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    Clinical Trial Results:
    Double blind randomized phase III study of maintenance Pazopanib versus placebo in NSCLC patients non progressive after first line chemotherapy. MAPPING, an EORTC Lung group study.

    Summary
    EudraCT number
    		 2010-018566-23
    Trial protocol
    		 BE   NL   DE   GB   GR   SI  
    Global end of trial date
    26 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jul 2016
    First version publication date
    30 Jul 2016
    Other versions
    Summary report(s)
    		 Summary 08092

    Trial information

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    Trial identification
    Sponsor protocol code
    08092
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01208064
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MAPPING: 08092
    Sponsors
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer
    Sponsor organisation address
    Avenue E. Mounier 83/11 , Brussels, Belgium, 1200
    Public contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27441062, regulatory@eortc.be
    Scientific contact
    Project, Budget and Regulatory Dept, European Organisation for Research and Treatment of Cancer, +32 27441062, regulatory@eortc.be
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the therapeutic benefit of maintenance pazopanib versus placebo after first-line treatment for Non-Small Cell Lung Cancer (NSCLC).
    Protection of trial subjects
    The responsible investigator ensured that this study was conducted in agreement with either the Declaration of Helsinki and/or the laws and regulations of the country, whichever provides the greatest protection of the patient. The protocol has been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP). The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.
    Background therapy
    		 The small molecule VEGFR inhibitor, pazopanib is in clinical development in the treatment of a variety of human cancers. Pazopanib (GW786034) is an orally active, multi-target tyrosine kinase inhibitor (TKI) with a potent and selective in vitro activity against VEGF receptor (VEGF receptor-1, -2, and -3), platelet-derived growth factor (PDGF) receptor-α and -β, and stem cell factor receptor (CD-117 or c-Kit ligand). In pre-clinical angiogenesis models, pazopanib inhibited VEGF-dependent angiogenesis in a dose-dependent manner. In xenograft tumor models, twice-daily administration of pazopanib significantly inhibited tumor growth in mice implanted with various human tumor cells. By targeting a wide range of tyrosine kinases both in the vasculature and stroma, pazopanib has the potential to be effective in lung cancer. Proof of concept has been established for pazopanib monotherapy in early stage NSCLC (ELCAP study; VEG105290) where 30 out of 35 (86%) patients achieved a reduction in tumor volume after pazopanib preoperative treatment. Pazopanib has now been approved by the U.S. Food and Drug Administration FDA for the treatment of patients with advanced renal cell carcinoma (NDA number 022465). Approximately 3000 subjects with cancer have been enrolled in clinical studies of pazopanib as of 09 September 2009. Data collected to date show that oral pazopanib is absorbed after administration and that pazopanib administration at 800 mg daily is associated with a reasonable safety profile and encouraging efficacy in various oncology settings.
    Evidence for comparator
    		 While pemetrexed and erlotinib have demonstrated efficacy as maintenance therapy they are not considered standard of care in the general NSCLC patient population. Currently there is no standard treatment in the broad NSCLC population (squamous and non-squamous histologies) in the maintenance setting. Consequently, placebo is considered an appropriate comparator for Phase III.
    Actual start date of recruitment
    18 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Slovenia: 10
    Country: Number of subjects enrolled
    United Kingdom: 52
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Egypt: 13
    Country: Number of subjects enrolled
    Germany: 5
    Worldwide total number of subjects
    102
    EEA total number of subjects
    89
    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)
    54
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient recruited on 18 July, 2011 Last patient recruited on 25 October, 2013

    Pre-assignment
    Screening details
    		 - Stage IIIB- IV (as per TNM version VII) newly diagnosed or recurrent NSCLC (after surgery or radical radiotherapy) proven on cytology or histology before induction chemotherapy - Patients must not have progressed during the four to six cycles of initial chemotherapy (all the selection criteria are given in the summary attachment)

    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
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    To blind the treatment allocation after the randomization procedure, the EORTC Headquarters uses the concept of “treatment box”. The drugs are packed in "boxes" displaying only a code. The program used for registering patients and running the minimization algorithm is identical to the one used for open label studies. A box containing the allocated treatment available at the institution is subsequently identified, and its code is displayed by the randomization program.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maintenance Pazopanib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pazopanib
    Investigational medicinal product code
    GW786034B
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The investigational product, pazopanib monohydrochloride salt (coded as GW786034B) tablets is provided as 200 mg tablets. Pazopanib treatment is starting at 600mg for 2 weeks then increasing to 800 mg daily till disease progression, unacceptable toxicity, best patient interest or patient refusal

    Arm title
    		 Placebo
    Arm description
    		 -
    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
    Placebo tablets matching the 200 mg pazopanib tablets will be used for the study as control and will be given daily till disease progression, unacceptable toxicity, best patient interest or patient refusal

    Number of subjects in period 1
    		Maintenance Pazopanib Placebo
    Started
    50
    52
    Started allocated treatment
    50
    50
    Completed
    45
    50
    Not completed
    5
    2
         still on treatment by the time of final analysis
    5
    -
         Treatment never started
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Maintenance Pazopanib
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Maintenance Pazopanib Placebo Total
    Number of subjects
    		 50 52 102
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 27 27 54
        From 65-84 years
    		 23 25 48
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 64.2 (28.4 to 81.1) 64.6 (25.9 to 80.7) -
    Gender categorical
    Collected at baseline
    Units: Subjects
        Female
    		 29 27 56
        Male
    		 21 25 46
    Histology
    Stratification factor
    Units: Subjects
        squamous
    		 9 11 20
        non-squamous
    		 41 41 82
    Tobacco Use
    Units: Subjects
        Never
    		 11 10 21
        Past
    		 26 35 61
        Current
    		 11 4 15
        Missing
    		 2 3 5
    Prior Surgery
    Did the patient previously undergo surgery for NSCLC?
    Units: Subjects
        no
    		 42 49 91
        yes
    		 8 3 11
    Prior Radiotherapy
    Did the patient receive prior radiotherapy
    Units: Subjects
        no
    		 43 44 87
        yes, palliative radiotherapy
    		 6 6 12
        yes, radical radiotherapy
    		 1 1 2
        both radical and palliative
    		 0 1 1
    Performance Status
    Stratification factor
    Units: Subjects
        PS 0
    		 18 11 29
        PS 1
    		 32 39 71
        PS 2
    		 0 2 2
    Response after the last cycle of induction therapy
    Stratification factor
    Units: Subjects
        Partial response
    		 16 14 30
        Stable disease
    		 34 38 72

    End points

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    End points reporting groups
    Reporting group title
    Maintenance Pazopanib
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival is measured from the time between the date of randomization and the date of death. Patients who are still alive when last traced are censored at the date of last follow-up.
    End point type
    Primary
    End point timeframe
    Overall survival rate at 1 year
    End point values
    		 Maintenance Pazopanib Placebo
    Number of subjects analysed
    50
    52
    Units: Percentages
        number (confidence interval 95%)
    57.2 (41.2 to 70.3)
    51.2 (34.2 to 65.9)
    Attachments
    		 OS 08092
    Statistical analysis title
    		 OS comparison in ITT population
    Statistical analysis description
    Comparison of overall survival maintenance pazopanib versus placebo in intent-to-treat (ITT) population (all randomized patient according to allocated treatment) and adjusted by stratification factors (histology, performance status, response after the last cycle of induction therapy).
    Comparison groups
    Maintenance Pazopanib v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.28
    Notes
    [1] - OS was the primary endpoint, yet at the interim analysis, decision to continue was based on the Progression Free Survival (PFS)
    [2] - Adjusted by stratification factors. Out of 3 stratification factors only Histology and Response after the last cycle of induction therapy were used in the adjustment. PS status (0/1 vs. 2) was not used since only 2 patients had PS=2

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression free survival is defined as the time between the date of randomization after completion of induction chemotherapy and the date of disease progression or death.
    End point type
    Secondary
    End point timeframe
    Median progression-free survival
    End point values
    		 Maintenance Pazopanib Placebo
    Number of subjects analysed
    50
    52
    Units: Months
        median (confidence interval 95%)
    4.3 (2.99 to 7.43)
    3.22 (2.07 to 5.09)
    Attachments
    		 PFS-08092
    Statistical analysis title
    		 PFS comparison in ITT population
    Statistical analysis description
    Comparison of progression-free survival of maintenance pazopanib versus placebo in intent-to-treat (ITT) population (all randomized patient according to allocated treatment) and adjusted by stratification factors (histology, performance status, response after the last cycle of induction therapy).
    Comparison groups
    Maintenance Pazopanib v Placebo
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.03
    Notes
    [3] - Adjusted by stratification factors. Out of 3 stratification factors only Histology and Response after the last cycle of induction therapy were used in the adjustment. PS status (0/1 vs. 2) was not used since only 2 patients had PS=2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected on a CRF to be submitted at pre-specified timepoint : prior to maintenance, after 2 weeks of maintenance, during maintenance every 4 weeks, at the end of maintenance
    Adverse event reporting additional description
    CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. (1% of AEs are reported as "other" and are not reported as not available from the list of SOC). AEs are evaluated using CTC v4, SAEs using MedDra. Non-SAEs has not been collected specifically, therefore all AEs (any grade) will be reported in non-SAE section.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Maintenance Pazopanib
    Reporting group description
    		 Safety population: patients who started maintenance Pazopanib

    Reporting group title
    Placebo
    Reporting group description
    		 Safety population: patients who started placebo

    Serious adverse events
    		 Maintenance Pazopanib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 50 (24.00%)
    5 / 50 (10.00%)
         number of deaths (all causes)
    20
    26
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Alanine aminotransferase increased
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Hypertension
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (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
    Neutropenia
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tracheobronchitis
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Varicella
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
    Additional description: From pharmacovigilance database
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Maintenance Pazopanib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 50 (98.00%)
    49 / 50 (98.00%)
    Vascular disorders
    Hypertension
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    40 / 50 (80.00%)
    30 / 50 (60.00%)
         occurrences all number
    230
    109
    Thromboembolic event
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    7 / 50 (14.00%)
    4 / 50 (8.00%)
         occurrences all number
    21
    6
    General disorders and administration site conditions
    Fatigue
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    33 / 50 (66.00%)
    24 / 50 (48.00%)
         occurrences all number
    171
    86
    Fever
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Non cardiac chest pain
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    12 / 50 (24.00%)
    6 / 50 (12.00%)
         occurrences all number
    29
    21
    Other GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    9 / 50 (18.00%)
    8 / 50 (16.00%)
         occurrences all number
    35
    21
    Reproductive system and breast disorders
    Other REPRODUCTIVE SYSTEM AND BREAST DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 50 (2.00%)
         occurrences all number
    6
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    15 / 50 (30.00%)
    15 / 50 (30.00%)
         occurrences all number
    57
    50
    Dyspnea
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    15 / 50 (30.00%)
    15 / 50 (30.00%)
         occurrences all number
    69
    47
    Other RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    14 / 50 (28.00%)
    12 / 50 (24.00%)
         occurrences all number
    51
    42
    Pleural effusion
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
         occurrences all number
    3
    7
    Psychiatric disorders
    Other PSYCHIATRIC DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 50 (12.00%)
    5 / 50 (10.00%)
         occurrences all number
    26
    7
    Investigations
    Electrocardiogram
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Other INJURY, POISONING AND PROCEDURAL COMPLICATIONS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Cardiac disorders
    Heart failure
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Myocardial infarction
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Dizziness
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    6 / 50 (12.00%)
    3 / 50 (6.00%)
         occurrences all number
    19
    7
    Other NERVOUS SYSTEM DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    14 / 50 (28.00%)
    6 / 50 (12.00%)
         occurrences all number
    57
    15
    Peripheral motor neuropathy
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    5
    Peripheral sensory neuropathy
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    13 / 50 (26.00%)
    9 / 50 (18.00%)
         occurrences all number
    71
    35
    Ear and labyrinth disorders
    Other EAR AND LABYRINTH DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 50 (8.00%)
    4 / 50 (8.00%)
         occurrences all number
    13
    11
    Eye disorders
    Other EYE DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    7 / 50 (14.00%)
    5 / 50 (10.00%)
         occurrences all number
    41
    14
    Gastrointestinal disorders
    Abdominal pain
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    11 / 50 (22.00%)
    6 / 50 (12.00%)
         occurrences all number
    25
    11
    Diarrhea
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    24 / 50 (48.00%)
    6 / 50 (12.00%)
         occurrences all number
    133
    12
    Nausea
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    20 / 50 (40.00%)
    13 / 50 (26.00%)
         occurrences all number
    56
    35
    Other GASTROINTESTINAL DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    19 / 50 (38.00%)
    15 / 50 (30.00%)
         occurrences all number
    103
    76
    Vomiting
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    12 / 50 (24.00%)
    9 / 50 (18.00%)
         occurrences all number
    25
    18
    Skin and subcutaneous tissue disorders
    Other SKIN AND SUBCUTANEOUS TISSUE DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    20 / 50 (40.00%)
    16 / 50 (32.00%)
         occurrences all number
    177
    57
    Rash
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    7 / 50 (14.00%)
    8 / 50 (16.00%)
         occurrences all number
    30
    18
    Renal and urinary disorders
    Other RENAL AND URINARY DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 50 (2.00%)
         occurrences all number
    10
    4
    Endocrine disorders
    Other ENDOCRINE DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Other MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    20 / 50 (40.00%)
    14 / 50 (28.00%)
         occurrences all number
    125
    54
    Infections and infestations
    Other INFECTIONS AND INFESTATIONS
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    12 / 50 (24.00%)
    16 / 50 (32.00%)
         occurrences all number
    24
    34
    Metabolism and nutrition disorders
    Anorexia
    Additional description: From clinical database: all clinical adverse events (any grade)
    alternative dictionary used: CTCAE 4.0
         subjects affected / exposed
    20 / 50 (40.00%)
    12 / 50 (24.00%)
         occurrences all number
    103
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2012
    The main rationale for this amendment is to update the protocol according to the comments received by the French Competent Authorities. This amendment has been discussed and agreed by the EORTC lung Group and the EORTC HQ. The comments made by the French authorities in their letter dated April 24, 2011 do not stop protocol for being activated but do request that the protocol be upgraded. The changes are not considered as altering profoundly the protocol and could be beneficial in any case to the whole protocol. The French authorities basically required additional safety checks at the time of dose increase and an additional visit has been introduced. Inclusion criteria do now request normal potassium and additional checks are inserted for QTc surveillance. A list of agents potentially interfering with QTc was provided. Several protocol timeframes were difficult to meet. There was an agreement to include protocol modifications making the timelines more close to clinical reality such as tumor assessment/documentation of non-progression and maintenance treatment start. We clarified that no confirmation CT/MRI is required and clarified the time window allowed for maintenance treatment initiation. The IB was also updated to version 9, as well as the Patient Information Sheet/Informed Consent to version 3.0.
    24 Sep 2012
    The following changes have been made to the protocol: • Some timelines have been modified so they are closer to clinical reality e.g. time interval from start of adjuvant treatment to induction chemotherapy for metastatic disease, and time interval from radical RT to initiation of chemotherapy for metastatic disease. • Clarification that concomitant treatment with statins is acceptable • Clarifications regarding other concomitant medication • New translational objective added (circulating tumour cell analysis). The following changes have been made to the PIS/IC: • Updated to include details of Circulating Tumor Cells (CTC) analysis.
    23 Apr 2014
    Updated Investigator’s Brochure for the IMP Pazopanib (version 11, dated January 2014). The changes to this document have been assessed and it was concluded that a protocol amendment is not required, as the safety of participants and the risk-benefit assessment of the study has not been altered.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    06 Aug 2013
    Temporary halt of the trial. The EORTC was informed on 21 December 2012 by GSK of their intention to withdraw their support to the study because of insufficient efficacy and/or poor tolerability of Pazopanib in lung cancer patients, and that accrual was considerably behind target. After discussions it was agreed that the study should remain open until 102 patients have been recruited or 53 events have been reported, and that an interim analysis should be performed to assess the future of the trial based on strong and reliable scientific evidence. The agreed target of 102 patients was reached on 06 August 2013 and all investigators have been notified that recruitment was on-hold. 25 October 2013: Decision to stop recruitment permanently. An Interim Analysis has been performed and the results have been reviewed by the EORTC IDMC. The Interim Analysis plan was conducted according to a modified futility test revised this year, towards a stringent futility stopping rule, due to emerging evidence from other Non-Small Cell Lung Cancer (NSCLC) pazopanib studies. Those studies were closed for various reasons, among others: poor recruitment, excess of toxicity, insufficient treatment adherence and efficacy. In addition, studies testing other tyrosine kinase inhibitors in NSCLC have shown there was no benefit for patients. Based on the data available in the current study, the IDMC has recommended stopping the trial since the efficacy results for the primary endpoint fulfill the extreme stopping rule for futility specified in the revised interim analysis plan. Moreover data have indicated that the adherence to the planned dosing of the experimental treatment beyond week 2 was rather poor. EORTC has accepted these recommendations and all investigators have been informed. As recruitment was stopped prematurely the trial never reached the End of Trial defined in the protocol. Therefore, the last patient’s last treatment was considered as the EoT.
    -

    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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