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    Clinical Trial Results:
    An open-label study to investigate the pharmacodynamics of a repeat dose regimen of bevacizumab (10mg/kg q2w) and escalating repeat doses of pazopanib in renal cell carcinoma

    Summary
    EudraCT number
    		 2008-005053-38
    Trial protocol
    		 GB  
    Global end of trial date
    01 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2016
    First version publication date
    17 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VDF111687
    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
    12 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the pharmacodynamic effect of bevacizumab (10mg/kg q2w) on various tumor characteristics in subjects with renal cell carcinoma who experience tumour progression on previous first-line (or greater) therapy.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Nov 2009
    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: 11
    Worldwide total number of subjects
    11
    EEA total number of subjects
    11
    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)
    9
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study is comprised of Part I and Part II followed by the Maintenance Phase. Participants (Par.) were administered bevacizumab 10 milligrams (mg)/kilogram (kg) during Part I and were randomized to receive pazopanib as escalating repeat doses during Part II and pazopanib in repeating 3-week cycles during the Part II Maintenance Phase.

    Period 1
    Period 1 title
    Part I
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Bevacizumab
    Arm description
    		 In Part I participants received 3 infusions of 10 mg/kg bevacizumab administered at 2-week intervals.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10mg/Kg every two weeks for a total of 3 infusions

    Number of subjects in period 1 [1]
    		Bevacizumab
    Started
    9
    Completed
    9
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 11 participants were enrolled and a total of 9 participants reveived at least one dose of bevacizumab.
    Period 2
    Period 2 title
    Part II
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pazopanib full cycle
    Arm description
    		 Following a 14-day washout, particpants entering Part II were randomized to receive treatment throughout each 3-week cycle (Group 1). Participants were administered escalating doses of pazopanib, which increased in a stepwise manner in 3-week cycles as follows: 1) 200 mg twice weekly (bid), 2) 200 mg every other day, 3) 200 mg once daily (qd), 4) 400 mg qd, 5) 800 mg qd, and 6) 1200 mg qd. During the Part II Maintenance Phase, 800 mg qd pazopanib was administered in repeating 3-week cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pazopanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Group1 (3 week cycle) 200 mg twice weekly for full cycle 200 mg qod for full cycle 200 mg qd for full cycle 400 mg qd for full cycle 800 mg qd for full cycle 1200 mg qd for full cycle Maintenance phase 800 mg qd for full cycle

    Arm title
    		 Pazopanib first 2 weeks
    Arm description
    		 Following a 14-day washout, particpants entering Part II were randomized to receive treatment for the first 2 weeks of each cycle only, i.e., discontinuous dosing (Group 2). Participants were administered escalating doses of pazopanib, which increased in a stepwise manner in 3-week cycles as follows: 1) 200 mg twice weekly (bid), 2) 200 mg every other day, 3) 200 mg once daily (qd), 4) 400 mg qd, 5) 800 mg qd, and 6) 1200 mg qd. During the Part II Maintenance Phase, 800 mg qd pazopanib was administered in repeating 3-week cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pazopanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Group 2 (dosed 2/3 week cycle) 200 mg twice weekly for 2 weeks 200 mg qod for 2 weeks 200 mg qd for 2 weeks 400 mg qd for 2 weeks 800 mg qd for 2 weeks 1200 mg qd for 2 weeks Maintenance phase 800 mg qd for full cycle

    Number of subjects in period 2
    		Pazopanib full cycle Pazopanib first 2 weeks
    Started
    4
    5
    Completed
    1
    4
    Not completed
    3
    1
         Physician decision
    2
    -
         Met Protocol-defined Stopping Criteria
    1
    -
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 In Part I participants received 3 infusions of 10 mg/kg bevacizumab administered at 2-week intervals.

    Reporting group values
    		 Bevacizumab Total
    Number of subjects
    		 9 9
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.2 ( 8.61 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 5 5
    Race
    Units: Subjects
        African American/African Heritage
    		 1 1
        White-White/Caucasian/European Heritage
    		 8 8

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 In Part I participants received 3 infusions of 10 mg/kg bevacizumab administered at 2-week intervals.
    Reporting group title
    Pazopanib full cycle
    Reporting group description
    		 Following a 14-day washout, particpants entering Part II were randomized to receive treatment throughout each 3-week cycle (Group 1). Participants were administered escalating doses of pazopanib, which increased in a stepwise manner in 3-week cycles as follows: 1) 200 mg twice weekly (bid), 2) 200 mg every other day, 3) 200 mg once daily (qd), 4) 400 mg qd, 5) 800 mg qd, and 6) 1200 mg qd. During the Part II Maintenance Phase, 800 mg qd pazopanib was administered in repeating 3-week cycles.

    Reporting group title
    Pazopanib first 2 weeks
    Reporting group description
    		 Following a 14-day washout, particpants entering Part II were randomized to receive treatment for the first 2 weeks of each cycle only, i.e., discontinuous dosing (Group 2). Participants were administered escalating doses of pazopanib, which increased in a stepwise manner in 3-week cycles as follows: 1) 200 mg twice weekly (bid), 2) 200 mg every other day, 3) 200 mg once daily (qd), 4) 400 mg qd, 5) 800 mg qd, and 6) 1200 mg qd. During the Part II Maintenance Phase, 800 mg qd pazopanib was administered in repeating 3-week cycles.

    Primary: Percent change from Baseline in tumor size at the Follow-up Visit

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    End point title
    		 Percent change from Baseline in tumor size at the Follow-up Visit [1]
    End point description
    Computed tomography (CT) is the standard clinical imaging modality for staging and follow-up of participants with renal cell carcinoma (RCC). In part I, CT was used to acquire images of the chest, abdomen, and pelvis after intravenous administration of iodine based contrast medium to monitor changes in tumor size in response to treatment. Tumor size was calculated by summing the longest diameters of all target lesions on the CT scan and expressed as a percent reduction from Baseline.
    End point type
    Primary
    End point timeframe
    Baseline and Follow-up Visit in Part I (assessed up to 6 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical Analysis is not applicable for this Outcome Measure.
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [2]
    Units: % change
        arithmetic mean (confidence interval 95%)
    3.65 (-5.12 to 12.42)
    Notes
    [2] - Safety Population: all participants who received at least one dose of bevacizumab.
    No statistical analyses for this end point

    Primary: Change from Baseline in transfer constant from plasma to extracellular space (Ktrans) at 4 hours post-dose and 3 days post-dose in Part I

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    End point title
    		 Change from Baseline in transfer constant from plasma to extracellular space (Ktrans) at 4 hours post-dose and 3 days post-dose in Part I [3]
    End point description
    Change in tumor perfusion was assessed by estimation of Ktrans using Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI). DCE-MRI enables noninvasive assessment of tumor perfusion and microvascular permeability and can help predict response to novel chemotherapy agents. An early increase in tumor perfusion was shown to correlate with tumor response following conventional chemo-radiotherapy. In Part I, marker lesions (larger than 2 centimeters [cm]) were chosen to perform quantitative analysis producing estimates of Ktrans as seen on DCE-MRI and was measured at Baseline (2 measurements at Baseline separated by at least 24 hours), at 4 hours post-dose and 3 days post-dose. Mean Baseline (the mean of the two Baseline measurements) was used for summarizing these data.
    End point type
    Primary
    End point timeframe
    Baseline, 4 hours post-dose and 3 days post-dose in Part I
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical Analysis is not applicable for this Outcome Measure.
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [4]
    Units: 1/minute
    arithmetic mean (confidence interval 95%)
        Mean Baseline
    0.157 (0.1025 to 0.2115)
        4 hours post-dose
    0.1394 (0.0845 to 0.1944)
        3 days post-dose
    0.123 (0.0747 to 0.1713)
    Notes
    [4] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with a best response as assessed by the independent reviewer

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    End point title
    		 Number of participants with a best response as assessed by the independent reviewer
    End point description
    Response was assessed by the independent reviewer according to Evaluation Criteria In Solid Tumors (RECIST), version 1.1. As per RECIST, complete response (CR): disappearance of all target lesions, partial response (PR): at least a 30% decrease in the sum of the longest diameter (LD) of target lesions; progressive disease (PD): at least a 20% increase in the sum of the LD of target lesions; stable disease (SD) implies neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, were assessed.
    End point type
    Secondary
    End point timeframe
    Day 10 of Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [5]
    Units: Participants
        CR
    0
        PR
    0
        SD
    7
        PD
    2
        Not Evaluable
    0
        Unknown
    0
    Notes
    [5] - Safety Population
    No statistical analyses for this end point

    Secondary: Measurement of tumor size by vascular volume

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    End point title
    		 Measurement of tumor size by vascular volume
    End point description
    CT is the standard clinical imaging modality for staging and follow-up of participants with RCC. CT was used to acquire images of the chest, abdomen, and pelvis after intravenous administration of iodine based contrast medium to monitor changes in vascular volume in response to treatment. This was an optional parameter and was not analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Follow-up Visit in Part I (assessed up to 6 weeks)
    End point values
    		 Bevacizumab
    Number of subjects analysed
    0 [6]
    Units: cubic millimeter (mm^3)
        arithmetic mean (standard deviation)
    ( )
    Notes
    [6] - Safety Population
    No statistical analyses for this end point

    Secondary: Measurement of tumor size by tumor volume

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    End point title
    		 Measurement of tumor size by tumor volume
    End point description
    MRI is widely available in clinical settings and enables evaluation of tumor characteristics, including perfusion, microvascular permeability, necrosis, and cellularity. This was an optional parameter and was not analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Follow-up Visit in Part I (assessed up to 6 weeks)
    End point values
    		 Bevacizumab
    Number of subjects analysed
    0 [7]
    Units: mm^3
        arithmetic mean (standard deviation)
    ( )
    Notes
    [7] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in contrast efflux from tumor (kep)

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    End point title
    		 Change from Baseline in contrast efflux from tumor (kep)
    End point description
    Changes in tumor perfusion was assessed by estimation of kep using DCE-MRI. DCE-MRI enables noninvasive assessment of tumor perfusion and microvascular permeability and can help predict response to novel chemotherapy agents. An early increase in tumor perfusion was shown to correlate with tumor response following conventional chemo-radiotherapy. Marker lesions (larger than 2 cm) were chosen to perform quantitative analysis producing estimates of kep as seen on DCE-MRI and was measured at Baseline (2 measurements at Baseline separated by at least 24 hours), at 4 hours post dose and 3 days post-dose. Mean Baseline (the mean of the two Baseline measurements) was used for summarizing these data.
    End point type
    Secondary
    End point timeframe
    Baseline, 4 hours post-dose and 3 days post-dose in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [8]
    Units: 1/Minute
    arithmetic mean (confidence interval 95%)
        Mean Baseline
    0.5132 (0.407 to 0.6193)
        4 hour post-dose
    0.4671 (0.3626 to 0.5717)
        3 days post-dose
    0.4603 (0.2834 to 0.6373)
    Notes
    [8] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in fractional volume of extravascular-extracellular space (Ve)

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    End point title
    		 Change from Baseline in fractional volume of extravascular-extracellular space (Ve)
    End point description
    Changes in tumor perfusion was assessed by estimation of Ve using Dynamic Contrast-Enhanced MRI (DCE-MRI). DCE-MRI enables noninvasive assessment of tumor perfusion and microvascular permeability and can help predict response to novel chemotherapy agents. An early increase in tumor perfusion was shown to correlate with tumor response following conventional chemo-radiotherapy. Marker lesions (larger than 2 cm) were chosen to perform quantitative analysis producing estimates of Ve as seen on DCE-MRI and was measured at Baseline (2 measurements at Baseline separated by at least 24 hours), at 4 hours post-dose and 3 days post-dose. Mean Baseline (the mean of the two Baseline measurements) was used for summarizing these data.
    End point type
    Secondary
    End point timeframe
    Baseline, 4 hours post-dose and 3 days post-dose in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [9]
    Units: Unitless
    arithmetic mean (confidence interval 95%)
        Mean Baseline
    0.3032 (0.2494 to 0.357)
        4 hours post-dose
    0.2772 (0.2198 to 0.3346)
        3 days post- dose
    0.281 (0.1836 to 0.3784)
    Notes
    [9] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in initial area under the concentration curve at 90 seconds after injection of contrast agent (IAUC90)

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    End point title
    		 Change from Baseline in initial area under the concentration curve at 90 seconds after injection of contrast agent (IAUC90)
    End point description
    Changes in tumor perfusion was assessed by estimation of IAUC90 using DCE-MRI. DCE-MRI enables noninvasive assessment of tumor perfusion and microvascular permeability and can help predict response to novel chemotherapy agents. An early increase in tumor perfusion was shown to correlate with tumor response following conventional chemo-radiotherapy. Marker lesions (larger than 2 cm) were chosen to perform quantitative analysis producing estimates of IAUC90 as seen on DCE-MRI and was measured at Baseline (2 measurements at Baseline separated by at least 24 hours), at 4 hours post-dose and 3 days post-dose. Mean Baseline (the mean of the two Baseline measurements) was used for summarizing these data.
    End point type
    Secondary
    End point timeframe
    Baseline, 4 hours post-dose and 3 days post-dose in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [10]
    Units: Millimoles/liter/second (MMOL/L/S)
    arithmetic mean (confidence interval 95%)
        Mean Baseline
    52.69 (36.32 to 69.06)
        4 hours post-dose
    47.71 (33.66 to 61.76)
        3 days post-dose
    42.58 (27.59 to 57.56)
    Notes
    [10] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in plasma volume (Vp)

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    End point title
    		 Change from Baseline in plasma volume (Vp)
    End point description
    Changes in tumor perfusion was assessed by estimation of Vp using DCE-MRI. DCE-MRI enables noninvasive assessment of tumor perfusion and microvascular permeability and can help predict response to novel chemotherapy agents. An early increase in tumor perfusion was shown to correlate with tumor response following conventional chemo-radiotherapy. Marker lesions (larger than 2 cm) were chosen to perform quantitative analysis producing estimates of Vp as seen on DCE-MRI and was measured at Baseline (2 measurements at Baseline separated by at least 24 hours), at 4 hours post-dose and 3 days post-dose. Mean Baseline (the mean of the two Baseline measurements) was used for summarizing these data.
    End point type
    Secondary
    End point timeframe
    Baseline, 4 hours post-dose and 3 days post-dose in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [11]
    Units: Unitless
    arithmetic mean (confidence interval 95%)
        Mean Baseline
    0.0309 (0.0155 to 0.0463)
        4 hour post-dose
    0.0292 (0.0176 to 0.0409)
        3 days post-dose
    0.0227 (0.0098 to 0.0355)
    Notes
    [11] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor perfusion (F) using [15O]Water-positron emission tomography (PET)

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    End point title
    		 Tumor perfusion (F) using [15O]Water-positron emission tomography (PET)
    End point description
    [15O]Water-PET is used to measure tumor blood flow including detection of changes in blood flow during anti-angiogenic therapy in different tumor settings. A radial arterial line was inserted using sterile technique prior to the [15O]Water-PET. The total volume of blood collected during a scan was approximately 40 milliliters (mL) for [15O]Water-PET. The [15O]Water-PET regional blood flow parameter was only available for one participant at both time points and for a single time point for one other participant and so this data was not analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 3 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    0 [12]
    Units: 1/min
        arithmetic mean (standard deviation)
    ( )
    Notes
    [12] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor Distribution volume (VT) by [15O]Water-positron emission tomography (PET)

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    End point title
    		 Tumor Distribution volume (VT) by [15O]Water-positron emission tomography (PET)
    End point description
    [15O]Water-PET is used to measure tumor blood flow including detection of changes in blood flow during anti-angiogenic therapy in different tumor settings. A radial arterial line was inserted using sterile technique prior to the [15O]Water-PET. The total volume of blood collected during a scan was approximately 40 mL for [15O]Water-PET. The [15O]Water-PET regional blood flow parameter was only available for one participant at both time points and for a single time point for one other participant and so this data was not analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 3 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    0 [13]
    Units: 1/min
        arithmetic mean (standard deviation)
    ( )
    Notes
    [13] - Safety Population
    No statistical analyses for this end point

    Secondary: Regional blood flow by [15O]Water-positron emission tomography (PET)

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    End point title
    		 Regional blood flow by [15O]Water-positron emission tomography (PET)
    End point description
    [15O]Water-PET is used to measure tumor blood flow including detection of changes in blood flow during anti-angiogenic therapy in different tumor settings. A radial arterial line was inserted using sterile technique prior to the [15O]Water-PET. The total volume of blood collected during a scan was approximately 40 mL for [15O]Water-PET. The [15O]Water-PET regional blood flow parameter was only available for one participant at both time points and for a single time point for one other participant and so this data was not analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 3 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    0 [14]
    Units: 1/min
        arithmetic mean (standard deviation)
    ( )
    Notes
    [14] - Safety Population
    No statistical analyses for this end point

    Secondary: Measurement of glucose metabolic rate by 18F-fluoro-2-deoxy-D-glucose-positron emission tomography ([18F]FDG-PET)

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    End point title
    		 Measurement of glucose metabolic rate by 18F-fluoro-2-deoxy-D-glucose-positron emission tomography ([18F]FDG-PET)
    End point description
    Glucose metabolism in malignancy differs from that in normal tissue due to alterations in glycolytic enzymes and increased expression of glucose transport proteins, leading to increased glucose uptake and consumption in cancer. PET imaging using [18F]FDG provides a quantitative assessment of tumor metabolism. As glucose metabolic rate within a tumor is not quantified directly, a surrogate measure of glucose metabolism was reported, maximum standardized uptake value (SUV; image value normalised by injected activity and weight or body surface area). Glucose metabolic rate was assessed at Baseline and the Follow-up Visit in Part I.
    End point type
    Secondary
    End point timeframe
    Baseline and Follow-up Visit in Part I (assessed up to 6 weeks)
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [15]
    Units: Ratio
    arithmetic mean (confidence interval 95%)
        Baseline
    13.04 (3.68 to 22.41)
        Part I Follow-up
    15.66 (7.22 to 24.09)
    Notes
    [15] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor hypoxia (ratio of tissue to blood [T/ B]) parameters

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    End point title
    		 Tumor hypoxia (ratio of tissue to blood [T/ B]) parameters
    End point description
    [18F] fluoromisonidazole (FMISO), a nitroimidazole derivative, enables PET imaging of hypoxia in tumors outside the central nervous system. A radial arterial line was inserted using sterile technique prior to [18F]FMISO-PET procedures. The total volume of blood collected during a scan was approximately 75 mL for [18F]FMISO-PET. Tissue clearence (K1), FMISO trapping rate constant, (K3) and net irreversible uptake rate constant (Ki) are respresented here.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 3 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [16]
    Units: 1/Minute
    arithmetic mean (confidence interval 95%)
        K1, Baseline
    0.2588 (0.1143 to 0.4034)
        K1, Part 1 Day 3
    0.1791 (0.0535 to 0.3048)
        K3, Baseline
    0.0127 (-0.0112 to 0.0365)
        K3, Part 1 Day 3
    0.0101 (-0.0052 to 0.0255)
        Ki, Baseline
    0.0037 (-0.0019 to 0.0092)
        Ki, Part 1 Day 3
    0.004 (-0.0013 to 0.0093)
    Notes
    [16] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor hypoxia (ratio of tissue to blood (T/ B) parameters- standardized uptake value (SUV) ratio

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    End point title
    		 Tumor hypoxia (ratio of tissue to blood (T/ B) parameters- standardized uptake value (SUV) ratio
    End point description
    [18F]FMISO, a nitroimidazole derivative, enables PET imaging of hypoxia in tumors outside the central nervous system. A radial arterial line was inserted using sterile technique prior to [18F]FMISO-PET procedures. The total volume of blood collected during a scan was approximately 75 mL for [18F]FMISO-PET. Mean SUV and maximum (Max) SUV is presented here.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 3 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [17]
    Units: grams per cubic centimeter (g/cm3)
    arithmetic mean (confidence interval 95%)
        Mean SUV, Baseline
    1.792 (0.3982 to 3.1858)
        Mean SUV, Part 1 Day 3
    2.1119 (0.3709 to 3.8529)
        Max SUV, Baseline
    2.6334 (0.7518 to 4.5151)
        Max SUV, Part 1 Day 3
    3.0703 (0.6965 to 5.4441)
    Notes
    [17] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor hypoxia as measured by apparent diffusion coefficient (ADC) using diffusion weighted imaging (DWI)

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    End point title
    		 Tumor hypoxia as measured by apparent diffusion coefficient (ADC) using diffusion weighted imaging (DWI)
    End point description
    DWI was acquired prior to contrast agent administration. At least four different b-values were selected within the range 0-1000 second (s)/mm^2. Values for ADC (in mm^2/second) and maps were calculated from the images acquired with the different b-values. Mean Baseline (the mean of the two Baseline measurements) is used for summarizing these data.
    End point type
    Secondary
    End point timeframe
    Baseline, 4 hours post-dose and 3 days post-dose in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [18]
    Units: micrometres squared/second (UM^2/SEC
    arithmetic mean (confidence interval 95%)
        Mean Baseline, n = 8
    1162.59 (1015.98 to 1309.21)
        4 hours post-dose, n = 8
    1096.69 (924.81 to 1268.57)
        3 days post-dose, n = 7
    1158.14 (965.21 to 1351.08)
    Notes
    [18] - Safety Population
    No statistical analyses for this end point

    Secondary: Analysis of plasma and serum biomarkers - IL8, KGF, M65, PDGFbb, P1GF, SDF1b, Tie2, VEGFA, VEGFC, VEGFD, VEGFR1, VEGFR2

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    End point title
    		 Analysis of plasma and serum biomarkers - IL8, KGF, M65, PDGFbb, P1GF, SDF1b, Tie2, VEGFA, VEGFC, VEGFD, VEGFR1, VEGFR2
    End point description
    The blood borne biomarkers were reviewed graphically but not summarized.
    End point type
    Secondary
    End point timeframe
    From the time of the first infusion of bevacizumab until Day 1 of Cycle 8 in Part II (up to 24 weeks)
    End point values
    		 Bevacizumab
    Number of subjects analysed
    0 [19]
    Units: pg/mL (picogram/milliliter)
        arithmetic mean (standard deviation)
    ( )
    Notes
    [19] - Safety Population
    No statistical analyses for this end point

    Secondary: Circulating tumor cell levels

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    End point title
    		 Circulating tumor cell levels
    End point description
    Blood samples (approximately 20 mL) were collected for measurement of circulating tumor cells (CTCs) in whole blood. Measurement of CTCs was to be performed using a validated assay. CTC could not be isolated and therefore whole blood levels of CTC have not been presented.
    End point type
    Secondary
    End point timeframe
    From the time of the first infusion of bevacizumab until Day 1 of Cycle 8 in Part II (up to 24 weeks)
    End point values
    		 Bevacizumab
    Number of subjects analysed
    0 [20]
    Units: cells/7.5 millilitres of blood
        arithmetic mean (standard deviation)
    ( )
    Notes
    [20] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor histology results for analyte: Ki67

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    End point title
    		 Tumor histology results for analyte: Ki67
    End point description
    CT or ultrasound-guided core needle biopsies were performed to obtain tissue specimens for immunohistological staining for markers of endothelial cells and VEGF signaling. Difference of post-dose and pre-dose are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 10 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    8 [21]
    Units: Proportion of cells
    number (not applicable)
        Analyte positive (AP) endothelial cells (EC)
    -0.0143
        AP tumor cells
    -0.0301
        Proportion (Pro.) of total cells (TC) that are AP
    -0.0285
        Pro. of TC tumor cells in images for each analyte
    -0.0502
        Pro. of TC that are EC in images for each analyte
    -0.0299
    Notes
    [21] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor histology results for analyte: pAKT

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    End point title
    		 Tumor histology results for analyte: pAKT
    End point description
    CT or ultrasound-guided core needle biopsies were performed to obtain tissue specimens for immunohistological staining for markers of endothelial cells and VEGF signaling. Difference of post-dose and pre-dose are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 10 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    8 [22]
    Units: Proportion of cells
    number (not applicable)
        Analyte positive (AP) endothelial cells (EC)
    -0.1841
        AP tumor cells
    -0.0756
        Pro. of TC that are AP
    -0.0773
        Pro. of TC tumor cells in images for each analyte
    0.0099
        Pro. of TC that are EC in images for each analyte
    -0.0335
    Notes
    [22] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor histology results for analyte: pERK

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    End point title
    		 Tumor histology results for analyte: pERK
    End point description
    CT or ultrasound-guided core needle biopsies were performed to obtain tissue specimens for immunohistological staining for markers of endothelial cells and VEGF signaling. Difference of post-dose and pre-dose are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 10 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    8 [23]
    Units: Proportion of cells
    number (not applicable)
        Analyte positive (AP) endothelial cells (EC)
    -0.1672
        AP tumor cells
    -0.2272
        Pro. of TC that are AP
    -0.2103
        Pro. of TC tumor cells in images for each analyte
    -0.0201
        Pro. of TC that are EC in images for each analyte
    -0.0567
    Notes
    [23] - Safety Population
    No statistical analyses for this end point

    Secondary: Tumor histology results for analyte: pSTAT3

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    End point title
    		 Tumor histology results for analyte: pSTAT3
    End point description
    CT or ultrasound-guided core needle biopsies were performed to obtain tissue specimens for immunohistological staining for markers of endothelial cells and VEGF signaling. Difference of post-dose and pre-dose are presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 10 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    8 [24]
    Units: Proportion of cells
    number (not applicable)
        Analyte positive (AP) endothelial cells (EC)
    -0.0035
        AP tumor cells
    -0.0739
        Pro. of TC that are AP
    -0.0474
        Pro. of TC tumor cells in images for each analyte
    0.0049
        Pro. of TC that are EC in images for each analyte
    -0.0294
    Notes
    [24] - Safety Population
    No statistical analyses for this end point

    Secondary: Bevacizumab pharmacokinetic parameter, elimination rate constant (K)

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    End point title
    		 Bevacizumab pharmacokinetic parameter, elimination rate constant (K)
    End point description
    Blood samples (approximately 2 mL) for the analysis of bevacizumab was collected in serum collection tubes (no anticoagulant) prior to the infusion (only on study Day 1), between 20 to 70 minutes after the start of the infusion and end of the infusion (or immediately prior to the end of the infusion in the case of pharmackinetc [PK] samples) on Day 3, Day 15 and Day 29. Bevacizumab plasma concentration-time data were described by a 1-compartment model with first order elimination. Pharmacokinetic (PK) Population: all participants in the Safety Population for whom at least one pharmacokinetic sample was obtained and analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 3, Day 15 and Day 29 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [25]
    Units: per day
        number (confidence interval 95%)
    0.0477 (0.0406 to 0.0561)
    Notes
    [25] - PK Population
    No statistical analyses for this end point

    Secondary: Bevacizumab pharmacokinetic parameter, volume of systemic compartment (V1)

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    End point title
    		 Bevacizumab pharmacokinetic parameter, volume of systemic compartment (V1)
    End point description
    Blood samples (approximately 2 mL) for the analysis of bevacizumab was collected in serum collection tubes (no anticoagulant) prior to the infusion (only on study Day 1), between 20 to 70 minutes after the start of the infusion and end of the infusion (or immediately prior to the end of the infusion in the case of PK samples) on Day 15 and Day 29. Bevacizumab plasma concentration-time data were described by a 1-compartment model with first order elimination.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 3, Day 15 and Day 29 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [26]
    Units: mL/kg
        number (confidence interval 95%)
    72.9 (65.9 to 80.7)
    Notes
    [26] - PK Population
    No statistical analyses for this end point

    Secondary: Bevacizumab plasma parameter, residual variability (RESIDUAL)

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    End point title
    		 Bevacizumab plasma parameter, residual variability (RESIDUAL)
    End point description
    Blood samples (approximately 2 mL) for the analysis of bevacizumab was collected in serum collection tubes (no anticoagulant) prior to the infusion (only on study Day 1), between 20 to 70 minutes after the start of the infusion and end of the infusion (or immediately prior to the end of the infusion in the case of PK samples) on Day 15 and Day 29. Bevacizumab plasma concentration-time data were described by a 1-compartment model with first order elimination.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 3, Day 15 and Day 29 in Part I
    End point values
    		 Bevacizumab
    Number of subjects analysed
    9 [27]
    Units: Unitless
        number (confidence interval 95%)
    0.356 (0.293 to 0.419)
    Notes
    [27] - PK Population
    No statistical analyses for this end point

    Secondary: Mean pre-dose plasma pazopanib concentrations from dose escalation phase of Part II

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    End point title
    		 Mean pre-dose plasma pazopanib concentrations from dose escalation phase of Part II
    End point description
    For pharmacokinetic analysis of pazopanib blood samples (approximately 2 mL) were collected in an ethylenediaminetetraacetic acid (EDTA) tube pre-dose on each dosing day and 3 hours post-dose on Day 1 and Day 8.
    End point type
    Secondary
    End point timeframe
    Cycle 3 Day 15, Cycle 4 Day 15, Cycle 5 Day 15, Cycle 6 Day 15 in Part II
    End point values
    		 Pazopanib full cycle Pazopanib first 2 weeks
    Number of subjects analysed
    4 [28]
    5 [29]
    Units: Nanogram (ng)/mL
    arithmetic mean (standard deviation)
        Cycle 2 Day 15, n= 4, 5
    8560.8 ( 7483.5 )
    4246.2 ( 5145.72 )
        Cycle 3 Day 15, n= 4, 5
    19197.3 ( 8193.33 )
    8946.8 ( 6326.35 )
        Cycle 4 Day 15, n= 3, 4
    20688.3 ( 3331.48 )
    12596.6 ( 8776.79 )
        Cycle 5 Day 15, n= 4, 4
    30948.3 ( 8678.94 )
    19425.3 ( 16845.11 )
        Cycle 6 Day 15, n= 4, 4
    32823.8 ( 13728.39 )
    24164.8 ( 19463.53 )
    Notes
    [28] - Safety Population
    [29] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with any adverse event (AE) or serious adverse event (SAE)

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    End point title
    		 Number of participants with any adverse event (AE) or serious adverse event (SAE)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or all grade 4 laboratory abnormalities.
    End point type
    Secondary
    End point timeframe
    From the time of the first infusion of bevacizumab until the last dose of pazopanib treatment (up to Week 111)
    End point values
    		 Bevacizumab Pazopanib full cycle Pazopanib first 2 weeks
    Number of subjects analysed
    9 [30]
    4 [31]
    5 [32]
    Units: Participants
        Any AE
    9
    4
    5
        Any SAE
    0
    2
    1
    Notes
    [30] - Safety Population
    [31] - Safety Population
    [32] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with worst-case on-therapy change from Baseline in laboratory parameters

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    End point title
    		 Number of participants with worst-case on-therapy change from Baseline in laboratory parameters
    End point description
    Laboratory parameters were assessed at Baseline (Day -21 to Day -1 in Part I); Day 1, 15, 29 for Part I and Day 1 of each cycle for Part II. Worst-case on-therapy changes from Baseline in laboratory parameters with respect to the normal ranges are presented. For the indicated test, 99999 (NA) represents that the data was not available.
    End point type
    Secondary
    End point timeframe
    Baseline until Day 29 for Part I or Day 1 of the last cycle for Part II (up to Week 111)
    End point values
    		 Bevacizumab Pazopanib full cycle Pazopanib first 2 weeks
    Number of subjects analysed
    9 [33]
    4 [34]
    5 [35]
    Units: Participants
        Chloride-Decrease to Low (DtL)
    1
    3
    1
        Chloride-Increase to High (ItH)
    0
    0
    1
        Lactate Dehydrogenase-DtL
    0
    0
    0
        Lactate Dehydrogenase-ItH
    0
    3
    2
        Total Protein-DtL
    0
    1
    0
        Total Protein-ItH
    1
    1
    0
        Urea/BUN-DtL
    0
    0
    0
        Urea/BUN-ItH
    2
    0
    1
        Uric acid-DtL
    0
    1
    1
        Uric acid-ItH
    0
    0
    1
        Activated Partial Thromboplastin Time-DtL
    0
    99999
    99999
        Activated Partial Thromboplastin Time (ItH)
    0
    99999
    99999
        Free T3-DtL
    0
    0
    0
        Free T3-ItH
    0
    0
    1
        Thyroid Stimulating Hormone-DtL
    0
    0
    0
        Thyroid Stimulating Hormone-ItH
    0
    1
    1
        Basophils-DtL
    0
    0
    0
        Basophils-ItH
    0
    0
    0
        Eosinophils-DtL
    0
    0
    0
        Eosinophils-ItH
    0
    0
    0
        Hematocrit-DtL
    0
    0
    3
        Hematocrit-ItH
    0
    0
    0
        Mean Corpuscle Hemoglobin-DtL
    0
    0
    2
        Mean Corpuscle Hemoglobin-ItH
    0
    1
    2
        Mean Corpuscle Volume-DtL
    1
    0
    0
        Mean Corpuscle Volume-ItH
    0
    0
    1
        Monocytes-DtL
    0
    0
    0
        Monocytes-ItH
    1
    2
    0
        Red Blood Cell count-DtL
    0
    3
    2
        Red Blood Cell count-ItH
    1
    0
    0
        Urine Total Protein/Creatinine ratio-DtL
    0
    0
    0
        Urine Total Protein/Creatinine ratio-ItH
    1
    2
    4
    Notes
    [33] - Safety Population
    [34] - Safety Population
    [35] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with worst-case on-therapy from Baseline in vital sign parameters

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    End point title
    		 Number of participants with worst-case on-therapy from Baseline in vital sign parameters
    End point description
    Vital signs included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and temperature. Vital sign measurements were taken at Baseline (Day -30 to Day -1 in Part I); Day 1, 8, 15, 29 for Part I and Day 1 of each cycle for Part II. Worst-case on-therapy from Baseline in vital signs are presented here. Worst case on therapy not analysed for temperature; therefore, , the value of 99999 was entered which represents NA.
    End point type
    Secondary
    End point timeframe
    Baseline until Day 29 for Part I or Day 1 of the last cycle for Part II (up to Week 111)
    End point values
    		 Bevacizumab Pazopanib full cycle Pazopanib first 2 weeks
    Number of subjects analysed
    9 [36]
    4 [37]
    5 [38]
    Units: Participants
        SBP-Any Grade Increase
    3
    3
    4
        SBP- Increase to Grade 3 (>=160)
    0
    0
    1
        DBP-Any Grade Increase
    4
    3
    3
        DBP-Increase to Grade 3 (>=100)
    0
    2
    1
        Heart rate- Decrease to <60
    0
    2
    1
        Heart rate-Change to Normal or No Change
    7
    2
    3
        Heart rate- Increase to >100
    2
    1
    1
        Temperature
    99999
    99999
    99999
    Notes
    [36] - Safety Population
    [37] - Safety Population
    [38] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in heart rate as an electrocardiogram (ECG) parameter in Part II

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    End point title
    		 Change from Baseline in heart rate as an electrocardiogram (ECG) parameter in Part II
    End point description
    A single 12-lead ECG was obtained using an ECG machine that automatically calculates the heart rate. Prior to each ECG test, the participant was at rest for approximately 10 minutes. The participant was in the semi-recumbent or supine position; the same position was required for all subsequent ECG tests. 12-Lead ECG was preformed only at Baseline (-30 to -1) in Part-I and on Day 1 of Cycle 1 and Day 1 of Cycle 7 in Part-II. Note only 0 or 1 participant was analyzed for the indicated treatment group/time point; therefore, the value of 99999 was entered which represents NA.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), Cycle 7 Day 1 in Part II
    End point values
    		 Pazopanib full cycle Pazopanib first 2 weeks
    Number of subjects analysed
    4 [39]
    5 [40]
    Units: Beats per minute
    arithmetic mean (standard deviation)
        Part 2 Cycle 1 Day 1, n= 3,5
    7 ( 9.54 )
    0.4 ( 6.43 )
        Part 2 Cycle 7-50 Day 1, n= 3,4
    -5 ( 6.24 )
    -3.5 ( 5.92 )
        Follow-up, n= 0,1
    99999 ( 99999 )
    1 ( 99999 )
    Notes
    [39] - Safety Population
    [40] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in electrocardiogram parameters (PR, RS, QT, QTcF)

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    End point title
    		 Change from Baseline in electrocardiogram parameters (PR, RS, QT, QTcF)
    End point description
    A single 12-lead ECG was obtained using an ECG machine that automatically calculates PR Interval (PR), QRS duration (QRS), QT Interval (QT), and corrected QT interval by Fridericia (QTcF) intervals at only Baseline (-30 to -1) in Part I and on Day 1 of Cycle 1 and Day 1 of Cycle 7 in Part-II. Prior to each ECG test, the participant was at rest for approximately 10 minutes. The participant was in the semi-recumbent or supine position; the same position was required for all subsequent ECG tests. Note only 0 or 1 participant was analyzed for the indicated treatment group/time point; therefore, the value of 99999 was entered which represents NA.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), Cycle 7 Day 1 in Part II
    End point values
    		 Pazopanib full cycle Pazopanib first 2 weeks
    Number of subjects analysed
    4 [41]
    5 [42]
    Units: Milliseconds (msec)
    arithmetic mean (standard deviation)
        PR-Part 2 C1 Day 1, n= 3,5
    1.3 ( 12.22 )
    8.8 ( 16.35 )
        PR-Part 2 C7-50 Day 1, n= 3,4
    4 ( 14.42 )
    0.3 ( 9.39 )
        PR-Follow-up, n= 0,1
    99999 ( 99999 )
    8 ( 99999 )
        QRS-Part 2 C1 Day 1, n= 3,5
    0.7 ( 1.15 )
    3.6 ( 10.33 )
        QRS-Part 2 C7-50 Day 1, n= 3,4
    0 ( 5.29 )
    3.5 ( 12.48 )
        QRS-Follow-up, n= 0,1
    99999 ( 99999 )
    1 ( 99999 )
        QT-Part 2 C1 Day 1, n= 3,5
    -13.3 ( 16.65 )
    -1.6 ( 25.39 )
        QT-Part 2 C7-50 Day 1, n= 3,4
    21 ( 14.93 )
    2.8 ( 25.21 )
        QT-Follow-up, n= 0,1
    99999 ( 99999 )
    0 ( 99999 )
        QTCF-Part 2 C1 Day 1, n= 3,5
    -0.7 ( 15.63 )
    -4.2 ( 12.05 )
        QTCF-Part 2 C7-50 Day 1, n= 3,4
    -1.7 ( 3.51 )
    0 ( 11.63 )
        QTCF-Follow-up, n= 0,1
    99999 ( 99999 )
    3.3 ( 99999 )
    Notes
    [41] - Safety Population
    [42] - Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment AEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Bevacizumab
    Reporting group description
    		 In Part I participants received 3 infusions of 10 mg/kg bevacizumab administered at 2-week intervals.

    Reporting group title
    Pazopanib full cycle
    Reporting group description
    		 Following a 14-day washout, particpants entering part II were randomized to receive treatment throughout each 3-week cycle (Group 1). Participants were administered escalating doses of pazopanib, which increased in a stepwise manner in 3-week cycles as follows: 1) 200 mg twice weekly (bid), 2) 200 mg every other day, 3) 200 mg once daily (qd), 4) 400 mg qd, 5) 800 mg qd, and 6) 1200 mg qd. During the Part II Maintenance Phase, 800 mg qd pazopanib was administered in repeating 3-week cycles.

    Reporting group title
    Pazopanib first 2 weeks
    Reporting group description
    		 Following a 14-day washout, particpants entering part II were randomized to receive treatment for the first 2 weeks of each cycle only, i.e., discontinuous dosing (Group 2). Participants were administered escalating doses of pazopanib, which increased in a stepwise manner in 3-week cycles as follows: 1) 200 mg twice weekly (bid), 2) 200 mg every other day, 3) 200 mg once daily (qd), 4) 400 mg qd, 5) 800 mg qd, and 6) 1200 mg qd. During the Part II Maintenance Phase, 800 mg qd pazopanib was administered in repeating 3-week cycles.

    Serious adverse events
    		 Bevacizumab Pazopanib full cycle Pazopanib first 2 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 4 (50.00%)
    1 / 5 (20.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (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
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (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
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (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
    Pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bevacizumab Pazopanib full cycle Pazopanib first 2 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    4 / 4 (100.00%)
    5 / 5 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 4 (50.00%)
    3 / 5 (60.00%)
         occurrences all number
    1
    2
    3
    Hypotension
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 9 (44.44%)
    3 / 4 (75.00%)
    3 / 5 (60.00%)
         occurrences all number
    4
    7
    4
    Pyrexia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    2
    0
    Influenza like illness
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    Oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 4 (50.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    4
    1
    Cough
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    0
    2
    Dysphonia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    1
    Epistaxis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumothorax
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Wheezing
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Arthropod bite
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Excoriation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Sunburn
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    1
    2
    Paraesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Burning sensation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Pernicious anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Eyelid pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 4 (50.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    7
    5
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 4 (50.00%)
    4 / 5 (80.00%)
         occurrences all number
    1
    3
    4
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 4 (50.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    3
    3
    Stomatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 4 (50.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    2
    Dyspepsia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    2
    Gingival bleeding
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Nausea
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Abdominal tenderness
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Oral pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 4 (50.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    2
    Dry skin
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Hair colour changes
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Blister
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Miliaria
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Seborrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Skin hypertrophy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    4
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 4 (75.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    3
    0
    Pain in extremity
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    1
    Back pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 4 (50.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    2
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    2
    Spinal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    1
    0
    Flank pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Joint swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Pain in jaw
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    2 / 5 (40.00%)
         occurrences all number
    0
    2
    2
    Sinusitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    0
    3
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    1
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 4 (50.00%)
    2 / 5 (40.00%)
         occurrences all number
    1
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2009
    Removal of pharmacogenetics at request of LREC due to small number of subjects to be recruited and correlations would be limited
    27 Jul 2009
    Extension of time line from 7 days to 21 days duration for baseline assessments to reduce the burden on the subjects, addition of previously collected pathology tissue to supplement the pre-treatment information, update to biomarkers to take into account advances in the state of knowledge
    14 Apr 2010
    Addition of head CT scan to screening to confirm eligibility, introduction of flexibility to allow inclusion of local safety practices following protocol defined procedures on case by case basis

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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