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    Clinical Trial Results:
    A Phase II, Open-Label, Randomized, Multicenter Trial of GW786034 (Pazopanib) in Combination with Lapatinib (GW572016) Compared to Lapatinib Alone as First Line Therapy in Subjects with Advanced or Metastatic Breast Cancer with ErbB2 Fluorescence In Situ Hybridization (FISH) Positive Tumors

    Summary
    EudraCT number
    		 2005-004350-28
    Trial protocol
    		 GB   HU  
    Global end of trial date
    14 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Mar 2016
    First version publication date
    02 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VEG20007
    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
    11 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the rate of disease progression at 12 weeks between pazopanib in combination with lapatinib versus lapatinib alone in subjects with locally advanced or metastatic breast cancer whose tumors are ErbB2 FISH+.
    Protection of trial subjects
    Dose modifications for pazopanib were permitted if hypertension, proteinuria, thrombosis or hemorrhage was experienced by the subject and the investigator considered pazopanib may contribute to the event. Pazopanib dose interruptions or reductions (200mg per time) were permitted. Dose interruption of pazopanib and lapatinib were permitted for up to 2 weeks in the event of toxicity. Subjects who experience at least a 20% absolute decrease in left ventricular cardiac ejection fraction (LVEF) from baseline should be monitored. Repeated similar or worsening results should result in lapatinib dose interruption or discontinuation. Dose interruptions were possible for subjects experiencing liver related treatment emergent AEs as pre-specified in protocol. Subjects could receive full supportive care during the study, including transfusion of blood and blood products, treatment with antibiotics, analgesics or bisphosphonates, when appropriate.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jul 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    India: 30
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Pakistan: 25
    Country: Number of subjects enrolled
    Peru: 38
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Thailand: 1
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    189
    EEA total number of subjects
    36
    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)
    159
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants (par.) were enrolled into two cohorts. Cohort 1: Par. were randomized 1:1 to lapatinib 1500 mg or lapatinib 1000 mg/pazopanib 400 mg. Cohort 2: After enrollment was complete for Cohort 1, par. were enrolled to lapatinib 1500 mg/pazopanib 800 mg. All par. who received study drug are accounted for in the Participant Flow module.

    Pre-assignment
    Screening details
    		 Female par. with >=18 years of age with histologically confirmed invasive breast cancer were enrolled in the study. Total 189 par. (Cohort 1, combination n = 76, lapatinib n = 73; Cohort 2, n = 40) received study drug.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Lapatinib 1500 mg
    Arm description
    		 Lapatinib 1500 milligrams (mg) administered orally once a day
    Arm type
    		 Active comparator

    Investigational medicinal product name
    lapatinib (GW572016) 1500 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1500 mg administered orally once daily.

    Arm title
    		 Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg
    Arm description
    		 Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    lapatinib (GW572016) 1000 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg administered orally once daily.

    Investigational medicinal product name
    pazopanib (GW786034) 400 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg administered orally once daily

    Arm title
    		 Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg
    Arm description
    		 Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
    Arm type
    		 Experimental

    Investigational medicinal product name
    lapatinib (GW572016) 1500 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1500 mg administered orally once daily.

    Investigational medicinal product name
    pazopanib (GW786034) 800 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg administered orally once daily

    Number of subjects in period 1
    		Cohort 1: Lapatinib 1500 mg Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg
    Started
    73
    76
    40
    Completed
    2
    0
    2
    Not completed
    71
    76
    38
         Consent withdrawn by subject
    6
    8
    -
         Physician decision
    1
    1
    -
         Death
    35
    42
    19
         Par. Started Other Treatment
    1
    1
    1
         Lost to follow-up
    11
    13
    -
         Missing
    2
    1
    2
         Sponsor terminated study
    15
    10
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Lapatinib 1500 mg
    Reporting group description
    		 Lapatinib 1500 milligrams (mg) administered orally once a day

    Reporting group title
    Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg
    Reporting group description
    		 Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day

    Reporting group title
    Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg
    Reporting group description
    		 Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day

    Reporting group values
    		 Cohort 1: Lapatinib 1500 mg Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg Total
    Number of subjects
    		 73 76 40 189
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.7 ( 11.23 ) 51.9 ( 12.48 ) 55 ( 12.71 ) -
    Gender categorical
    Units: Subjects
        Female
    		 73 76 40 189
        Male
    		 0 0 0 0
    Race, customized
    Units: Subjects
        African American/African Heritage
    		 0 2 0 2
        American Indian or Alaska Native
    		 20 18 0 38
        Asian
    		 33 33 4 70
        White
    		 20 22 35 77
        Unknown
    		 0 1 1 2
    Child-Bearing Potential
    Units: Subjects
        Post-Menopausal
    		 50 51 26 127
        Sterile (of child-bearing age)
    		 3 2 5 10
        Potentially able to bear children
    		 20 23 9 52

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Lapatinib 1500 mg
    Reporting group description
    		 Lapatinib 1500 milligrams (mg) administered orally once a day

    Reporting group title
    Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg
    Reporting group description
    		 Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day

    Reporting group title
    Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg
    Reporting group description
    		 Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day

    Primary: Percentage of Participants with Progressive Disease at Week 12 in Cohort 1

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    End point title
    		 Percentage of Participants with Progressive Disease at Week 12 in Cohort 1 [1]
    End point description
    The percentage of participants with progressive disease (PD) 12 weeks after randomization was measured. Per Response Evaluation Criteria In Solid Tumors (RECIST), a response of PD is defined as a >=20% increase in target lesions. Participants were also classified as having PD if their response at Week 12 was unknown or missing. Response was determined by an independent radiologist and by an investigator. Cohort 1: Modified Intent-to-Treat (ITT) Population (all randomized, centrally confirmed ErbB2 FISH-positive participants).
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of the endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Cohort 1: Lapatinib 1500 mg Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg
    Number of subjects analysed
    72 [2]
    69 [3]
    Units: percentage of participants
    number (not applicable)
        Independently Evaluated
    38.9
    36.2
        Investigator Evaluated
    43.1
    37.7
    Notes
    [2] - Cohort 1: Modified ITT Population
    [3] - Cohort 1: Modified ITT Population
    Statistical analysis title
    		 Statisticial Analysis 1
    Comparison groups
    Cohort 1: Lapatinib 1500 mg v Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.3724
    Method
    		 Chi-squared
    Parameter type
    		 Percentage Difference
    Point estimate
    2.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 16.3
    Notes
    [4] - Difference in the percentage of independently-evaluated PD between lapatinib and combination therapy (lapatinib plus pazopanib)
    Statistical analysis title
    		 Statisticial Analysis 2
    Comparison groups
    Cohort 1: Lapatinib 1500 mg v Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.2578
    Method
    		 Chi-squared
    Parameter type
    		 Percentage Difference
    Point estimate
    5.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 19.2
    Notes
    [5] - Difference in the percentage of investigator-evaluated PD between lapatinib and combination therapy (lapatinib plus pazopanib)

    Secondary: Overall Survival for Cohort 1

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    End point title
    		 Overall Survival for Cohort 1 [6]
    End point description
    Overall survival (OS) is defined as the time from randomization until death due to any cause. Participants who are alive as of the date of last contact are censored. There was insufficient follow-up to adequately assess OS for Cohort 2. Median OS cannot be presented for the lapatinib arm because the upper bound of the 95% confidence interval is undefined due to insufficient follow-up.
    End point type
    Secondary
    End point timeframe
    Randomization until death due to any cause (up to 106.43 weeks)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of the endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Cohort 1: Lapatinib 1500 mg Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg
    Number of subjects analysed
    0 [7]
    69 [8]
    Units: weeks
        median (confidence interval 95%)
    ( to )
    91 (69.4 to 91)
    Notes
    [7] - MITT Population
    [8] - MITT Population
    No statistical analyses for this end point

    Secondary: Response at Week 12 for Cohort 1 and Cohort 2

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    End point title
    		 Response at Week 12 for Cohort 1 and Cohort 2
    End point description
    The percentage of participants achieving either a complete (CR) or partial (PR) tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) is presented. CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum; Progressive disease (PD), a >=20% increase in target lesions; Stable Disease, small changes that do not meet previously given criteria. IRC, independent review committee. Participants with an unknown or missing response were treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Cohort 1: Lapatinib 1500 mg Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg
    Number of subjects analysed
    72 [9]
    69 [10]
    36 [11]
    Units: percentage of participants
        Complete response, IRC evaluated
    0
    0
    0
        Complete response, Investigator evaluated
    1
    0
    0
        Partial response, IRC evaluated
    22
    36
    33
        Partial response, Investigator evaluated
    26
    45
    50
        Stable disease, IRC evaluated
    39
    28
    31
        Stable disease, Investigator evaluated
    29
    17
    14
        Progressive disease, IRC evaluated
    17
    20
    8
        Progressive disease, Investigator evaluated
    38
    20
    11
        Unknown/missing, IRC evaluated
    22
    15
    28
        Unknown/missing, Investigator
    6
    17
    25
    Notes
    [9] - MITT Population
    [10] - MITT Population
    [11] - MITT Population
    No statistical analyses for this end point

    Secondary: Duration of Response in Cohort 1

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    End point title
    		 Duration of Response in Cohort 1 [12]
    End point description
    Duration of response is defined as the length of time from the time from the first observation of response until progression of disease or death. Duration of response depends on two things: (1) when response is counted as starting; (2) when response is counted as ending.There were insufficient data to adequately assess duration of response for Cohort 2. IRC, independent review committee. For participants who do not progress or die, duration of response was censored at the date of last adequate assessment.
    End point type
    Secondary
    End point timeframe
    time from first documented evidence of complete or partial response until the first documented sign of disease progression or death due to any cause (up to 106.71 weeks)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of the endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Cohort 1: Lapatinib 1500 mg Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg
    Number of subjects analysed
    72 [13]
    69 [14]
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    27.1 (24.3 to 27.7)
    24.3 (12.3 to 24.3)
    Notes
    [13] - MITT Population
    [14] - MITT Population
    No statistical analyses for this end point

    Secondary: Time to Response (Complete or Partial Response) in Cohort 1 and Cohort 2

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    End point title
    		 Time to Response (Complete or Partial Response) in Cohort 1 and Cohort 2
    End point description
    Time to response is defined as the time from randomization to the time of first documented evidence of a complete (CR) or partial response (PR). The time to response will depend on when the response is counted as starting. Per RECIST: CR, all detectable tumor has disappeared; PR, a >=30% decrease in the sum of the target dimensions of the target lesions taking as a reference the baseline sum.
    End point type
    Secondary
    End point timeframe
    the time from randomization to the time of first documented evidence of complete or partial response (up to 81.14 weeks for Cohort 1 and 44.29 weeks for Cohort 2)
    End point values
    		 Cohort 1: Lapatinib 1500 mg Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg
    Number of subjects analysed
    72 [15]
    69 [16]
    36 [17]
    Units: Weeks
    median (confidence interval 95%)
        IRC evaluated
    8.1 (7.9 to 11.4)
    8.3 (8 to 11.9)
    8.3 (7.4 to 8.7)
        Investigator Evaluated
    8 (7.9 to 8.1)
    8.1 (8 to 8.4)
    8 (7.3 to 8.6)
    Notes
    [15] - MITT Population
    [16] - MITT Population
    [17] - MITT Population
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Progressive Disease at Week 12

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    End point title
    		 Percentage of Participants with Progressive Disease at Week 12 [18]
    End point description
    The percentage of participants with progressive disease (PD) 12 weeks after randomization was measured. Participants were classified as having PD if their response at Week 12 was unknown or missing. Per Response Evaluation Criteria In Solid Tumors (RECIST), PD is defined as a >=20% increase in target lesions. IRC, independent review committee.
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The analysis of the endpoint was descriptive i.e. no statistical hypothesis test was performed.
    End point values
    		 Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg
    Number of subjects analysed
    36 [19]
    Units: Percentage of participants
        PD+Missing+Unknown, IRC evaluated
    36
        PD+Missing+Unknown, Investigator Evaluated
    36
    Notes
    [19] - Cohort 2: MITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study Entry until 28 days after the last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Cohort 1: Lapatinib 1500 mg
    Reporting group description
    		 Lapatinib 1500 milligrams (mg) administered orally once a day

    Reporting group title
    Cohort 1 Lapatinib 1000 mg / Pazopanib 400 mg
    Reporting group description
    		 Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day

    Reporting group title
    Cohort 2: Lapatinib 1500 mg / Pazopanib 800 mg
    Reporting group description
    		 Cohort 2: Lapatinib 1500 mg / Pazopanib 800 mg administered orally once a day

    Serious adverse events
    		 Cohort 1: Lapatinib 1500 mg Cohort 1 Lapatinib 1000 mg / Pazopanib 400 mg Cohort 2: Lapatinib 1500 mg / Pazopanib 800 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 73 (13.70%)
    18 / 76 (23.68%)
    13 / 40 (32.50%)
         number of deaths (all causes)
    35
    43
    22
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    4 / 40 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 76 (1.32%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 76 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    3 / 76 (3.95%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 76 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 73 (2.74%)
    1 / 76 (1.32%)
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 76 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 76 (1.32%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 73 (4.11%)
    0 / 76 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 76 (1.32%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Lapatinib 1500 mg Cohort 1 Lapatinib 1000 mg / Pazopanib 400 mg Cohort 2: Lapatinib 1500 mg / Pazopanib 800 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 73 (86.30%)
    71 / 76 (93.42%)
    39 / 40 (97.50%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 73 (5.48%)
    20 / 76 (26.32%)
    15 / 40 (37.50%)
         occurrences all number
    7
    25
    25
    Hot flush
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 73 (12.33%)
    9 / 76 (11.84%)
    5 / 40 (12.50%)
         occurrences all number
    13
    11
    5
    Chest discomfort
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Chest pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    4
    Fatigue
         subjects affected / exposed
    7 / 73 (9.59%)
    12 / 76 (15.79%)
    23 / 40 (57.50%)
         occurrences all number
    7
    18
    25
    Mucosal inflammation
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    7 / 73 (9.59%)
    6 / 76 (7.89%)
    0 / 40 (0.00%)
         occurrences all number
    10
    7
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 73 (6.85%)
    7 / 76 (9.21%)
    2 / 40 (5.00%)
         occurrences all number
    5
    8
    3
    Dysphonia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Epistaxis
         subjects affected / exposed
    4 / 73 (5.48%)
    7 / 76 (9.21%)
    13 / 40 (32.50%)
         occurrences all number
    9
    10
    15
    Oropharyngeal pain
         subjects affected / exposed
    4 / 73 (5.48%)
    5 / 76 (6.58%)
    0 / 40 (0.00%)
         occurrences all number
    4
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 73 (1.37%)
    8 / 76 (10.53%)
    5 / 40 (12.50%)
         occurrences all number
    1
    10
    5
    Depression
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 73 (17.81%)
    25 / 76 (32.89%)
    15 / 40 (37.50%)
         occurrences all number
    21
    39
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 73 (17.81%)
    26 / 76 (34.21%)
    15 / 40 (37.50%)
         occurrences all number
    16
    40
    22
    Blood bilirubin increased
         subjects affected / exposed
    3 / 73 (4.11%)
    10 / 76 (13.16%)
    0 / 40 (0.00%)
         occurrences all number
    4
    17
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    7 / 40 (17.50%)
         occurrences all number
    0
    0
    8
    Platelet count decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    6
    Crystal urine present
         subjects affected / exposed
    0 / 73 (0.00%)
    5 / 76 (6.58%)
    0 / 40 (0.00%)
         occurrences all number
    0
    5
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 73 (0.00%)
    4 / 76 (5.26%)
    0 / 40 (0.00%)
         occurrences all number
    0
    5
    0
    Weight decreased
         subjects affected / exposed
    3 / 73 (4.11%)
    8 / 76 (10.53%)
    5 / 40 (12.50%)
         occurrences all number
    4
    10
    6
    Ejection fraction decreased
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    10 / 73 (13.70%)
    9 / 76 (11.84%)
    5 / 40 (12.50%)
         occurrences all number
    10
    9
    6
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 73 (8.22%)
    4 / 76 (5.26%)
    7 / 40 (17.50%)
         occurrences all number
    6
    5
    10
    Dysgeusia
         subjects affected / exposed
    1 / 73 (1.37%)
    12 / 76 (15.79%)
    12 / 40 (30.00%)
         occurrences all number
    1
    13
    12
    Headache
         subjects affected / exposed
    7 / 73 (9.59%)
    6 / 76 (7.89%)
    11 / 40 (27.50%)
         occurrences all number
    12
    14
    15
    Neuropathy peripheral
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 73 (5.48%)
    4 / 76 (5.26%)
    0 / 40 (0.00%)
         occurrences all number
    4
    10
    0
    Leukopenia
         subjects affected / exposed
    0 / 73 (0.00%)
    6 / 76 (7.89%)
    2 / 40 (5.00%)
         occurrences all number
    0
    8
    10
    Neutropenia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    5
    Thrombocytopenia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    8 / 73 (10.96%)
    3 / 76 (3.95%)
    0 / 40 (0.00%)
         occurrences all number
    8
    3
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    3
    Abdominal pain
         subjects affected / exposed
    3 / 73 (4.11%)
    7 / 76 (9.21%)
    11 / 40 (27.50%)
         occurrences all number
    3
    7
    14
    Abdominal pain upper
         subjects affected / exposed
    2 / 73 (2.74%)
    7 / 76 (9.21%)
    3 / 40 (7.50%)
         occurrences all number
    3
    7
    4
    Constipation
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    4
    0
    2
    Diarrhoea
         subjects affected / exposed
    41 / 73 (56.16%)
    52 / 76 (68.42%)
    34 / 40 (85.00%)
         occurrences all number
    81
    172
    86
    Dry mouth
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Dyspepsia
         subjects affected / exposed
    6 / 73 (8.22%)
    8 / 76 (10.53%)
    7 / 40 (17.50%)
         occurrences all number
    9
    10
    8
    Nausea
         subjects affected / exposed
    13 / 73 (17.81%)
    23 / 76 (30.26%)
    28 / 40 (70.00%)
         occurrences all number
    18
    31
    35
    Rectal haemorrhage
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Stomatitis
         subjects affected / exposed
    5 / 73 (6.85%)
    5 / 76 (6.58%)
    5 / 40 (12.50%)
         occurrences all number
    6
    22
    7
    Vomiting
         subjects affected / exposed
    6 / 73 (8.22%)
    15 / 76 (19.74%)
    13 / 40 (32.50%)
         occurrences all number
    10
    28
    19
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 73 (4.11%)
    11 / 76 (14.47%)
    10 / 40 (25.00%)
         occurrences all number
    3
    13
    11
    Dermatitis acneiform
         subjects affected / exposed
    3 / 73 (4.11%)
    5 / 76 (6.58%)
    2 / 40 (5.00%)
         occurrences all number
    4
    5
    3
    Dry skin
         subjects affected / exposed
    7 / 73 (9.59%)
    5 / 76 (6.58%)
    2 / 40 (5.00%)
         occurrences all number
    7
    5
    2
    Hair colour changes
         subjects affected / exposed
    0 / 73 (0.00%)
    14 / 76 (18.42%)
    11 / 40 (27.50%)
         occurrences all number
    0
    14
    13
    Nail disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    4
    Pruritus
         subjects affected / exposed
    10 / 73 (13.70%)
    5 / 76 (6.58%)
    4 / 40 (10.00%)
         occurrences all number
    12
    5
    5
    Rash
         subjects affected / exposed
    21 / 73 (28.77%)
    21 / 76 (27.63%)
    16 / 40 (40.00%)
         occurrences all number
    30
    27
    26
    Rash macular
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Skin hypopigmentation
         subjects affected / exposed
    0 / 73 (0.00%)
    4 / 76 (5.26%)
    0 / 40 (0.00%)
         occurrences all number
    0
    4
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    2
    Proteinuria
         subjects affected / exposed
    2 / 73 (2.74%)
    8 / 76 (10.53%)
    0 / 40 (0.00%)
         occurrences all number
    2
    12
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 73 (0.00%)
    6 / 76 (7.89%)
    0 / 40 (0.00%)
         occurrences all number
    0
    7
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    6 / 40 (15.00%)
         occurrences all number
    0
    0
    8
    Back pain
         subjects affected / exposed
    5 / 73 (6.85%)
    4 / 76 (5.26%)
    5 / 40 (12.50%)
         occurrences all number
    8
    4
    5
    Musculoskeletal pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    4
    Myalgia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Neck pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Pain in extremity
         subjects affected / exposed
    8 / 73 (10.96%)
    9 / 76 (11.84%)
    4 / 40 (10.00%)
         occurrences all number
    9
    13
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    3
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 73 (9.59%)
    4 / 76 (5.26%)
    2 / 40 (5.00%)
         occurrences all number
    8
    6
    2
    Paronychia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    4
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 73 (0.00%)
    4 / 76 (5.26%)
    0 / 40 (0.00%)
         occurrences all number
    0
    11
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 76 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    5
    Decreased appetite
         subjects affected / exposed
    10 / 73 (13.70%)
    17 / 76 (22.37%)
    14 / 40 (35.00%)
         occurrences all number
    12
    21
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2006
    To correct omissions, include additional safety testing and make updates based on current clinical practice and recent experience.
    23 Apr 2007
    To add safety monitoring, interim analysis, evaluation of a higher combination dose regimen of lapatinib 1500 mg with pazapanib 800 mg.
    19 Jun 2008
    To update the safety information for lapatinib and pazopanib, modify the liver toxicity management guidelines, and add IDMC evaluation for safety.
    28 Oct 2011
    Study has met and reported primary and secondary objectives. Sites to discontinue collection of many assessments, whilst allowing 1 remaining subject to continue on treatment until unacceptable toxicity or disease progression. Collection of core safety data. Replace use of 100 & 500 mg tablets pazopanib with 200 & 400 mg tablets.

    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.
    In 2008 at primary completion, study was terminated. In 2011, protocol amendment 4 (Am4), allowed continuation of treatment until PD for the 1 par. This par. completed the study per Am 4. Par. last visit occurred, the study is considered completed.
    For support, Contact us.
    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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