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    Clinical Trial Results:
    A phase II/III, randomised, two-arm comparison of maintenance lapatinib versus placebo after firrst-line chemotherapy in patients with HER1 and/or HER2 over expressing locally advanced or metastatic bladder cancer.

    Summary
    EudraCT number
    2007-001826-28
    Trial protocol
    GB  
    Global end of trial date
    07 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Aug 2017
    First version publication date
    16 Aug 2017
    Other versions
    Summary report(s)
    JCO 2016 Powles et al

    Trial information

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    Trial identification
    Sponsor protocol code
    BL-2007-02
    Additional study identifiers
    ISRCTN number
    ISRCTN35418671
    US NCT number
    NCT00949455
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Queen Mary University London
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    Charlotte Ackerman, Centre for Experimental Cancer Medicine, +44 2078828497, bci-lamb@qmul.ac.uk
    Scientific contact
    Thomas Powles, Centre for Experimental Cancer Medicine, +44 2078828497, bci-lamb@qmul.ac.uk
    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
    07 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to compare progression-free survival (PFS) in patients with HER1 and/or HER2 over expressing stage IV bladder cancer who have been randomised to maintenance therapy with lapatinib or placebo following first-line chemotherapy
    Protection of trial subjects
    Patients were closely monitored as part of the clinical trial and were seen monthly. ECHOs were carried out in case of any cardiac issues from the lapatinib. The standard of care for these patients is surveillance, and therefore no patients were deviating from this by having placebo.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Feb 2009
    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
    United Kingdom: 232
    Worldwide total number of subjects
    232
    EEA total number of subjects
    232
    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)
    59
    From 65 to 84 years
    169
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    From 17/2/2009, 455 patients were screened for eligibility for the LaMB trial. 236 patients were subsequently randomised to treatment. Patients were recruited from multiple centres within the UK only.

    Pre-assignment
    Screening details
    Patients with histologically confirmed metastatic or locally advanced stage IV transitional cell carcinoma of the urothelium and with an objective response or stable disease upon completion of first-line chemotherapy, were tested for HER1/2 status. Patients with positive status were randomised between lapatinib and placebo maintenance treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lapatinib
    Arm description
    IMP
    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
    Lapatinib was given continuously at 1500mg once daily (6 x 250mg tablets). In the placebo group 6 visually identical tablets were given instead.

    Arm title
    Placebo
    Arm description
    Placebo
    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
    6 visually identical tablets to lapatinib

    Number of subjects in period 1
    Lapatinib Placebo
    Started
    116
    116
    Completed
    116
    116

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lapatinib
    Reporting group description
    IMP

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Reporting group values
    Lapatinib Placebo Total
    Number of subjects
    116 116 232
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    29 30 59
        From 65-84 years
    81 79 160
        85 years and over
    2 2 4
        Not recorded
    4 5 9
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    70.7 (63.9 to 77.2) 71.1 (63.8 to 76.3) -
    Gender categorical
    Units: Subjects
        Female
    28 32 60
        Male
    88 84 172
    ECOG performance status
    ECOG performance status
    Units: Subjects
        Fully active
    53 52 105
        Ambulatory, capable of light work
    52 51 103
        Ambulatory but not capable of work
    11 13 24
    Response to previous chemotherapy
    Units: Subjects
        CR or PR
    80 78 158
        SD
    36 38 74
        PD
    0 0 0
    Tumour grade
    Units: Subjects
        Grade 1 or 2
    4 4 8
        Grade 3 or 4
    98 98 196
        not recorded
    14 14 28
    Visceral metastasis
    Units: Subjects
        Yes
    60 47 107
        No
    52 62 114
        not recorded
    4 7 11
    HER status
    Units: Subjects
        HER1 positive
    53 49 102
        HER2 positive
    21 21 42
        HER1 and HER2 positive
    42 46 88
        HER negative
    0 0 0
    Previous cisplatin base chemotherapy
    Units: Subjects
        Yes
    71 73 144
        No
    40 39 79
        Not recorded
    5 4 9
    Haemoglobin
    Units: Subjects
        Normal
    31 26 57
        Low
    78 90 168
        not recorded
    7 0 7
    Albumin
    Units: Subjects
        Normal
    108 111 219
        Low
    1 3 4
        not recorded
    7 2 9
    Creatinine
    Units: Subjects
        Normal
    49 36 85
        High
    60 78 138
        not recorded
    7 2 9
    Subject analysis sets

    Subject analysis set title
    Trial patient analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Patients who meet inclusion/exclusion criteria and were randomised to receive treatment

    Subject analysis sets values
    Trial patient analysis
    Number of subjects
    232
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    59
        From 65-84 years
    160
        85 years and over
    4
        Not recorded
    9
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    70.7 (64.2 to 77.1)
    Gender categorical
    Units: Subjects
        Female
    60
        Male
    172
    ECOG performance status
    ECOG performance status
    Units: Subjects
        Fully active
    105
        Ambulatory, capable of light work
    103
        Ambulatory but not capable of work
    24
    Response to previous chemotherapy
    Units: Subjects
        CR or PR
    158
        SD
    74
        PD
    0
    Tumour grade
    Units: Subjects
        Grade 1 or 2
    8
        Grade 3 or 4
    196
        not recorded
    28
    Visceral metastasis
    Units: Subjects
        Yes
    107
        No
    114
        not recorded
    11
    HER status
    Units: Subjects
        HER1 positive
    102
        HER2 positive
    42
        HER1 and HER2 positive
    88
        HER negative
    0
    Previous cisplatin base chemotherapy
    Units: Subjects
        Yes
    144
        No
    79
        Not recorded
    9
    Haemoglobin
    Units: Subjects
        Normal
    57
        Low
    168
        not recorded
    7
    Albumin
    Units: Subjects
        Normal
    219
        Low
    4
        not recorded
    9
    Creatinine
    Units: Subjects
        Normal
    85
        High
    138
        not recorded
    9

    End points

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    End points reporting groups
    Reporting group title
    Lapatinib
    Reporting group description
    IMP

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Subject analysis set title
    Trial patient analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Patients who meet inclusion/exclusion criteria and were randomised to receive treatment

    Primary: Progression-free survival

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    End point title
    Progression-free survival
    End point description
    End point type
    Primary
    End point timeframe
    Date of randomisation until disease progression or death from any cause
    End point values
    Lapatinib Placebo
    Number of subjects analysed
    116
    116
    Units: months
        median (confidence interval 95%)
    4.5 (2.8 to 5.4)
    5.1 (3 to 5.8)
    Statistical analysis title
    Progression-free survival
    Comparison groups
    Lapatinib v Placebo
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.63
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.43

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Date of randomisation until death from any cause
    End point values
    Lapatinib Placebo
    Number of subjects analysed
    116
    116
    Units: months
        median (confidence interval 95%)
    12.6 (9 to 16.2)
    12 (10.5 to 14.9)
    Statistical analysis title
    Overall survival
    Comparison groups
    Lapatinib v Placebo
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.31

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire trial
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTC
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Lapatinib
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Lapatinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    82 / 116 (70.69%)
    82 / 116 (70.69%)
         number of deaths (all causes)
    42
    42
         number of deaths resulting from adverse events
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
         subjects affected / exposed
    4 / 116 (3.45%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    10 / 116 (8.62%)
    6 / 116 (5.17%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    0 / 116 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Investigations
         subjects affected / exposed
    2 / 116 (1.72%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    2 / 116 (1.72%)
    3 / 116 (2.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    0 / 116 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary/Upper Respiratory
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    3 / 116 (2.59%)
    6 / 116 (5.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Nervous System Disorder
         subjects affected / exposed
    2 / 116 (1.72%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    7 / 116 (6.03%)
    7 / 116 (6.03%)
         occurrences causally related to treatment / all
    6 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    10 / 116 (8.62%)
    11 / 116 (9.48%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    0 / 116 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    0 / 116 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Infections and Infestations
         subjects affected / exposed
    8 / 116 (6.90%)
    5 / 116 (4.31%)
         occurrences causally related to treatment / all
    1 / 9
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Lapatinib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    97 / 116 (83.62%)
    99 / 116 (85.34%)
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    4 / 116 (3.45%)
    7 / 116 (6.03%)
         occurrences all number
    4
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 116 (6.90%)
    10 / 116 (8.62%)
         occurrences all number
    8
    10
    Respiratory
         subjects affected / exposed
    3 / 116 (2.59%)
    7 / 116 (6.03%)
         occurrences all number
    3
    7
    Shortness of breath
         subjects affected / exposed
    12 / 116 (10.34%)
    10 / 116 (8.62%)
         occurrences all number
    12
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 116 (1.72%)
    10 / 116 (8.62%)
         occurrences all number
    2
    10
    Nervous system disorders
    Neuropathy
         subjects affected / exposed
    7 / 116 (6.03%)
    14 / 116 (12.07%)
         occurrences all number
    7
    14
    Neurotoxicity
         subjects affected / exposed
    7 / 116 (6.03%)
    1 / 116 (0.86%)
         occurrences all number
    7
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    38 / 116 (32.76%)
    42 / 116 (36.21%)
         occurrences all number
    38
    42
    Oedema
         subjects affected / exposed
    5 / 116 (4.31%)
    8 / 116 (6.90%)
         occurrences all number
    5
    8
    Pain
         subjects affected / exposed
    47 / 116 (40.52%)
    47 / 116 (40.52%)
         occurrences all number
    47
    47
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    16 / 116 (13.79%)
    18 / 116 (15.52%)
         occurrences all number
    16
    18
    Diarrhoea
         subjects affected / exposed
    58 / 116 (50.00%)
    23 / 116 (19.83%)
         occurrences all number
    65
    23
    Nausea
         subjects affected / exposed
    23 / 116 (19.83%)
    20 / 116 (17.24%)
         occurrences all number
    23
    20
    Vomiting
         subjects affected / exposed
    18 / 116 (15.52%)
    16 / 116 (13.79%)
         occurrences all number
    18
    16
    Hepatobiliary disorders
    Creatinine
         subjects affected / exposed
    4 / 116 (3.45%)
    7 / 116 (6.03%)
         occurrences all number
    4
    7
    Renal and urinary disorders
    Bladder symptoms
         subjects affected / exposed
    5 / 116 (4.31%)
    6 / 116 (5.17%)
         occurrences all number
    6
    6
    Haematuria
         subjects affected / exposed
    11 / 116 (9.48%)
    6 / 116 (5.17%)
         occurrences all number
    11
    6
    Renal Impairment
         subjects affected / exposed
    6 / 116 (5.17%)
    7 / 116 (6.03%)
         occurrences all number
    6
    7
    Skin and subcutaneous tissue disorders
    Cutaneous
         subjects affected / exposed
    5 / 116 (4.31%)
    1 / 116 (0.86%)
         occurrences all number
    5
    1
    Dry skin
         subjects affected / exposed
    6 / 116 (5.17%)
    2 / 116 (1.72%)
         occurrences all number
    6
    2
    Itch
         subjects affected / exposed
    12 / 116 (10.34%)
    10 / 116 (8.62%)
         occurrences all number
    12
    12
    Rash
         subjects affected / exposed
    45 / 116 (38.79%)
    21 / 116 (18.10%)
         occurrences all number
    45
    21
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    12 / 116 (10.34%)
    7 / 116 (6.03%)
         occurrences all number
    12
    7
    Infections and infestations
    Infection
         subjects affected / exposed
    31 / 116 (26.72%)
    18 / 116 (15.52%)
         occurrences all number
    31
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jan 2008
    Addition of an interim analysis to the protocol Prohinbited drugs list added to PIS Scan schedule changed to every 12 weeks rather than 10 weeks Correction to IMP storage conditions in protocol.
    11 Feb 2009
    Study amended from Phase III to Phase II/III. Administrative corrections throughout protocol. Two stratification factors removed from the randomisation (prior ciplatin chemotherapy, hospital site) Inclusion of patients with HER2+ intensity on IHC Haemaglobin levels (>8.0 g/dL) added to inclusion criteria Clarifications to assessment schedule Instructions to sites regarding IMP management at end of the study added to protocol Dose management guidance added to protocol in the event of liver chemistry, LVEF and hepatobiliary abnormalities
    02 Jul 2009
    Patients with bladder cancer in the urothelial tract eligible for entry. Following updated safety information from IMP manufacturer - herbal supplements are prohibited from use and diarrhoea supportive care guidance provided.
    25 Aug 2009
    Amendment to allow metastatic bladder cancer patients with bone metastases (alkaline phosphatase levels removed from the inclusion criteria). Administrative clarifications to assessment schedule
    24 May 2010
    Amendment to protocol to allow for capture of follow-up data for all patients screened that are HER negative, but did not proceed to study treatment. Addition of testing for HER3 and 4 status Administrative clarifications to protocol
    18 Oct 2010
    Update to exclusion criteria - remove previous HER1/2 therapy from the exclusion criteria Time allowed between randomisation and treatment commencement increased to 10 weeks
    13 Jan 2011
    Addition of sites and change of Principal Investigator only
    19 May 2011
    Amendment to protocol to allow for capture of follow-up data for all patients screened that are HER positive, but did not proceed to study treatment.
    23 Jun 2011
    Addition of sites and change of Principal Investigator only
    30 Nov 2011
    Changes to Principal Investigators only
    17 Apr 2012
    Addition of new sites only
    01 Aug 2012
    Change of Principal Investigator only
    22 Oct 2012
    Change of Principal Investigator only
    30 Jul 2013
    Increase to sample size Change to Principal Investigators
    27 Jan 2015
    Clarification of end of trial procedures in protocol

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/28034079
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