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    Clinical Trial Results:
    A randomized phase II study to explore the efficacy and feasibility of upfront bi-monthly rotations between Everolimus and Pazopanib with sequential treatment of first line Pazopanib and second line Everolimus until progression in patients with advanced or metastatic clear cell renal cancer.

    Summary
    EudraCT number
    		 2011-000127-32
    Trial protocol
    		 NL  
    Global end of trial date
    05 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jun 2022
    First version publication date
    15 Jun 2022
    Other versions
    Summary report(s)
    		 Statistical report

    Trial information

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    Trial identification
    Sponsor protocol code
    ROPETAR
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01408004
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    WIN-O
    Sponsor organisation address
    Postbus 821, Zeist, Netherlands, 3700 AV
    Public contact
    Medical oncology/G.A. Cirkel, UMC Utrecht, +31 887556265, g.a.cirkel-2@umcutrecht.nl
    Scientific contact
    Medical oncology/G.A. Cirkel, UMC Utrecht, +31 887556265, g.a.cirkel-2@umcutrecht.nl
    Sponsor organisation name
    WIN-O
    Sponsor organisation address
    Postbus 821, Zeist , Netherlands, 3700 AV
    Public contact
    Jeanine Eikmans, WIN-O, +31 639488702 , nfo@win-o.nl
    Scientific contact
    Jeanine Eikmans, I WIN-O, +31 639488702 , info@win-o.nl
    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 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the progression-free survival of patients who receive bi-monthly rotations of Pazopanib and Everolimus versus patients who receive Pazopanib as a first line treatment.
    Protection of trial subjects
    NA
    Background therapy
    		 NA
    Evidence for comparator
    		 COMPARZ trial
    Actual start date of recruitment
    15 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 101
    Worldwide total number of subjects
    101
    EEA total number of subjects
    101
    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)
    60
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Within time limits, between September 2012 and April 2014

    Pre-assignment
    Screening details
    		 NA

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental
    Arm description
    		 Experimental: rotating treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    pazopanib
    Investigational medicinal product code
    Other name
    Votrient
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800mg 1dd 8 weeks (rotating)

    Investigational medicinal product name
    everolimus
    Investigational medicinal product code
    Other name
    afinitor
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg QD, 8 weeks, rotating

    Arm title
    		 Comparator
    Arm description
    		 pazopaninbg until PD, then everolimus
    Arm type
    		 Active comparator

    Investigational medicinal product name
    pazopanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800mg QD until PD

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg QD, until PD

    Number of subjects in period 1
    		Experimental Comparator
    Started
    52
    49
    Completed
    52
    49

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 101 101
    Age categorical
    Age Median Experimental: 65 Comparator: 67 Overall: 66 0% 25% 75% 100% quantile Experimental: 44 59 71 87 Comparator: 38 58 72 82 Overall: 38 58 72 87 Mean 65 65 65 Standard Deviation 10 10 10
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        Age > 18 years
    		 101 101
    Gender categorical
    Units: Subjects
        Female
    		 32 32
        Male
    		 69 69
    Reference
    Please refer to JAMA Oncol. 2017;3(4):501-508 for a complete overview of baseline characteristics
    Units: Subjects
        Link to paper
    		 101 101

    End points

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    End points reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 Experimental: rotating treatment

    Reporting group title
    Comparator
    Reporting group description
    		 pazopaninbg until PD, then everolimus

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    survival until first progression or death.
    End point type
    Primary
    End point timeframe
    Randomisation to survival until first progression or death.
    End point values
    		 Experimental Comparator
    Number of subjects analysed
    52
    49
    Units: month
        median (confidence interval 95%)
    7.4 (5.6 to 18.4)
    9.4 (6.6 to 11.9)
    Attachments
    		 Charts in paper
    Statistical analysis title
    		 Statistical Methods
    Statistical analysis description
    A total sample size of 100 patients was planned. From literature it was estimated that the 1-year PFS1 in the control arm would be 50%. An increase from 50% to 80% 1-year PFS of the rotating schedule over standard of care with first-line VEGFR-TKI was considered to be clinically relevant. Primary analysis was planned when over 60 events (first progression or death) were recorded, enabling detection of an increase in 1-year PFS to 80% (power 90%, α = .05, 2-tailed test).
    Comparison groups
    Experimental v Comparator
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Cox
    Parameter type
    		 Median difference (final values)
    Point estimate
    50
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 50
         upper limit
    		 80
    Variability estimate
    Standard deviation
    Dispersion value
    0

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time between first drug dose and 30 days after EOT
    Adverse event reporting additional description
    NA
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTC
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 Experimental: rotating treatment

    Reporting group title
    Comparator
    Reporting group description
    		 pazopanib until PD, then everolimus

    Serious adverse events
    		 Experimental Comparator
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 52 (42.31%)
    24 / 49 (48.98%)
         number of deaths (all causes)
    5
    7
         number of deaths resulting from adverse events
    2
    2
    Investigations
    Adverse event
    Additional description: It;s impossible to enter all SAEs manually. Please refer to fullpaper: JAMA Oncol. 2017;3(4):501-508 and separate uploaded PDF with all AEs/SAEs details
         subjects affected / exposed
    22 / 52 (42.31%)
    24 / 49 (48.98%)
         occurrences causally related to treatment / all
    22 / 22
    24 / 24
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Experimental Comparator
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 52 (100.00%)
    49 / 49 (100.00%)
    Investigations
    Adverse event
         subjects affected / exposed
    52 / 52 (100.00%)
    49 / 49 (100.00%)
         occurrences all number
    52
    49

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Not all required data are available and/or impossible to enter in this overview. PLEASE REFER TO FULL PAPER IN JAMA ONCOLOGY OR ATTACHED STATISTICAL REPORT FOR VALIDATED DATA

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27918762
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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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