
    No statistical analyses for this end point

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

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    End point title
    		 Number of participants with Overall Response (OR), as assessed by the investigator
    End point description
    Participants with OR were those who achieved either a CR or partial response (PR) from the assessment of overall tumor response at 6 months (24 weeks) following completion of CRT (data cut-off 30-Sep-2010). Per RECIST, CR is defined as the disappearance of all target and non-target lesions; PR is defined as at least a 30% decrease in the sum of the long diameter (LD) of target lesions, taking as a reference, the baseline sum LD. Data are based on Week 24 scans from participants receiving study treatment at that time point.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until 6 months post chemoradiation treatment, assessed for a median of 13 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [25]
    34 [26]
    Units: Participants
    15
    21
    Notes
    [25] - ITT Population
    [26] - ITT Population
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Chemoradiotherapy + Placebo, followed by Placebo v Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.1969 [28]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in overall response rate
    Point estimate
    16.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.6
         upper limit
    		 42.1
    Notes
    [27] - Overall response was defined as the percentage of participants achieving a PR or CR as determined by the investigator.
    [28] - From exact test that common odds ratio equals 1

    Secondary: Number of participants positive and negative for the expression of biomarkers in tumor tissue: human epidermal growth factor receptor (HER)-1, HER2, HER3, HER4, P16, and transforming growth factor (TGF-alpha)

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    End point title
    		 Number of participants positive and negative for the expression of biomarkers in tumor tissue: human epidermal growth factor receptor (HER)-1, HER2, HER3, HER4, P16, and transforming growth factor (TGF-alpha)
    End point description
    Paraffin-embedded tissue block (or sections) from archived tumor tissue sample, if available (from time of original diagnosis) or fresh tumor tissue, was sent for testing to determine intra-tumoral biomarker expression by immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) assay. Stained tumor slides or tissue micro arrays (TMAs) were scored by a pathologist from 0 (no expression) to 3+ (high expression). An expression level of >=2+ was considered positive.
    End point type
    Secondary
    End point timeframe
    Up to 28 days prior to the date of the first dose of lapatinib/placebo start
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    30 [29]
    27 [30]
    Units: Participants
        HER1, Positive, n=27, 24
    27
    19
        HER1, Negative, n=27, 24
    0
    5
        HER2, Positive, n=26, 25
    3
    0
        HER2, Negative, n=26, 25
    23
    24
        HER2, Missing, n=26, 25
    0
    1
        HER3, Positive, n=27, 22
    8
    5
        HER3, Negative, n=27, 22
    18
    16
        HER3, Missing, n=27, 22
    1
    1
        HER4, Positive, n=26, 25
    0
    0
        HER4, Negative, n=26, 25
    26
    24
        HER4, Missing, n=26, 25
    0
    1
        P16 Positive, n=23, 23
    3
    4
        P16, Negative, n=23, 23
    20
    19
        TGF-alpha, Positive, n=24, 25
    7
    4
        TGF-alpha, Negative, n=24, 25
    17
    20
        TGF-alpha, Missing, n=24, 25
    0
    1
    Notes
    [29] - ITT Population. Only those participants who had sufficient tumor sample for testing were analyzed.
    [30] - ITT Population. Only those participants who had sufficient tumor sample for testing were analyzed.
    No statistical analyses for this end point

    Secondary: Plasma Proteome Analysis

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    End point title
    		 Plasma Proteome Analysis
    End point description
    Proteomic analyses of blood plasma samples were to be conducted to identify any changes in the proteome profile that could be related to the treatment response. Examination of pre-dosing (screening) plasma protein profiles could uncover novel blood-borne protein candidate biomarkers/profiles, which could be used to predict drug response. Plasma proteome data have not been analyzed (tested); thus, data are not available to disclose. Based on the negative outcome of Study EGF102988 (NCT00424255), no suitable analyses have been proposed for this small sample size.
    End point type
    Secondary
    End point timeframe
    From up to 28 days prior to the first dose of lapatinib/placebo start to 8 weeks after the first dose
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    0 [31]
    0 [32]
    Units: Participants
    Notes
    [31] - ITT Population
    [32] - ITT Population
    No statistical analyses for this end point

    Secondary: Analysis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) from tumor samples

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    End point title
    		 Analysis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) from tumor samples
    End point description
    No analysis was performed for tumor sample RNA/DNA. DNA/RNA from tumors has not been analyzed (tested); therefore, data are not available. No suitable analyses of DNA/RNA have been proposed for this small sample size of tumor samples.
    End point type
    Secondary
    End point timeframe
    Screening
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    0 [33]
    0 [34]
    Units: Participants
    Notes
    [33] - ITT Population
    [34] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants negative and positive for Human Papilloma Virus (HPV) infection, as determined from tumor samples

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    End point title
    		 Number of participants negative and positive for Human Papilloma Virus (HPV) infection, as determined from tumor samples
    End point description
    Analysis was performed for HPV infection analysis from the tumor biopsy samples obtained during the Screening period. p16 was used as a marker for HPV; thus, "negative" participants did not have the p16 marker.
    End point type
    Secondary
    End point timeframe
    Up to 28 days prior to the first dose of lapatinib/placebo
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [35]
    34 [36]
    Units: Participants
        Negative
    20
    19
        Positive
    3
    4
        Unknown
    10
    11
    Notes
    [35] - ITT Population
    [36] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants positive and negative for biomarker HER1/ErbB1 categorized in the indicated independent review panel-assessed tumor responses by expression of biomarkers from tumor tissue: sensitivity analysis - 0 versus (1, 2, 3)

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    End point title
    		 Number of participants positive and negative for biomarker HER1/ErbB1 categorized in the indicated independent review panel-assessed tumor responses by expression of biomarkers from tumor tissue: sensitivity analysis - 0 versus (1, 2, 3)
    End point description
    Tumor tissue (fresh or archived) was sent to a central laboratory for biomarker HER1/ErbB1 and tumor genetics analysis up to 1 week after randomization. Per RECIST: CR, disappearance of all lesions; PR, a >=30% decrease in the sum of the longest dimensions (LD) of the target lesions (TLs) taking as a reference the baseline sum LD; Progressive disease (PD), a >=20% increase in the sum of the LD of TLs, or the appearance of >=1 new lesion; Stable Disease (SD), neither PR nor PD, persistence of >=1 non-TL. 0=negative; 1, 2, 3=positive (increasing level of biomarker expression).
    End point type
    Secondary
    End point timeframe
    From the date of randomization until 6 months post chemoradiation treatment, assessed for up to 24 weeks
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    27 [37]
    24 [38]
    Units: Participants
        Negative, CR
    0
    0
        Negative, PR
    0
    0
        Negative, SD
    0
    0
        Negative, PD (Week 24)
    0
    0
        Negative, PD or Death (prior to Week 24)
    0
    0
        Negative, Not Evaluable
    0
    0
        Negative, Unknown
    0
    0
        Positive, CR
    9
    14
        Positive, PR
    4
    3
        Positive, SD
    0
    0
        Positive, PD (Week 24)
    4
    1
        Positive, PD or Death (prior to Week 24)
    5
    4
        Positive, Not Evaluable
    1
    0
        Positive, Unknown
    4
    2
    Notes
    [37] - ITT Population. Participants assessed for HER1/ ErbB1 expression were analyzed.
    [38] - ITT Population. Participants assessed for HER1/ ErbB1 expression were analyzed.
    No statistical analyses for this end point

    Secondary: Number of participants positive and negative for biomarker HER1/ErbB1 categorized in the indicated independent review panel-assessed tumor responses by expression of biomarkers from tumor tissues: sensitivity analysis - 0, 1, 2 versus 3

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    End point title
    		 Number of participants positive and negative for biomarker HER1/ErbB1 categorized in the indicated independent review panel-assessed tumor responses by expression of biomarkers from tumor tissues: sensitivity analysis - 0, 1, 2 versus 3
    End point description
    Tumor tissue (fresh or archived) was sent to a central laboratory for biomarker HER1/ErbB1 and tumor genetics analysis up to 1 week after randomization. Per RECIST: CR, disappearance of all lesions; PR, a >=30% decrease in the sum of the longest dimensions (LD) of the target lesions (TLs) taking as a reference the baseline sum LD; Progressive disease (PD), a >=20% increase in the sum of the LD of TLs, or the appearance of >=1 new lesion; Stable Disease (SD), neither PR nor PD, persistence of >=1 non-TL. 0=negative; 1, 2, 3=positive (increasing level of biomarker expression).
    End point type
    Secondary
    End point timeframe
    From the date of randomization until 6 months post chemoradiation treatment, assessed for up to 24 weeks
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    33 [39]
    34 [40]
    Units: Participants
        Negative, CR
    5
    9
        Negative, PR
    2
    2
        Negative, SD
    0
    0
        Negative, PD (Week 24)
    1
    0
        Negative, PD or Death (prior to Week 24)
    2
    4
        Negative, Not Evaluable
    0
    0
        Negative, Unknown
    1
    1
        Positive, CR
    4
    5
        Positive, PR
    2
    1
        Positive, SD
    0
    0
        Positive, PD (Week 24)
    3
    1
        Positive, PD or Death (prior to Week 24)
    3
    0
        Positive, Not Evaluable
    1
    0
        Positive, Unknown
    3
    1
    Notes
    [39] - ITT Population. Participants assessed for HER1/ ErbB1 expression were analyzed.
    [40] - ITT Population. Participants assessed for HER1/ ErbB1 expression were analyzed.
    No statistical analyses for this end point

    Secondary: Number of participants classified as responders, as per volumetric tumor response

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    End point title
    		 Number of participants classified as responders, as per volumetric tumor response
    End point description
    A formal analysis of this outcome measure was never performed; thus data are not available and cannot be reported.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until 6 months post chemoradiation treatment, assessed for a median of 13 months
    End point values
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Number of subjects analysed
    0 [41]
    0 [42]
    Units: Participants
    Notes
    [41] - ITT Population
    [42] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Data are presented as of the cut-off date of 1-August-2014.
    Adverse event reporting additional description
    Data are presented for the Safety Population (SP)=participants (par.) who were randomized and took >=1 dose of study medication (SM). One par. randomized to placebo received lapatinib in error and was assigned to the lapatinib arm in the SP. One par. randomized to placebo withdrew from the study prior to receiving SM and was not included in the SP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Chemoradiotherapy + Placebo, followed by Placebo
    Reporting group description
    		 Participants received radiotherapy once daily (OD), with a dose/fraction <2.5 Gray (Gy) to a total dose of 70 Gy (using two-dimensional [2D] or 3D techniques) or 65 Gy (using Intensity Modulated Radiation Therapy [IMRT]) to the gross site of disease. Concurrent chemotherapy of cisplatin 100 milligrams per meters squared (mg/m^2) was administered intravenously (IV) on Days 1, 22, and 43 of the course of radiotherapy (Study Days 8, 29, and 50). Matching placebo administration commenced 1 week (or less than or equal to 3 days) prior to the concurrent administration with chemoradiation for a duration of up to 6 to 7 weeks. After the completion of chemoradiotherapy, placebo monotherapy was administered until disease progression or withdrawal.

    Reporting group title
    Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Reporting group description
    		 Participants received radiotherapy once daily (OD), with a dose/fraction <2.5 Gy to a total dose of 70 Gy (using 2D or 3D techniques) or 65 Gy (using IMRT) to the gross site of disease. Concurrent chemotherapy of cisplatin 100 mg/m^2 was administered IV on Days 1, 22, and 43 of the course of radiotherapy (Study Days 8, 29, and 50). Lapatinib 1500 mg OD administration commenced 1 week (or less than or equal to 3 days) prior to the concurrent administration with chemoradiation for a duration of up to 6 to 7 weeks. After the completion of chemoradiotherapy, lapatinib 1500 mg OD monotherapy was administered until disease progression or withdrawal.

    Serious adverse events
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 31 (58.06%)
    22 / 35 (62.86%)
         number of deaths (all causes)
    16
    16
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 35 (8.57%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue inflammation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         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
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal ulceration
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stridor
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Gastrostomy failure
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Somnolence
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (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
    Anaemia
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 35 (8.57%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotid gland inflammation
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal tubular disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 35 (8.57%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 35 (2.86%)
         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: 5%
    Non-serious adverse events
    		 Chemoradiotherapy + Placebo, followed by Placebo Chemoradiotherapy + Lapatinib, followed by Lapatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 31 (100.00%)
    34 / 35 (97.14%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 31 (45.16%)
    4 / 35 (11.43%)
         occurrences all number
    16
    6
    Chills
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Face oedema
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 35 (8.57%)
         occurrences all number
    1
    3
    Fatigue
         subjects affected / exposed
    2 / 31 (6.45%)
    6 / 35 (17.14%)
         occurrences all number
    2
    9
    Fibrosis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    3
    Influenza like illness
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Localised oedema
         subjects affected / exposed
    7 / 31 (22.58%)
    4 / 35 (11.43%)
         occurrences all number
    9
    6
    Mucosal inflammation
         subjects affected / exposed
    14 / 31 (45.16%)
    14 / 35 (40.00%)
         occurrences all number
    14
    17
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Oedema peripheral
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 35 (5.71%)
         occurrences all number
    3
    2
    Pain
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 35 (8.57%)
         occurrences all number
    3
    3
    Pyrexia
         subjects affected / exposed
    6 / 31 (19.35%)
    11 / 35 (31.43%)
         occurrences all number
    6
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 31 (12.90%)
    4 / 35 (11.43%)
         occurrences all number
    6
    12
    Dysphonia
         subjects affected / exposed
    6 / 31 (19.35%)
    5 / 35 (14.29%)
         occurrences all number
    7
    7
    Dyspnoea
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 35 (5.71%)
         occurrences all number
    3
    3
    Epiglottic oedema
         subjects affected / exposed
    4 / 31 (12.90%)
    0 / 35 (0.00%)
         occurrences all number
    4
    0
    Haemoptysis
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    Increased upper airway secretion
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 35 (2.86%)
         occurrences all number
    3
    1
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 35 (5.71%)
         occurrences all number
    3
    2
    Laryngeal oedema
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 35 (8.57%)
         occurrences all number
    2
    3
    Oropharyngeal pain
         subjects affected / exposed
    7 / 31 (22.58%)
    11 / 35 (31.43%)
         occurrences all number
    11
    12
    Productive cough
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 31 (12.90%)
    5 / 35 (14.29%)
         occurrences all number
    4
    5
    Depressed mood
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Depression
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Insomnia
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 35 (11.43%)
         occurrences all number
    3
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 31 (9.68%)
    4 / 35 (11.43%)
         occurrences all number
    7
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 31 (22.58%)
    1 / 35 (2.86%)
         occurrences all number
    7
    1
    Blood bilirubin increased
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 35 (5.71%)
         occurrences all number
    4
    2
    Blood creatinine increased
         subjects affected / exposed
    8 / 31 (25.81%)
    2 / 35 (5.71%)
         occurrences all number
    9
    3
    Blood sodium decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Blood urea increased
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    4 / 31 (12.90%)
    6 / 35 (17.14%)
         occurrences all number
    6
    9
    Ejection fraction decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Haemoglobin decreased
         subjects affected / exposed
    7 / 31 (22.58%)
    7 / 35 (20.00%)
         occurrences all number
    9
    11
    Neutrophil count increased
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 35 (5.71%)
         occurrences all number
    3
    2
    Weight decreased
         subjects affected / exposed
    12 / 31 (38.71%)
    11 / 35 (31.43%)
         occurrences all number
    12
    11
    White blood cell count decreased
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 35 (2.86%)
         occurrences all number
    2
    2
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 35 (0.00%)
         occurrences all number
    3
    0
    Radiation mucositis
         subjects affected / exposed
    5 / 31 (16.13%)
    4 / 35 (11.43%)
         occurrences all number
    5
    4
    Radiation skin injury
         subjects affected / exposed
    9 / 31 (29.03%)
    5 / 35 (14.29%)
         occurrences all number
    9
    5
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 35 (8.57%)
         occurrences all number
    2
    3
    Dysgeusia
         subjects affected / exposed
    8 / 31 (25.81%)
    5 / 35 (14.29%)
         occurrences all number
    8
    5
    Headache
         subjects affected / exposed
    6 / 31 (19.35%)
    6 / 35 (17.14%)
         occurrences all number
    8
    7
    Lethargy
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 35 (8.57%)
         occurrences all number
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 31 (35.48%)
    9 / 35 (25.71%)
         occurrences all number
    11
    10
    Leukocytosis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Leukopenia
         subjects affected / exposed
    7 / 31 (22.58%)
    5 / 35 (14.29%)
         occurrences all number
    8
    5
    Lymphopenia
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Neutropenia
         subjects affected / exposed
    13 / 31 (41.94%)
    7 / 35 (20.00%)
         occurrences all number
    16
    9
    Thrombocytopenia
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 35 (2.86%)
         occurrences all number
    4
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    4 / 31 (12.90%)
    2 / 35 (5.71%)
         occurrences all number
    8
    3
    Hypoacusis
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    4
    Tinnitus
         subjects affected / exposed
    3 / 31 (9.68%)
    6 / 35 (17.14%)
         occurrences all number
    4
    7
    Vertigo
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Aphagia
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Aptyalism
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Cheilitis
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    13 / 31 (41.94%)
    9 / 35 (25.71%)
         occurrences all number
    16
    12
    Dental caries
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    2 / 31 (6.45%)
    18 / 35 (51.43%)
         occurrences all number
    2
    53
    Dry mouth
         subjects affected / exposed
    13 / 31 (41.94%)
    15 / 35 (42.86%)
         occurrences all number
    19
    25
    Dyspepsia
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 35 (11.43%)
         occurrences all number
    2
    5
    Dysphagia
         subjects affected / exposed
    11 / 31 (35.48%)
    10 / 35 (28.57%)
         occurrences all number
    12
    10
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 35 (5.71%)
         occurrences all number
    5
    3
    Glossitis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    3
    Mouth ulceration
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 35 (8.57%)
         occurrences all number
    1
    3
    Nausea
         subjects affected / exposed
    17 / 31 (54.84%)
    22 / 35 (62.86%)
         occurrences all number
    25
    40
    Odynophagia
         subjects affected / exposed
    9 / 31 (29.03%)
    7 / 35 (20.00%)
         occurrences all number
    10
    11
    Oral mucosal erythema
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    4
    Oral pain
         subjects affected / exposed
    8 / 31 (25.81%)
    7 / 35 (20.00%)
         occurrences all number
    9
    7
    Proctalgia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Salivary gland disorder
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    Stomatitis
         subjects affected / exposed
    6 / 31 (19.35%)
    5 / 35 (14.29%)
         occurrences all number
    7
    5
    Tongue ulceration
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    3
    Vomiting
         subjects affected / exposed
    10 / 31 (32.26%)
    14 / 35 (40.00%)
         occurrences all number
    15
    25
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 35 (8.57%)
         occurrences all number
    1
    3
    Nail disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 35 (8.57%)
         occurrences all number
    2
    3
    Rash
         subjects affected / exposed
    8 / 31 (25.81%)
    17 / 35 (48.57%)
         occurrences all number
    12
    34
    Skin reaction
         subjects affected / exposed
    5 / 31 (16.13%)
    8 / 35 (22.86%)
         occurrences all number
    5
    8
    Swelling face
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 35 (2.86%)
         occurrences all number
    4
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 35 (2.86%)
         occurrences all number
    3
    1
    Neck pain
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 35 (11.43%)
         occurrences all number
    8
    5
    Trismus
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    2
    4
    Candida infection
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Catheter site infection
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Fungal infection
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    4
    Influenza
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 35 (2.86%)
         occurrences all number
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    6
    Oral candidiasis
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 35 (11.43%)
         occurrences all number
    7
    4
    Oral fungal infection
         subjects affected / exposed
    5 / 31 (16.13%)
    3 / 35 (8.57%)
         occurrences all number
    6
    3
    Oral infection
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 35 (5.71%)
         occurrences all number
    3
    2
    Rhinitis
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Sinusitis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 35 (2.86%)
         occurrences all number
    4
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 35 (11.43%)
         occurrences all number
    7
    4
    Dehydration
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 35 (0.00%)
         occurrences all number
    4
    0
    Gout
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 31 (12.90%)
    7 / 35 (20.00%)
         occurrences all number
    4
    7
    Hyponatraemia
         subjects affected / exposed
    5 / 31 (16.13%)
    4 / 35 (11.43%)
         occurrences all number
    5
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Sep 2006
    Exclude only patients with T1 or T2 disease and N1. Increase the required creatinine clearance of the subjects at entry. Add CR/MRI scans of chest and upper abdomen throughout the study. Add fiberoptic endoscopy during the maintenance period. Implement the recording of alcohol and tobacco use.
    14 Feb 2008
    Allow enrollment of subjects with tumours with 2+ ErbB1 expression by immunohistochemistry. Remove the confirmatory scans at 12 weeks. Extend maintenance treatment until disease progression. Allow the use of carboplatin for subjects who cannot tolerate cisplatin (after consultation with the medical monitor). Clarify radiotherapy quality assurance process. Clarify the intended dose of radiotherapy for subjects receiving 2D/3D or IMRT. Clarify PET/CT scan requirements. Clarify screening windows for bone scan and panendoscopy procedures. Clarify the dose modifications required in the event of toxicities. Clarify the dose of concurrent dexamethasone allowed. Change the definition of the evaluable population. Remove the requirement that only subjects in the evaluable population would be treated in the maintenance phase. Remove the serum EGFR assessments. Reduce the radiological assessments during the follow-up phase.
    03 Jul 2008
    Amend exclusion criteria to exclude patients with active hepatic disease. Add additional SAE definition, reporting criteria and follow-up assessments for hepatic toxicity. Add additional liver function assessments every 4 weeks. Amend inclusion criteria to remove the requirement for EGFR overexpression. Remove the requirement for a plasma sample for proteomic analysis to be taken at withdrawal from study medication. Include interim analysis and amend sample size for decision making purposes. Amend sample size for decision making purposes. Add overall response rate as a secondary endpoint. Change study medication dose reduction and delay instructions.
    29 Aug 2012
    Discontinue the blinded phase of the study. Stop the study for patients receiving placebo or in post treatment follow-up. Continue access to active clinical trial medication for subjects ongoing on lapatinib. Discontinue many study specific efficacy and safety assessments. Update to Prohibited Medications, regarding use of PPI. Describe the results of the efficacy and safety analyses of the blinded part of the study.

    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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