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    Clinical Trial Results:
    An Extension Treatment Protocol for Subjects who have Participated in a Phase 3 Study of Tivozanib vs. Sorafenib in Renal Cell Carcinoma (Protocol AV-951-09-301)

    Summary
    EudraCT number
    		 2009-015987-32
    Trial protocol
    		 FR   IT   CZ   HU   PL   BG   GB  
    Global end of trial date
    04 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Aug 2021
    First version publication date
    25 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AV-951-09-902
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01076010
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AVEO Pharmaceuticals, Inc.
    Sponsor organisation address
    30 Winter Street, Boston, MA , United States, 02108
    Public contact
    Chief Medical Officer, AVEO Pharmaceuticals, Inc., 857 400-0101, clinical@aveooncology.com
    Scientific contact
    Chief Medical Officer, AVEO Pharmaceuticals, Inc., 857 400-0101, clinical@aveooncology.com
    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
    03 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    •To allow access to tivozanib for subjects who participated in Protocol AV-951-09-301 and AV-951-09-902 and failed sorafenib treatment on either protocol. •To allow long-term access to tivozanib for subjects who participated in Protocol AV-951-09-301 and demonstrated clinical benefit and acceptable tolerability to tivozanib •To allow long-term access to sorafenib for subjects who participated in Protocol AV-951-09-301 and demonstrated clinical benefit and acceptable tolerability to sorafenib •To assess long-term safety in subjects who continued treatment with tivozanib
    Protection of trial subjects
    The protocol and amendments, informed consent forms, and any other appropriate study-related information were reviewed and approved by the appropriate Institutional Review Board (IRB) or Ethics Committee (EC). The study was conducted in accordance with the protocol (and subsequent amendments), the United States (US) Code of Federal Regulations, Title 21 CFR Part 56, principles of Good Clinical Practice (GCP), the International Conference on Harmonization (ICH) Guideline for GCP [E6 (R1)] (reference number CPMP/ICH/135/95), the national laws and regulations of the country in which the research was conducted, and the principles of the Declaration of Helsinki (54th World Medical Association General Assembly, Washington, USA, 2002). Prior to any study-related procedures, the Investigator explained to each subject the aims, methods, anticipated benefits and potential hazards, which were relevant to the subject's decision to participate. An informed consent document approved by the IRB/EC was signed by the subject and the Investigator before any study-related procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 May 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    India: 6
    Country: Number of subjects enrolled
    Ukraine: 51
    Country: Number of subjects enrolled
    Russian Federation: 103
    Country: Number of subjects enrolled
    Serbia: 15
    Worldwide total number of subjects
    277
    EEA total number of subjects
    86
    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)
    195
    From 65 to 84 years
    80
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 55 sites (4 sites in Bulgaria, 1 site in Canada, 2 sites in Chile, 1 site in Czech Republic, 2 sites in Hungary, 4 sites in India, 2 sites in Italy, 6 sites in Poland, 4 sites in Romania, 17 sites in Russia, 4 sites in Serbia, 6 sites in Ukraine, 1 site in the United Kingdom, and 1 site in the United States).

    Pre-assignment
    Screening details
    		 All subjects underwent inclusion and exclusion criteria assessment and all eligible subjects signed the informed consent before undergoing any study related procedures. All the study assessments were performed as per the schedule of assessment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sorafenib Crossover to Tivozanib
    Arm description
    		 The subjects who failed sorafenib (had Response Evaluation Criteria in Solid Tumors [ RECIST]-defined progressive disease) on the parent Protocol AV- 951-09-301 were offered tivozanib hydrochloride on Protocol AV- 951-09-902.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tivozanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tivozanib was administered at a dose of 1.5 mg orally once daily (QD), at least 1 hour before or 2 hours after ingesting any food or other medication, for as long as the subject tolerated treatment in the absence of disease progression or unacceptable toxicity. Grapefruit juice could not have been ingested during the study. All subjects receiving tivozanib followed the dosing schedule of 3 weeks on treatment (beginning on Day 1) followed by 1 week off treatment. One cycle was defined as 4 weeks of treatment.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered orally, at a dose of 400 mg (2 x 200 mg tablets) twice daily, beginning on Day 1 of Cycle 1. Subjects received sorafenib continuously (1 cycle = 4 weeks). Sorafenib was to be taken at least 1 hour before or 2 hours after ingesting any food or other medications.

    Arm title
    		 First Line Tivozanib
    Arm description
    		 The subjects who were randomized to tivozanib (continued from the parent Protocol AV-951-09-301), and demonstrated clinical benefit and acceptable tolerability in Protocol AV-951-09-301.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tivozanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tivozanib was administered at a dose of 1.5 mg orally once daily (QD), at least 1 hour before or 2 hours after ingesting any food or other medication, for as long as the subject tolerated treatment in the absence of disease progression or unacceptable toxicity. Grapefruit juice could not have been ingested during the study. All subjects receiving tivozanib followed the dosing schedule of 3 weeks on treatment (beginning on Day 1) followed by 1 week off treatment. One cycle was defined as 4 weeks of treatment.

    Arm title
    		 First Line Sorafenib
    Arm description
    		 The subjects who were randomized to sorafenib (continued from the parent Protocol AV-951-09-301) and demonstrated clinical benefit and acceptable tolerability were offered long term access to sorafenib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered orally, at a dose of 400 mg (2 x 200 mg tablets) twice daily, beginning on Day 1 of Cycle 1. Subjects received sorafenib continuously (1 cycle = 4 weeks). Sorafenib was to be taken at least 1 hour before or 2 hours after ingesting any food or other medications.

    Number of subjects in period 1
    		Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Started
    161
    88
    28
    Completed
    36
    49
    26
    Not completed
    125
    39
    2
         Treatment Interruption for > 2 Weeks
    -
    1
    -
         Requirement for a Significant Surgical Procedure
    -
    1
    -
         Consent withdrawn by subject
    3
    -
    1
         Death
    15
    1
    -
         Other
    5
    2
    -
         Significant Protocol Deviation
    -
    1
    -
         Adverse event
    7
    2
    -
         Progressive disease
    90
    30
    1
         Lack of efficacy
    4
    -
    -
         Noncompliance
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sorafenib Crossover to Tivozanib
    Reporting group description
    		 The subjects who failed sorafenib (had Response Evaluation Criteria in Solid Tumors [ RECIST]-defined progressive disease) on the parent Protocol AV- 951-09-301 were offered tivozanib hydrochloride on Protocol AV- 951-09-902.

    Reporting group title
    First Line Tivozanib
    Reporting group description
    		 The subjects who were randomized to tivozanib (continued from the parent Protocol AV-951-09-301), and demonstrated clinical benefit and acceptable tolerability in Protocol AV-951-09-301.

    Reporting group title
    First Line Sorafenib
    Reporting group description
    		 The subjects who were randomized to sorafenib (continued from the parent Protocol AV-951-09-301) and demonstrated clinical benefit and acceptable tolerability were offered long term access to sorafenib.

    Reporting group values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib Total
    Number of subjects
    		 161 88 28 277
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 120 58 17 195
        From 65-84 years
    		 40 29 11 80
        85 years and over
    		 1 1 0 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.6 ( 9.98 ) 61.6 ( 9.31 ) 61.5 ( 8.75 ) -
    Gender categorical
    Units: Subjects
        Female
    		 46 33 9 88
        Male
    		 115 55 19 189

    End points

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    End points reporting groups
    Reporting group title
    Sorafenib Crossover to Tivozanib
    Reporting group description
    		 The subjects who failed sorafenib (had Response Evaluation Criteria in Solid Tumors [ RECIST]-defined progressive disease) on the parent Protocol AV- 951-09-301 were offered tivozanib hydrochloride on Protocol AV- 951-09-902.

    Reporting group title
    First Line Tivozanib
    Reporting group description
    		 The subjects who were randomized to tivozanib (continued from the parent Protocol AV-951-09-301), and demonstrated clinical benefit and acceptable tolerability in Protocol AV-951-09-301.

    Reporting group title
    First Line Sorafenib
    Reporting group description
    		 The subjects who were randomized to sorafenib (continued from the parent Protocol AV-951-09-301) and demonstrated clinical benefit and acceptable tolerability were offered long term access to sorafenib.

    Primary: Number of Days Subjects Received Treatment in Each Treatment Arm

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    End point title
    		 Number of Days Subjects Received Treatment in Each Treatment Arm [1]
    End point description
    Number of days subjects received treatment who were from Protocol AV-951-09-301 who either continued on tivozanib (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib (crossover subjects), and who continued on sorafenib (subjects with first-line experience on sorafenib treatment) in this trial. Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD.
    End point type
    Primary
    End point timeframe
    From enrollment to until all subjects discontinued (due to documented progressive disease [PD] or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902.
    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: No statistical analysis is available for this endpoint.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    160
    88
    28
    Units: Days
    arithmetic mean (standard deviation)
        Duration of treatment
    290.0 ( 234.37 )
    325.3 ( 137.79 )
    369.4 ( 107.60 )
        Total days receiving drug
    222.36 ( 181.722 )
    241.00 ( 105.928 )
    368.14 ( 107.946 )
    No statistical analyses for this end point

    Primary: Number of Cycles Subjects Received Treatment in Each Treatment Arm

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    End point title
    		 Number of Cycles Subjects Received Treatment in Each Treatment Arm [2]
    End point description
    Number of cycles subjects received treatment who were from Protocol AV-951-09-301 who either continued on tivozanib (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib (crossover subjects), and who continued on sorafenib (subjects with first-line experience on sorafenib treatment) in this trial. Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD.
    End point type
    Primary
    End point timeframe
    From enrollment to until all subjects discontinued (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902.
    Notes
    [2] - 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: No statistical analysis is available for this endpoint.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    160
    88
    28
    Units: Number of cycles started
        arithmetic mean (standard deviation)
    10.6 ( 8.36 )
    11.8 ( 4.85 )
    13.2 ( 3.83 )
    No statistical analyses for this end point

    Primary: Total Dose Administered to Subjects in Each Treatment Arm (mg)

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    End point title
    		 Total Dose Administered to Subjects in Each Treatment Arm (mg) [3]
    End point description
    The total dose administered to subjects who were from Protocol AV-951-09-301 who either continued on tivozanib (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib (crossover subjects), and who continued on sorafenib (subjects with first-line experience on sorafenib treatment) in this trial. Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD.
    End point type
    Primary
    End point timeframe
    From enrollment to until all subjects discontinued (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902.
    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: No statistical analysis is available for this endpoint.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    160
    88
    28
    Units: mg
    arithmetic mean (standard deviation)
        Total dose administered
    318.84 ( 256.241 )
    344.58 ( 152.131 )
    244014.29 ( 116816.715 )
    No statistical analyses for this end point

    Primary: Relative Dose Intensity (RDI) of Treatment Administered to Subjects in Each Treatment Arm

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    End point title
    		 Relative Dose Intensity (RDI) of Treatment Administered to Subjects in Each Treatment Arm [4]
    End point description
    Relative Dose Intensity was defined as 100% times the actual dose intensity divided by the intended dose intensity. The RDI of subjects from Protocol AV-951-09-301 who either continued on tivozanib (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib (crossover subjects), and who continued on sorafenib (subjects with first-line experience on sorafenib treatment) in this trial. Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD.
    End point type
    Primary
    End point timeframe
    From enrollment to until all subjects discontinued (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902.
    Notes
    [4] - 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: No statistical analysis is available for this endpoint.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    160
    88
    28
    Units: Percentage of Dose
        arithmetic mean (standard deviation)
    95.21 ( 9.393 )
    91.12 ( 14.762 )
    80.60 ( 28.603 )
    No statistical analyses for this end point

    Primary: Number of Subjects With Adverse Events

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    End point title
    		 Number of Subjects With Adverse Events [5]
    End point description
    Number of subjects with treatment-emergent adverse events (AEs) as assessed by Common Terminology Criteria for Adverse Events v3.0.
    End point type
    Primary
    End point timeframe
    From enrollment assessed up to 3 years of treatment or until follow-up (up to 30 days end-of-trial visit after treatment discontinuation), whichever occured earlier.
    Notes
    [5] - 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: No statistical analysis is available for this endpoint.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    161
    88
    28
    Units: Subjects
    number (not applicable)
        Any Adverse Event (AE)
    124
    85
    28
        Any AE of Grade 3 or Higher
    77
    55
    19
        Any Treatment-Related AE
    86
    76
    27
        Any Treatment-Related AE of Grade 3 or Higher
    39
    35
    15
        Any AE With Outcome of Death
    21
    3
    0
        Any Treatment-Related AE With Outcome of Death
    1
    1
    0
        Any Serious Adverse Event (SAE)
    49
    17
    4
        Any Treatment-Related SAE
    7
    7
    2
        AE Leading to Study Drug Discontinuation (AEDC)
    19
    4
    0
        Any Treatment-Related AEDC
    3
    0
    0
        Any AE Leading to Study Drug Interruption
    27
    26
    12
        Treatment-Related AE-Study Drug Interruption
    13
    17
    10
        Any AE Leading to Study Drug Dose Reduction
    11
    11
    10
        Treatment-Related AE- Study Drug Dose Reduction
    9
    11
    10
    No statistical analyses for this end point

    Primary: Average Daily Dose Administered to Subjects in Each Treatment Arm

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    End point title
    		 Average Daily Dose Administered to Subjects in Each Treatment Arm [6]
    End point description
    The average daily dose administered to subjects who were from Protocol AV-951-09-301 who either continued on tivozanib (subjects with first-line experience on tivozanib treatment), who crossed over from sorafenib to tivozanib (crossover subjects), and who continued on sorafenib (subjects with first-line experience on sorafenib treatment) in this trial. Subjects could be discontinued due to unacceptable toxicities or clinical or documented PD.
    End point type
    Primary
    End point timeframe
    From enrollment to until all subjects discontinued (due to documented PD or unacceptable toxicities) or until 3 years after the first subject was enrolled in Protocol AV-951-09-902.
    Notes
    [6] - 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: No statistical analysis is available for this endpoint.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    160
    88
    28
    Units: mg/day
        arithmetic mean (standard deviation)
    1.46 ( 0.121 )
    1.40 ( 0.196 )
    651.47 ( 225.410 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib

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    End point title
    		 Number of Subjects with Objective Response Rate (ORR) Who Continued Treatment With Tivozanib or Sorafenib and Who Received Tivozanib After Failure of Sorafenib
    End point description
    ORR is defined as the proportion of subjects with confirmed complete response (CR) or confirmed partial response (PR) according to RECIST (Version 1.0), relative to the total population of dosed subjects. CR is disappearance of all target and non-target lesions and normalization of tumor marker levels. At least a 30% decrease in the sum of the loading dose (LD) of target lesions, taking as reference the baseline sum LD. To allow long-term access to sorafenib for subjects who participated in Protocol AV-951-09-301 (NCT01030783), and demonstrated clinical benefit and acceptable tolerability to sorafenib. Objective did not allow for a measured outcome.
    End point type
    Secondary
    End point timeframe
    From Day 1 to the end of treatment (EOT) Visit, approximately every 8 weeks.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    161
    88
    28
    Units: Subjects
    number (not applicable)
        Overall Confirmed ORR
    29
    49
    16
        Overall Unconfirmed ORR
    43
    55
    16
    No statistical analyses for this end point

    Secondary: Duration of Response (DR)

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    End point title
    		 Duration of Response (DR)
    End point description
    Duration of Response was defined as the time from the first documentation of objective tumor response (confirmed CR or confirmed PR) according to RECIST (Version 1.0) to the first documentation of objective tumor progression or to death due to any reason. DR was calculated for the subgroup of subjects with a confirmed objective tumor response (PR or CR). CR is disappearance of all target and non-target lesions and normalization of tumor marker levels. PR is at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. 99.9999 = Not Available; DR was only summarized for subjects who had an objective tumor response.
    End point type
    Secondary
    End point timeframe
    From the first documentation of objective tumor response to the first documentation of objective tumor progression, assessed up to treatment discontinuation or to death due to any reason or maximum up to 3 years, whichever occurred earlier.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    29
    49
    16
    Units: Months
    number (confidence interval 95%)
        25% Quartile
    8.0 (4.4 to 12.9)
    12.9 (5.6 to 99.9999)
    99.9999 (99.9999 to 99.9999)
        50% Quartile
    15.2 (11.1 to 99.9999)
    99.9999 (99.9999 to 99.9999)
    99.9999 (99.9999 to 99.9999)
        75% Quartile
    99.9999 (12.9 to 99.9999)
    99.9999 (99.9999 to 99.9999)
    99.9999 (99.9999 to 99.9999)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS was defined as the date of first dose of study drug to the first documentation of objective tumor progression or death due to any reason, whichever occurred first. For the crossover subjects and subjects with first-line experience on tivozanib treatment, the timeframe for PFS assessment started from the date of first dose of tivozanib in the AV-951-09-902 study. For subjects with first-line experience on sorafenib treatment, the timeframe for PFS assessment started from the date of first dose of sorafenib in the AV-951-09-902. 99.9999 = Not available, For the crossover and first line tivozanib subjects the PFS time was calculated from the first dose date of tivozanib in the AV-951-09-902 study. For the first line sorafenib subjects the first dose date of sorafenib in the AV-951-09-902 was used in the PFS calculation.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug (tivozanib or sorafenib) in the AV-951-09-902 study to the first documentation of objective tumor progression or death due to any reason or maximum up to 3 years, whichever occurred first.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    161
    88
    28
    Units: Months
    number (confidence interval 95%)
        25% Quartile
    3.6 (1.9 to 5.2)
    7.2 (3.5 to 9.2)
    99.9999 (99.9999 to 99.9999)
        50% Quartile
    11.0 (7.3 to 12.7)
    99.9999 (10.9 to 99.9999)
    99.9999 (99.9999 to 99.9999)
        75% Quartile
    20.9 (16.5 to 99.9999)
    99.9999 (99.9999 to 99.9999)
    99.9999 (99.9999 to 99.9999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the first dose of study drug (tivozanib or sorafenib) date on this study to date of death due to any cause. 99.9999 = Not Available, For the crossover and first line tivozanib subjects the overall survival time was calculated from the first dose date of tivozanib in the AV-951-09-902 study. For the first line sorafenib subjects the first dose date of sorafenib in the AV-951-09-902 was used in the overall survival time calculation.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug (tivozanib or sorafenib) in the AV-951-09-902 study to death due to any reason or maximum up to 3 years, whichever occurred first.
    End point values
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Number of subjects analysed
    161
    88
    28
    Units: Months
    number (confidence interval 95%)
        25% Quartile
    8.2 (6.0 to 12.1)
    99.9999 (99.9999 to 99.9999)
    99.9999 (99.9999 to 99.9999)
        50% Quartile
    21.6 (17.0 to 27.6)
    99.9999 (99.9999 to 99.9999)
    99.9999 (99.9999 to 99.9999)
        75% Quartile
    30.7 (28.8 to 99.9999)
    99.9999 (99.9999 to 99.9999)
    99.9999 (99.9999 to 99.9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment assessed up to 3 years of treatment or until follow-up (up to 30 days end-of-trial visit after treatment discontinuation), whichever occured earlier
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Sorafenib Crossover to Tivozanib
    Reporting group description
    		 The subjects who failed sorafenib (had Response Evaluation Criteria in Solid Tumors [ RECIST]-defined progressive disease) on the parent Protocol AV- 951-09-301 were offered tivozanib hydrochloride on Protocol AV- 951-09-902.

    Reporting group title
    First Line Tivozanib
    Reporting group description
    		 The subjects who were randomized to tivozanib (continued from the parent Protocol AV-951-09-301), and demonstrated clinical benefit and acceptable tolerability in Protocol AV-951-09-301.

    Reporting group title
    First Line Sorafenib
    Reporting group description
    		 The subjects who were randomized to sorafenib (continued from the parent Protocol AV-951-09-301) and demonstrated clinical benefit and acceptable tolerability were to be offered long term access to sorafenib.

    Serious adverse events
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 161 (30.43%)
    17 / 88 (19.32%)
    4 / 28 (14.29%)
         number of deaths (all causes)
    21
    3
    0
         number of deaths resulting from adverse events
    21
    3
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to pleura
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Metastases to soft tissue
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Metastases to the mediastinum
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Neoplasm progression
         subjects affected / exposed
    4 / 161 (2.48%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    3 / 161 (1.86%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Hypertension
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Hypertensive crisis
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Peripheral ischaemia
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 161 (1.24%)
    1 / 88 (1.14%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    General physical health deterioration
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Multi-organ failure
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic fluid collection
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Pleural effusion
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Pulmonary embolism
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 88 (1.14%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Respiratory failure
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Psychiatric disorders
    Delusional disorder, somatic type
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Head injury
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 88 (1.14%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Myocardial infarction
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Loss of consciousness
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 88 (1.14%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Pancreatitis acute
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Salivary gland mass
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Cholangitis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Cholecystitis acute
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Myxoedema
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Pathological fracture
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 88 (1.14%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Device related infection
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Pneumonia viral
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 88 (1.14%)
    0 / 28 (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
    Sepsis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Hypoglycaemia
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 88 (0.00%)
    0 / 28 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sorafenib Crossover to Tivozanib First Line Tivozanib First Line Sorafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    87 / 161 (54.04%)
    82 / 88 (93.18%)
    28 / 28 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    41 / 161 (25.47%)
    44 / 88 (50.00%)
    16 / 28 (57.14%)
         occurrences all number
    47
    85
    21
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    20 / 161 (12.42%)
    20 / 88 (22.73%)
    3 / 28 (10.71%)
         occurrences all number
    26
    35
    3
    Fatigue
         subjects affected / exposed
    21 / 161 (13.04%)
    20 / 88 (22.73%)
    3 / 28 (10.71%)
         occurrences all number
    34
    39
    3
    Oedema peripheral
         subjects affected / exposed
    0 / 161 (0.00%)
    5 / 88 (5.68%)
    0 / 28 (0.00%)
         occurrences all number
    0
    9
    0
    Pyrexia
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 161 (5.59%)
    13 / 88 (14.77%)
    2 / 28 (7.14%)
         occurrences all number
    10
    19
    2
    Dysphonia
         subjects affected / exposed
    9 / 161 (5.59%)
    16 / 88 (18.18%)
    0 / 28 (0.00%)
         occurrences all number
    29
    27
    0
    Dyspnoea
         subjects affected / exposed
    9 / 161 (5.59%)
    10 / 88 (11.36%)
    3 / 28 (10.71%)
         occurrences all number
    11
    16
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 161 (0.00%)
    6 / 88 (6.82%)
    0 / 28 (0.00%)
         occurrences all number
    0
    9
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 161 (0.00%)
    5 / 88 (5.68%)
    0 / 28 (0.00%)
         occurrences all number
    0
    6
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    7
    Amylase increased
         subjects affected / exposed
    0 / 161 (0.00%)
    6 / 88 (6.82%)
    0 / 28 (0.00%)
         occurrences all number
    0
    9
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    4
    Blood creatinine increased
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    6
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    5 / 28 (17.86%)
         occurrences all number
    0
    0
    23
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 161 (0.00%)
    8 / 88 (9.09%)
    0 / 28 (0.00%)
         occurrences all number
    0
    13
    0
    Lipase increased
         subjects affected / exposed
    0 / 161 (0.00%)
    6 / 88 (6.82%)
    2 / 28 (7.14%)
         occurrences all number
    0
    21
    4
    Weight decreased
         subjects affected / exposed
    0 / 161 (0.00%)
    21 / 88 (23.86%)
    9 / 28 (32.14%)
         occurrences all number
    0
    43
    18
    Weight increased
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    3
    Neutrophil count decreased
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 161 (0.00%)
    14 / 88 (15.91%)
    2 / 28 (7.14%)
         occurrences all number
    0
    16
    4
    Somnolence
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 161 (0.00%)
    5 / 88 (5.68%)
    0 / 28 (0.00%)
         occurrences all number
    0
    6
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 161 (0.00%)
    9 / 88 (10.23%)
    3 / 28 (10.71%)
         occurrences all number
    0
    10
    7
    Abdominal pain upper
         subjects affected / exposed
    0 / 161 (0.00%)
    10 / 88 (11.36%)
    0 / 28 (0.00%)
         occurrences all number
    0
    15
    0
    Constipation
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Diarrhoea
         subjects affected / exposed
    22 / 161 (13.66%)
    35 / 88 (39.77%)
    12 / 28 (42.86%)
         occurrences all number
    66
    155
    22
    Dyspepsia
         subjects affected / exposed
    0 / 161 (0.00%)
    7 / 88 (7.95%)
    0 / 28 (0.00%)
         occurrences all number
    0
    8
    0
    Gastritis
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    5
    Nausea
         subjects affected / exposed
    0 / 161 (0.00%)
    21 / 88 (23.86%)
    0 / 28 (0.00%)
         occurrences all number
    0
    40
    0
    Stomatitis
         subjects affected / exposed
    0 / 161 (0.00%)
    11 / 88 (12.50%)
    0 / 28 (0.00%)
         occurrences all number
    0
    40
    0
    Vomiting
         subjects affected / exposed
    0 / 161 (0.00%)
    9 / 88 (10.23%)
    0 / 28 (0.00%)
         occurrences all number
    0
    13
    0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    3
    Generalised erythema
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    4 / 28 (14.29%)
         occurrences all number
    0
    0
    6
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    16 / 161 (9.94%)
    21 / 88 (23.86%)
    16 / 28 (57.14%)
         occurrences all number
    32
    68
    38
    Pruritus
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    5
    Rash erythematous
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    7
    Skin exfoliation
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Alopecia
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    6 / 28 (21.43%)
         occurrences all number
    0
    0
    7
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 161 (0.00%)
    10 / 88 (11.36%)
    3 / 28 (10.71%)
         occurrences all number
    0
    60
    12
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 161 (0.00%)
    9 / 88 (10.23%)
    0 / 28 (0.00%)
         occurrences all number
    0
    10
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 161 (0.00%)
    11 / 88 (12.50%)
    0 / 28 (0.00%)
         occurrences all number
    0
    12
    0
    Back pain
         subjects affected / exposed
    0 / 161 (0.00%)
    10 / 88 (11.36%)
    4 / 28 (14.29%)
         occurrences all number
    0
    11
    4
    Myalgia
         subjects affected / exposed
    0 / 161 (0.00%)
    6 / 88 (6.82%)
    0 / 28 (0.00%)
         occurrences all number
    0
    10
    0
    Pain in extremity
         subjects affected / exposed
    0 / 161 (0.00%)
    9 / 88 (10.23%)
    0 / 28 (0.00%)
         occurrences all number
    0
    12
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Rash pustular
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 88 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 161 (5.59%)
    11 / 88 (12.50%)
    2 / 28 (7.14%)
         occurrences all number
    23
    23
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2010
    • Added further language regarding long-term survival follow-up. • Updated subject enrollment window to occur within the specified timeframe outlined in the eligibility criteria. • Revised Exclusion Criterion #1, added Exclusion Criteria #2 and #3, and renumbered criteria due to addition of new criteria. • Modified visit windows. • Modified window for clinic visits to occur. • Clarified use of end of treatment (EOT) Visit data for subjects initiating tivozanib and those continuing sorafenib or tivozanib from Protocol AV-951-09-301. • Modified language referring to frequency of labs in the Schedule of Activities. • Clarified that further imaging was required for subjects who had progressive disease (PD) and crossed over to tivozanib after sorafenib failure on this study. • Removed substrates from the cytochrome P450 enzyme 3A4 (CYP3A4) inhibitors and inducers table. • Removed criteria that tumor evaluation would be repeated 4 weeks to allow for confirmation of tumor status for patients with SD. • Modified that follow-up measurements had to have met stable disease (SD) criteria at least once after study entry, at a minimum interval of 4 weeks.
    10 Nov 2010
    • Updated pharmacovigilance contact name. • Revised Inclusion Criterion #1 for clarity. • Revised language regarding contact for OS. • Clarified in Table 1: "Schedule of Study Events for Subjects Continuing Tivozanib or Sorafenib Therapy from AV-951-09-301" that the ± 2 day window applied to all visit procedures except study drug administration. • Reformatted Table 2: "Schedule of Study Events for Subjects Initiating Tivozanib After Sorafenib Failure on AV-951-09-301" and combined Cycles 1 and 2 to allow the addition of Cycle 4 (and all even numbered cycles) column. • Clarified the following in Table 2: "Schedule of Study Events for Subjects Initiating Tivozanib After Sorafenib Failure on AV-951-09-301": ± 2 day window applied to all visit procedures except study drug administration, coagulation parameters and thyroid function tests were collected on Day 1 of Cycle 1 only, and disease assessment (CT scan) was performed at end of Cycle 2 only. • Repositioned the “x” under Cycle 3 (and all odd numbered cycles) to show tivozanib administration. • Added a Cycle 4 (and all even numbered cycles) column and the timing of procedures and evaluations required at those time points. • Added contact information for reporting deaths, SAEs, and unexpected AEs.

    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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