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    Clinical Trial Results:
    A Phase 2, Open Label, Multicenter, Randomized Trial Comparing Tivozanib in Combination with mFOLFOX6 with Bevacizumab in Combination with mFOLFOX6 in Stage IV Metastatic Corectal Cancer (mCRC) Subjects

    Summary
    EudraCT number
    		 2011-003502-24
    Trial protocol
    		 BE   GB   CZ   ES   AT   HU   FI   NL   IT  
    Global end of trial date
    07 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Apr 2016
    First version publication date
    07 Mar 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    4130-CL-0201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01478594
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc.
    Sponsor organisation address
    1 Astellas Way, Northbrook, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.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
    28 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare progression-free survival (PFS) between tivozanib in combination with mFOLFOX6 with bevacizumab in combination with mFOLFOX6 based on investigator radiological tumor assessment.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Dec 2011
    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?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    Hungary: 32
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    United States: 70
    Worldwide total number of subjects
    265
    EEA total number of subjects
    154
    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)
    149
    From 65 to 84 years
    116
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were at least 18 years of age with Stage IV metastatic colorectal cancer (mCRC) and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria (Version 1.1). Participants who completed are participants still on study as of 28 February 2014.

    Pre-assignment
    Screening details
    		 Participants were to be randomized in a 2:1 ratio (estimated 168 patients in the Tivozanib+mFOLFOX6 arm and estimated 84 patients in the Bevazicumab+mFOLFOX6 arm) and stratified by: Lactate Dehydrogenase (LDH) status (< 1.5 x the upper limit of normal [ULN] or > 1.5 x ULN), origin of cancer (rectal or colon), number of metastatic sites (1 or ≥ 2).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tivozanib + mFOLFOX6
    Arm description
    		 Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tivozanib
    Investigational medicinal product code
    ASP4130
    Other name
    Tivozanib Hydrochloride
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment. On days when patients received both tivozanib and mFOLFOX6, tivozanib was to be administered at least 1 hour prior to the start of the mFOLFOX6 chemotherapy regimen or per institutional guidelines.

    Investigational medicinal product name
    mFOLFOX6
    Investigational medicinal product code
    Other name
    modified FOLFOX-6
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    mFOLFOX6 is the sixth variation of a combination chemotherapy regimen consisting of folininc acid (leucovorin), fluorouracil and oxaliplatin (Oxaliplatin: days 1 and 15, 85 mg/m^2 intravenous bolus in 500 mL of 5% dextrose in water (D5W) over 2 hours; Leucovorin calcium: days 1 and 15, 400 mg/m^2 intravenous bolus in 500 mL of D5W over 2 hours (could have been given concurrently with oxaliplatin through a separate intravenous line; Fluorouracil bolus: days 1 and 15, 400 mg/m^2 intravenous bolus over 5 to 15 minutes; Fluorouracil infusion: days 1 to 3 and 15 to 17, 2400 mg/m^2 continuous intravenous infusion via infusion pump over 46 hours). Participants received mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle.

    Arm title
    		 Bevacizumab + mFOLFOX6
    Arm description
    		 Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle. Bevacizumab was to be administered prior to the start of the mFOLFOX6 chemotherapy regimen or per institution guidelines.

    Investigational medicinal product name
    mFOLFOX6
    Investigational medicinal product code
    Other name
    modified FOLFOX-6
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use , Intravenous use
    Dosage and administration details
    mFOLFOX6 is the sixth variation of a combination chemotherapy regimen consisting of folininc acid (leucovorin), fluorouracil and oxaliplatin (Oxaliplatin: days 1 and 15, 85 mg/m^2 intravenous bolus in 500 mL of 5% dextrose in water (D5W) over 2 hours; Leucovorin calcium: days 1 and 15, 400 mg/m^2 intravenous bolus in 500 mL of D5W over 2 hours (could have been given concurrently with oxaliplatin through a separate intravenous line; Fluorouracil bolus: days 1 and 15, 400 mg/m^2 intravenous bolus over 5 to 15 minutes; Fluorouracil infusion: days 1 to 3 and 15 to 17, 2400 mg/m^2 continuous intravenous infusion via infusion pump over 46 hours). Participants received mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle.

    Number of subjects in period 1
    		Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Started
    177
    88
    Received treatment
    177
    87
    Completed
    112
    60
    Not completed
    65
    28
         Randomized but never received study drug
    -
    1
         Consent withdrawn by subject
    9
    3
         Death
    45
    18
         Study terminated by sponsor
    8
    5
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tivozanib + mFOLFOX6
    Reporting group description
    		 Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.

    Reporting group title
    Bevacizumab + mFOLFOX6
    Reporting group description
    		 Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.

    Reporting group values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6 Total
    Number of subjects
    		 177 88 265
    Age categorical
    Units: Subjects
        < 65 years
    		 101 48 149
        ≥ 65 years
    		 76 40 116
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.9 ± 9.58 62.6 ± 11.17 -
    Gender categorical
    Units: Subjects
        Female
    		 59 33 92
        Male
    		 118 55 173
    Race
    Units: Subjects
        White
    		 169 85 254
        Black or African American
    		 2 0 2
        Asian
    		 3 2 5
        Native Hawaiian or other Pacific Islander
    		 1 1 2
        Other
    		 2 0 2
    Ethinicity
    Units: Subjects
        Not Hispanic or Latino
    		 170 86 256
        Hispanic or Latino
    		 6 2 8
        Unknown or Not reported
    		 1 0 1
    ECOG performance status
    Eastern Cooperative Oncology Group (ECOG); ECOG criteria: 0: Fully active. 1: Ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of all self-care. 3: Capable of limited self-care, confined to bed or chair more than 50% of waking hours. 4: Completely disabled, no self-care, totally confined to bed or chair. 5: Dead.
    Units: Subjects
        ECOG=0
    		 95 58 153
        ECOG=1
    		 82 30 112
        ECOG=2
    		 0 0 0
        ECOG=3
    		 0 0 0
        ECOG=4
    		 0 0 0
        ECOG=5
    		 0 0 0
    LDH Status
    Lactate dehydrogenase (LDH); The upper limit of normal (ULN) from the site was used.
    Units: Subjects
        < 1.5 x ULN
    		 127 64 191
        ≥ 1.5 x ULN
    		 50 24 74
    Origin of Cancer
    Units: Subjects
        Rectal
    		 53 24 77
        Colon
    		 124 64 188
    Number of metastatic sites/organs
    Units: Subjects
        One (1)
    		 56 30 86
        Two (2)
    		 80 34 114
        Three (3)
    		 29 21 50
        ≥ Four (4)
    		 12 3 15
    KRAS Mutation Status
    Kirsten rat sarcoma (KRAS)
    Units: Subjects
        Wild-type
    		 33 21 54
        Mutant
    		 23 16 39
        Unknown
    		 121 51 172
    Time since initial diagnosis
    Units: months
        arithmetic mean (standard deviation)
    		 9.41 ± 20.473 10.88 ± 21.055 -
    Number of metastatic sites at screening
    Units: metastatic sites
        arithmetic mean (standard deviation)
    		 2 ± 1.02 2 ± 0.85 -

    End points

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    End points reporting groups
    Reporting group title
    Tivozanib + mFOLFOX6
    Reporting group description
    		 Participants received 1.5 mg tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.

    Reporting group title
    Bevacizumab + mFOLFOX6
    Reporting group description
    		 Participants received 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle and mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.

    Subject analysis set title
    Tivozanib + mFOLFOX6: LDH < 1.5 ULN
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Lactate Dehydrogenase (LDH) < 1.5 ULN received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: LDH < 1.5 ULN
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with LDH < 1.5 ULN received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle.

    Subject analysis set title
    Tivozanib + mFOLFOX6: LDH ≥ 1.5 ULN
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with LDH ≥ 1.5 ULN received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: LDH ≥ 1.5 ULN
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with LDH ≥ 1.5 ULN received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-A < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Vascular Endothelial Growth Factor-A (VEGF-A) < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: VEGF-A < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-A < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-A ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-A ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: VEGF-A ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-A ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-C < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Vascular Endothelial Growth Factor-C (VEGF-C) < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: VEGF-C < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-C < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-C ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-C ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: VEGF-C ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-C ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-C/VEGF-A < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-C/VEGF-A < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples avialable.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-C/VEGF-A < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-C/VEGF-A ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-C/VEGF-A ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with VEGF-C/VEGF-A ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: sVEGFR-2 < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: sVEGFR-2 < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with sVEGFR-2 < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: sVEGFR-2 ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with sVEGFR-2 ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: sVEGFR-2 ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with sVEGFR-2 ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: sVEGFR-3 < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: sVEGFR-3 < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with sVEGFR-3 < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: sVEGFR-3 ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with sVEGFR-3 ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: sVEGFR-3 ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with sVEGFR-3 ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: IL-8 < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Interleukin-8 (IL-8) < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: IL-8 < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with IL-8 < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: IL-8 ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with IL-8 ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: IL-8 ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with IL-8 ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: Neuropilin < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Neuropilin < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: Neuropilin < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Neuropilin < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + MFOLFOX6: Neuropilin ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Neuropilin ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: Neuropilin ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with Neuropilin ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with serum samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-A RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-A Ribonucleic Acid (RNA) < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: VEGF-A RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-A RNA < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-A RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-A RNA ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: VEGF-A RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-A RNA ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-C RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-C RNA < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: VEGF-C RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-C RNA < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-C RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-C RNA ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: VEGF-C RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-C RNA ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-C/VEGF-A RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-C/VEGF-A RNA < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-C/VEGF-A < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-C/VEGF-A RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-C/VEGF-A RNA ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-C/VEGF-A RNA ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-D RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor Vascular Endothelial Growth Factor-D (VEGF-D) RNA < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: VEGF-D RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-D RNA < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: VEGF-D RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-D RNA ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: VEGF-D RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor VEGF-D RNA ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: PIGF RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor Placental Growth Factor (PIGF) RNA < median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: PIGF RNA < Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor PIGF RNA < median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Tivozanib + mFOLFOX6: PIGF RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor PIGF RNA ≥ median received 1.5 mg of tivozanib orally once daily beginning on day 1 of each cycle for 21 days followed by 7 days off treatment and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Subject analysis set title
    Bevacizumab + mFOLFOX: PIGF RNA ≥ Median
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with tumor PIGF RNA ≥ median received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on days 1 and 15 of each cycle and mFOLFOX6 every 2 weeks on days 1 and 15 of each treatment cycle. Analysis population as FAS with tumor biopsy RNA samples available.

    Primary: Investigator-assessed Progression-Free Survival (PFS)

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    End point title
    		 Investigator-assessed Progression-Free Survival (PFS)
    End point description
    The time from the date of randomization until objective tumor progression or death due to any cause. Objective tumor progression was determined through radiological imaging and based on the requirements of the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1): Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions or the appearance of one or more new lesions. Participants who did not progress or had not died at the time of the analysis were censored at the date of last tumor assessment where non-progression was documented. The analysis population is the Full Analysis Set (FAS), which included all randomized patients.
    End point type
    Primary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Number of subjects analysed
    177
    88
    Units: months
        median (confidence interval 95%)
    9.4 (8.5 to 10.1)
    10.7 (7.5 to 12.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    An interim futility analysis was planned to be performed when approximately 83 investigator-assessed PFS events (50% of the total PFS events) were observed. The Lans DeMets beta spending function with an O’Brien-Fleming boundary was used to derive the futility boundary. If the HR for PFS was greater than 1.0581, enrollment was to be stopped. With this futility stopping rule, the adjusted study power was 78.6%.
    Comparison groups
    Tivozanib + mFOLFOX6 v Bevacizumab + mFOLFOX6
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.706 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.693
         upper limit
    		 1.718
    Notes
    [1] - Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).

    Secondary: Progression-Free Survival (PFS) based on Independent Radiological Review (IRR)

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    End point title
    		 Progression-Free Survival (PFS) based on Independent Radiological Review (IRR)
    End point description
    The time from the date of randomization until the date of radiological disease progression assessed by the IRR or until death due to any cause, even in the absence of radiological progression.
    End point type
    Secondary
    End point timeframe
    3 Years
    End point values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: months
    Notes
    [2] - Due to the early termination of the study, this endpoint was was not assessed.
    [3] - Due to the early termination of the study, this endpoint was was not assessed.
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    The time from the date of randomization until the documented date of death. Participants still alive at the time of analysis were censored on the last day the participant was known to be alive. Overall Survival in months could not be estimated due to low number of events at the time of interim analysis, instead the number of participants who died is presented. The analysis population is the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Number of subjects analysed
    177
    88
    Units: participants
    26
    12
    Statistical analysis title
    		 Statistical Anlaysis 1
    Comparison groups
    Tivozanib + mFOLFOX6 v Bevacizumab + mFOLFOX6
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.754 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.116
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.561
         upper limit
    		 2.218
    Notes
    [4] - Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    The percentage of participants with a best overall response of complete response (CR) or partial response (PR) confirmed a minimum of four weeks apart based on RECIST 1.1 criteria. CR: Disappearance of all target and non-target lesions and no new lesions. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and no progression of non-target lesions and no new lesions, or, disappearance of all target lesions and persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits and no new lesions. The analysis population is the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Number of subjects analysed
    177
    88
    Units: percentage of participants
        number (not applicable)
    45.2
    43.2
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6 v Bevacizumab + mFOLFOX6
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.718 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    The time from the date of the first documented response of CR or PR (whichever is first recorded) to documented progression or death. If a participant did not progress or had not died at the time of analysis, the duration of response was censored at the date of last tumor assessment. Duration of response is only defined for participants whose best overall response was CR or PR. The analysis population is the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Number of subjects analysed
    80
    38
    Units: months
        median (confidence interval 95%)
    7.4 (5.6 to 11.3)
    9.3 (7.3 to 10.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6 v Bevacizumab + mFOLFOX6
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.437 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.389
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.604
         upper limit
    		 3.194
    Notes
    [6] - Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).

    Secondary: Time to Treatment Failure (TTF)

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    End point title
    		 Time to Treatment Failure (TTF)
    End point description
    The time from randomization to last dose date of tivozanib/bevacizumab. If a participant discontinued treatment for any reason, the participant was considered as an event. Participants remaining on treatment at the time of analysis were censored at date of last dose. The analysis population is the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Number of subjects analysed
    177
    88
    Units: months
        median (confidence interval 95%)
    5.5 (4.9 to 7.1)
    5.4 (3.7 to 6.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6 v Bevacizumab + mFOLFOX6
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.967 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.006
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.746
         upper limit
    		 1.358
    Notes
    [7] - Stratification factors were LDH status (< 1.5 x ULN or ≥ 1.5 x ULN), origin of cancer (rectal or colon) and number of metastatic sites (1 or ≥ 2).

    Secondary: Health Related Quality of life (HRQoL)

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    End point title
    		 Health Related Quality of life (HRQoL)
    End point description
    Defined as the time to deterioration in HRQoL measured by the CRC subscale of the FACT-C scale, change in score from baseline using the EQ-5D and FCSI (FACT Colorectal Symptom Index).
    End point type
    Secondary
    End point timeframe
    3 Years
    End point values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: scores in a scale
    Notes
    [8] - Due to the early termination of the study, this endpoint was not assessed.
    [9] - Due to the early termination of the study, this endpoint was not assessed.
    No statistical analyses for this end point

    Secondary: Safety as assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events

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    End point title
    		 Safety as assessed by Physical Examination, Vital Signs, Laboratory Assessments, 12-lead Electrocardiogram (ECGs), and Adverse Events
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a patient administered a study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a study drug, whether or not related to the study drug. An AE was considered “serious" (SAE) if it resulted in death; was life threatening; resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions; resulted in a congenital anomaly or birth defect; required inpatient hospitalization or led to prolongation of hospitalization. AEs, including abnormal clinical laboratory values, were to be graded using the National Cancer Institute Common Terminology Criteria for Grading Adverse Events (NCI-CTCAE) guidelines (v4.03).
    End point type
    Secondary
    End point timeframe
    From the first dose through 30 days after last dose of either tivozanib or bevacizumab, until the data cut-off date of 28 February 2014; median time of treatment was 168 days in the tivozanib arm and 162 days in the bevacizumab arm
    End point values
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Number of subjects analysed
    177
    87
    Units: participants
        Any AE
    177
    87
        CTCAE Grade ≥3 AE
    156
    76
        Any tivozanib (tivo)/bevacizumab (beva)-related AE
    158
    74
        Any mFOLFOX6-related AE
    169
    84
        Any tivo/beva and mFOLFOX6-related AE
    138
    59
        Any tivo/beva-related AE CTCAE Grade ≥3
    104
    31
        Any mFOLFOX6-related AE with CTCAE Grade ≥3
    126
    61
        Any tivo/beva & mFOLFOX6-related CTCAE Grade ≥3
    75
    23
        Any AE with an outcome of death
    8
    2
        Any tivo/beva-related AE w/ an outcome of death
    3
    2
        Any mFOLFOX6-related AE w/ an outcome of death
    3
    2
        Any tivo/beva & mFOLFOX6-related AE of death
    3
    2
        Any serious AE
    82
    42
        Any tivo/beva-related SAE
    38
    15
        Any mFOLFOX6-related SAE
    45
    23
        Any tivo/beva & mFOLFOX6-related SAE
    30
    11
        Any AE leading to tivo/beva discontinuation
    73
    30
        Any AE leading to tivo/beva interruption
    138
    63
        Any AE leading to tivo/beva reduction
    17
    0
    No statistical analyses for this end point

    Secondary: Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level

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    End point title
    		 Progression-free Survival Events by Lactate Dehydrogenase (LDH) Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum lactate dehydrogenase status.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: LDH < 1.5 ULN Bevacizumab + mFOLFOX6: LDH < 1.5 ULN Tivozanib + mFOLFOX6: LDH ≥ 1.5 ULN Bevacizumab + mFOLFOX6: LDH ≥ 1.5 ULN
    Number of subjects analysed
    127
    64
    50
    24
    Units: participants
    42
    16
    24
    13
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: LDH < 1.5 ULN v Bevacizumab + mFOLFOX6: LDH < 1.5 ULN
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.331
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.746
         upper limit
    		 2.375
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: LDH ≥ 1.5 ULN v Bevacizumab + mFOLFOX6: LDH ≥ 1.5 ULN
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.575
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.285
         upper limit
    		 1.16

    Secondary: Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level

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    End point title
    		 Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-A (VEGF-A) Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum vascular endothelial growth factor-A (VEGF-A) level. VEGF-A protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: VEGF-A < Median Bevacizumab + mFOLFOX: VEGF-A < Median Tivozanib + mFOLFOX6: VEGF-A ≥ Median Bevacizumab + mFOLFOX: VEGF-A ≥ Median
    Number of subjects analysed
    54
    29
    54
    26
    Units: participants
    20
    6
    24
    12
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-A < Median v Bevacizumab + mFOLFOX: VEGF-A < Median
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.608
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.635
         upper limit
    		 4.073
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-A ≥ Median v Bevacizumab + mFOLFOX: VEGF-A ≥ Median
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.755
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.375
         upper limit
    		 1.521

    Secondary: Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level

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    End point title
    		 Progression-free Survival Events by Serum Vascular Endothelial Growth Factor-C (VEGF-C) Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C level. VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: VEGF-C < Median Bevacizumab + mFOLFOX6: VEGF-C < Median Tivozanib + mFOLFOX6: VEGF-C ≥ Median Bevacizumab + mFOLFOX6: VEGF-C ≥ Median
    Number of subjects analysed
    52
    27
    56
    28
    Units: participants
    15
    8
    29
    10
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Bevacizumab + mFOLFOX6: VEGF-C < Median v Tivozanib + mFOLFOX6: VEGF-C < Median
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.877
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.366
         upper limit
    		 2.1
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-C ≥ Median v Bevacizumab + mFOLFOX6: VEGF-C ≥ Median
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.275
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.614
         upper limit
    		 2.646

    Secondary: Progression-free Survival Events by Serum VEGF-C/VEGF-A Ratio

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    End point title
    		 Progression-free Survival Events by Serum VEGF-C/VEGF-A Ratio
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum VEGF-C/VEGF-A ratio. VEGF-A and VEGF-C protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the ratio is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: VEGF-C/VEGF-A < Median Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A < Median Tivozanib + mFOLFOX6: VEGF-C/VEGF-A ≥ Median Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A ≥ Median
    Number of subjects analysed
    53
    26
    55
    29
    Units: participants
    21
    11
    23
    7
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-C/VEGF-A < Median v Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A < Median
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.721
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.345
         upper limit
    		 1.507
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-C/VEGF-A ≥ Median v Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A ≥ Median
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.597
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.672
         upper limit
    		 3.795

    Secondary: Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level

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    End point title
    		 Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-2 level. sVEGFR-2 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: sVEGFR-2 < Median Bevacizumab + mFOLFOX6: sVEGFR-2 < Median Tivozanib + mFOLFOX6: sVEGFR-2 ≥ Median Bevacizumab + mFOLFOX6: sVEGFR-2 ≥ Median
    Number of subjects analysed
    46
    27
    62
    28
    Units: participants
    15
    5
    29
    13
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: sVEGFR-2 < Median v Bevacizumab + mFOLFOX6: sVEGFR-2 < Median
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.627
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 4.564
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: sVEGFR-2 ≥ Median v Bevacizumab + mFOLFOX6: sVEGFR-2 ≥ Median
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.779
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.397
         upper limit
    		 1.531

    Secondary: Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level

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    End point title
    		 Progression-Free Survival Events by Soluble Vascular Endothelial Growth Factor Receptor-3 (sVEGFR-3) Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum sVEGFR-3 level. sVEGFR-3 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: sVEGFR-3 < Median Bevacizumab + mFOLFOX6: sVEGFR-3 < Median Tivozanib + mFOLFOX6: sVEGFR-3 ≥ Median Bevacizumab + mFOLFOX6: sVEGFR-3 ≥ Median
    Number of subjects analysed
    50
    30
    58
    25
    Units: participants
    14
    4
    30
    14
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: sVEGFR-3 < Median v Bevacizumab + mFOLFOX6: sVEGFR-3 < Median
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.946
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.636
         upper limit
    		 5.956
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: sVEGFR-3 ≥ Median v Bevacizumab + mFOLFOX6: sVEGFR-3 ≥ Median
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.806
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.422
         upper limit
    		 1.538

    Secondary: Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level

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    End point title
    		 Progression-Free Survival Events by Serum Interleukin-8 (IL-8) Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum interleukin-8 level. IL-8 protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: IL-8 < Median Bevacizumab + mFOLFOX6: IL-8 < Median Tivozanib + mFOLFOX6: IL-8 ≥ Median Bevacizumab + mFOLFOX6: IL-8 ≥ Median
    Number of subjects analysed
    53
    27
    55
    28
    Units: participants
    14
    7
    30
    11
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: IL-8 < Median v Bevacizumab + mFOLFOX6: IL-8 < Median
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.776
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.303
         upper limit
    		 1.991
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: IL-8 ≥ Median v Bevacizumab + mFOLFOX6: IL-8 ≥ Median
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.241
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.615
         upper limit
    		 2.501

    Secondary: Progression-Free Survival Events by Serum Neuropilin Level

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    End point title
    		 Progression-Free Survival Events by Serum Neuropilin Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline serum neuropilin level. Neuropilin protein levels were quantified using enzyme-liked immunosorbent assay (ELISA); the level of protein is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: Neuropilin < Median Bevacizumab + mFOLFOX6: Neuropilin < Median Tivozanib + MFOLFOX6: Neuropilin ≥ Median Bevacizumab + mFOLFOX6: Neuropilin ≥ Median
    Number of subjects analysed
    53
    30
    55
    25
    Units: participants
    10
    6
    34
    12
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: Neuropilin < Median v Bevacizumab + mFOLFOX6: Neuropilin < Median
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.343
         upper limit
    		 2.63
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + MFOLFOX6: Neuropilin ≥ Median v Bevacizumab + mFOLFOX6: Neuropilin ≥ Median
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.983
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.503
         upper limit
    		 1.918

    Secondary: Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level

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    End point title
    		 Progression-Free Survival Events by Tumor VEGF-A Ribonucleic Acid (RNA) Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-A RNA level. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: VEGF-A RNA < Median Bevacizumab + mFOLFOX: VEGF-A RNA < Median Tivozanib + mFOLFOX6: VEGF-A RNA ≥ Median Bevacizumab + mFOLFOX: VEGF-A RNA ≥ Median
    Number of subjects analysed
    40
    18
    38
    17
    Units: participants
    13
    7
    18
    5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-A RNA < Median v Bevacizumab + mFOLFOX: VEGF-A RNA < Median
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.226
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.468
         upper limit
    		 3.214
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-A RNA ≥ Median v Bevacizumab + mFOLFOX: VEGF-A RNA ≥ Median
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.232
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.447
         upper limit
    		 3.396

    Secondary: Progression-Free Survival Events by Tumor VEGF-C RNA Level

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    End point title
    		 Progression-Free Survival Events by Tumor VEGF-C RNA Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C RNA level. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: VEGF-C RNA < Median Bevacizumab + mFOLFOX: VEGF-C RNA < Median Tivozanib + mFOLFOX6: VEGF-C RNA ≥ Median Bevacizumab + mFOLFOX: VEGF-C RNA ≥ Median
    Number of subjects analysed
    41
    16
    37
    19
    Units: participants
    14
    6
    17
    6
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-C RNA < Median v Bevacizumab + mFOLFOX: VEGF-C RNA < Median
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.803
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.307
         upper limit
    		 2.1
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-C RNA ≥ Median v Bevacizumab + mFOLFOX: VEGF-C RNA ≥ Median
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.505
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.585
         upper limit
    		 3.873

    Secondary: Progression-Free Survival Events by Tumor VEGF-C/VEGF-A RNA Ratio

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    End point title
    		 Progression-Free Survival Events by Tumor VEGF-C/VEGF-A RNA Ratio
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-C/VEGF-A RNA ratio. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: VEGF-C/VEGF-A RNA < Median Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A RNA < Median Tivozanib + mFOLFOX6: VEGF-C/VEGF-A RNA ≥ Median Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A RNA ≥ Median
    Number of subjects analysed
    38
    16
    40
    19
    Units: participants
    16
    6
    15
    6
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-C/VEGF-A RNA < Median v Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A RNA < Median
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.921
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.356
         upper limit
    		 2.385
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-C/VEGF-A RNA ≥ Median v Bevacizumab + mFOLFOX6: VEGF-C/VEGF-A RNA ≥ Median
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.462
         upper limit
    		 3.22

    Secondary: Progression-Free Survival Events by Tumor VEGF-D RNA Level

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    End point title
    		 Progression-Free Survival Events by Tumor VEGF-D RNA Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor VEGF-D RNA level. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: VEGF-D RNA < Median Bevacizumab + mFOLFOX: VEGF-D RNA < Median Tivozanib + mFOLFOX6: VEGF-D RNA ≥ Median Bevacizumab + mFOLFOX: VEGF-D RNA ≥ Median
    Number of subjects analysed
    42
    14
    36
    21
    Units: participants
    16
    5
    15
    7
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-D RNA < Median v Bevacizumab + mFOLFOX: VEGF-D RNA < Median
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.915
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.334
         upper limit
    		 2.512
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: VEGF-D RNA ≥ Median v Bevacizumab + mFOLFOX: VEGF-D RNA ≥ Median
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.384
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.554
         upper limit
    		 3.455

    Secondary: Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level

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    End point title
    		 Progression-Free Survival Events by Tumor Placental Growth Factor (PIGF) RNA Level
    End point description
    The number of participants with a progression-free survival event (radiological progression assessed by the investigator or death due to any cause) reported by Baseline tumor PIGF RNA level. RNA was purified from biopsy tissue and measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Since low cycle threshold (CT) values reflect high RNA expression, the inverse of CT values were used to derive tumor categories. RNA level is expressed relative to the observed median level.
    End point type
    Secondary
    End point timeframe
    From randomization until the analysis cut-off date of 13 September 2013; median time on study drug was 167 days in the tivozanib group and 162 days in the bevacizumab group
    End point values
    		 Tivozanib + mFOLFOX6: PIGF RNA < Median Bevacizumab + mFOLFOX: PIGF RNA < Median Tivozanib + mFOLFOX6: PIGF RNA ≥ Median Bevacizumab + mFOLFOX: PIGF RNA ≥ Median
    Number of subjects analysed
    39
    17
    39
    18
    Units: participants
    14
    5
    17
    7
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Tivozanib + mFOLFOX6: PIGF RNA < Median v Bevacizumab + mFOLFOX: PIGF RNA < Median
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.538
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.548
         upper limit
    		 4.32
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Tivozanib + mFOLFOX6: PIGF RNA ≥ Median v Bevacizumab + mFOLFOX: PIGF RNA ≥ Median
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.744
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.299
         upper limit
    		 1.85

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug intake (tivozanib/bevacizumab) until 30 days after the last study drug intake, until the data cut-off date of 28 Feb 2014. The median duration of treatment was 168 days in the tivozanib arm and 162 days in the bevacizumab arm
    Adverse event reporting additional description
    The Safety Analysis Set (SAF) includes all patients who received 1 dose of drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Tivozanib + mFOLFOX6
    Reporting group description
    		 Participants received 1.5 mg of tivozanib orally once daily beginning on Day 1 of each cycle for 21 days followed by 7 days off treatment. Participants also received mFOLFOX6) chemotherapy every 2 weeks on Days 1 and 15 of each cycle.

    Reporting group title
    Bevacizumab + mFOLFOX6
    Reporting group description
    		 Participants received a dose of 5 mg/kg bevacizumab via intravenous infusion every 2 weeks on Days 1 and 15 of each cycle. Participants also received mFOLFOX6 chemotherapy every 2 weeks on Days 1 and 15 of each cycle.

    Serious adverse events
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    82 / 177 (46.33%)
    42 / 87 (48.28%)
         number of deaths (all causes)
    8
    2
         number of deaths resulting from adverse events
    3
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angiomyolipoma
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal neoplasm
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    4 / 177 (2.26%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Anorectal operation
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemotherapy
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Catheter site erythema
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration deterioration
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 177 (2.26%)
    7 / 87 (8.05%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent malfunction
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal fistula
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 177 (3.95%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart rate increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound necrosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve disease
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reversible posterior leukoencephalopathy syndrome
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 177 (2.82%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    5 / 177 (2.82%)
    4 / 87 (4.60%)
         occurrences causally related to treatment / all
    1 / 6
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 177 (3.95%)
    5 / 87 (5.75%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 177 (2.26%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nausea
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 177 (2.82%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Jaundice cholestatic
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 177 (1.13%)
    3 / 87 (3.45%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis viral
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perihepatic abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 177 (2.26%)
    4 / 87 (4.60%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tivozanib + mFOLFOX6 Bevacizumab + mFOLFOX6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    176 / 177 (99.44%)
    87 / 87 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    77 / 177 (43.50%)
    25 / 87 (28.74%)
         occurrences all number
    137
    39
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    37 / 177 (20.90%)
    17 / 87 (19.54%)
         occurrences all number
    77
    27
    Chest pain
         subjects affected / exposed
    2 / 177 (1.13%)
    5 / 87 (5.75%)
         occurrences all number
    2
    6
    Fatigue
         subjects affected / exposed
    95 / 177 (53.67%)
    45 / 87 (51.72%)
         occurrences all number
    221
    90
    Infusion related reaction
         subjects affected / exposed
    9 / 177 (5.08%)
    3 / 87 (3.45%)
         occurrences all number
    15
    3
    Mucosal inflammation
         subjects affected / exposed
    40 / 177 (22.60%)
    28 / 87 (32.18%)
         occurrences all number
    85
    50
    Oedema peripheral
         subjects affected / exposed
    14 / 177 (7.91%)
    6 / 87 (6.90%)
         occurrences all number
    15
    9
    Pain
         subjects affected / exposed
    5 / 177 (2.82%)
    5 / 87 (5.75%)
         occurrences all number
    6
    5
    Pyrexia
         subjects affected / exposed
    17 / 177 (9.60%)
    13 / 87 (14.94%)
         occurrences all number
    24
    16
    Temperature intolerance
         subjects affected / exposed
    11 / 177 (6.21%)
    9 / 87 (10.34%)
         occurrences all number
    16
    10
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 177 (1.69%)
    6 / 87 (6.90%)
         occurrences all number
    3
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 177 (11.30%)
    12 / 87 (13.79%)
         occurrences all number
    25
    16
    Dysphonia
         subjects affected / exposed
    42 / 177 (23.73%)
    13 / 87 (14.94%)
         occurrences all number
    59
    14
    Dyspnoea
         subjects affected / exposed
    26 / 177 (14.69%)
    13 / 87 (14.94%)
         occurrences all number
    28
    15
    Epistaxis
         subjects affected / exposed
    33 / 177 (18.64%)
    25 / 87 (28.74%)
         occurrences all number
    45
    30
    Hiccups
         subjects affected / exposed
    10 / 177 (5.65%)
    2 / 87 (2.30%)
         occurrences all number
    20
    5
    Oropharyngeal pain
         subjects affected / exposed
    16 / 177 (9.04%)
    6 / 87 (6.90%)
         occurrences all number
    18
    7
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 177 (4.52%)
    6 / 87 (6.90%)
         occurrences all number
    9
    9
    Insomnia
         subjects affected / exposed
    23 / 177 (12.99%)
    15 / 87 (17.24%)
         occurrences all number
    38
    41
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 177 (5.65%)
    3 / 87 (3.45%)
         occurrences all number
    16
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 177 (5.65%)
    4 / 87 (4.60%)
         occurrences all number
    14
    4
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    9 / 177 (5.08%)
    0 / 87 (0.00%)
         occurrences all number
    10
    0
    Neutrophil count decreased
         subjects affected / exposed
    14 / 177 (7.91%)
    8 / 87 (9.20%)
         occurrences all number
    23
    17
    Platelet count decreased
         subjects affected / exposed
    10 / 177 (5.65%)
    3 / 87 (3.45%)
         occurrences all number
    16
    7
    Weight decreased
         subjects affected / exposed
    34 / 177 (19.21%)
    7 / 87 (8.05%)
         occurrences all number
    45
    7
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 177 (0.56%)
    5 / 87 (5.75%)
         occurrences all number
    1
    5
    Dizziness
         subjects affected / exposed
    17 / 177 (9.60%)
    6 / 87 (6.90%)
         occurrences all number
    17
    6
    Dysaesthesia
         subjects affected / exposed
    12 / 177 (6.78%)
    5 / 87 (5.75%)
         occurrences all number
    39
    12
    Dysgeusia
         subjects affected / exposed
    26 / 177 (14.69%)
    18 / 87 (20.69%)
         occurrences all number
    33
    21
    Headache
         subjects affected / exposed
    28 / 177 (15.82%)
    12 / 87 (13.79%)
         occurrences all number
    42
    14
    Hypoaesthesia
         subjects affected / exposed
    5 / 177 (2.82%)
    5 / 87 (5.75%)
         occurrences all number
    10
    7
    Lethargy
         subjects affected / exposed
    11 / 177 (6.21%)
    3 / 87 (3.45%)
         occurrences all number
    30
    17
    Neuropathy peripheral
         subjects affected / exposed
    74 / 177 (41.81%)
    34 / 87 (39.08%)
         occurrences all number
    181
    87
    Neurotoxicity
         subjects affected / exposed
    10 / 177 (5.65%)
    3 / 87 (3.45%)
         occurrences all number
    21
    4
    Paraesthesia
         subjects affected / exposed
    46 / 177 (25.99%)
    20 / 87 (22.99%)
         occurrences all number
    108
    40
    Peripheral sensory neuropathy
         subjects affected / exposed
    21 / 177 (11.86%)
    13 / 87 (14.94%)
         occurrences all number
    45
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 177 (11.30%)
    9 / 87 (10.34%)
         occurrences all number
    30
    24
    Leukopenia
         subjects affected / exposed
    19 / 177 (10.73%)
    9 / 87 (10.34%)
         occurrences all number
    37
    18
    Neutropenia
         subjects affected / exposed
    93 / 177 (52.54%)
    36 / 87 (41.38%)
         occurrences all number
    254
    77
    Thrombocytopenia
         subjects affected / exposed
    54 / 177 (30.51%)
    13 / 87 (14.94%)
         occurrences all number
    256
    33
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 177 (1.69%)
    5 / 87 (5.75%)
         occurrences all number
    3
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    42 / 177 (23.73%)
    16 / 87 (18.39%)
         occurrences all number
    52
    25
    Abdominal pain upper
         subjects affected / exposed
    13 / 177 (7.34%)
    8 / 87 (9.20%)
         occurrences all number
    28
    9
    Aphthous stomatitis
         subjects affected / exposed
    9 / 177 (5.08%)
    1 / 87 (1.15%)
         occurrences all number
    22
    2
    Constipation
         subjects affected / exposed
    50 / 177 (28.25%)
    32 / 87 (36.78%)
         occurrences all number
    87
    49
    Diarrhoea
         subjects affected / exposed
    101 / 177 (57.06%)
    49 / 87 (56.32%)
         occurrences all number
    316
    101
    Dry mouth
         subjects affected / exposed
    9 / 177 (5.08%)
    2 / 87 (2.30%)
         occurrences all number
    10
    2
    Dyspepsia
         subjects affected / exposed
    23 / 177 (12.99%)
    9 / 87 (10.34%)
         occurrences all number
    37
    14
    Dysphagia
         subjects affected / exposed
    9 / 177 (5.08%)
    3 / 87 (3.45%)
         occurrences all number
    9
    3
    Flatulence
         subjects affected / exposed
    6 / 177 (3.39%)
    5 / 87 (5.75%)
         occurrences all number
    6
    5
    Nausea
         subjects affected / exposed
    97 / 177 (54.80%)
    47 / 87 (54.02%)
         occurrences all number
    234
    112
    Rectal haemorrhage
         subjects affected / exposed
    7 / 177 (3.95%)
    5 / 87 (5.75%)
         occurrences all number
    7
    5
    Stomatitis
         subjects affected / exposed
    36 / 177 (20.34%)
    14 / 87 (16.09%)
         occurrences all number
    51
    29
    Vomiting
         subjects affected / exposed
    59 / 177 (33.33%)
    24 / 87 (27.59%)
         occurrences all number
    107
    37
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 177 (10.17%)
    14 / 87 (16.09%)
         occurrences all number
    19
    14
    Hyperhidrosis
         subjects affected / exposed
    1 / 177 (0.56%)
    5 / 87 (5.75%)
         occurrences all number
    1
    6
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    34 / 177 (19.21%)
    7 / 87 (8.05%)
         occurrences all number
    58
    9
    Pruritus
         subjects affected / exposed
    7 / 177 (3.95%)
    7 / 87 (8.05%)
         occurrences all number
    7
    8
    Rash
         subjects affected / exposed
    16 / 177 (9.04%)
    4 / 87 (4.60%)
         occurrences all number
    29
    4
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    19 / 177 (10.73%)
    5 / 87 (5.75%)
         occurrences all number
    60
    10
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    25 / 177 (14.12%)
    1 / 87 (1.15%)
         occurrences all number
    28
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 177 (5.65%)
    5 / 87 (5.75%)
         occurrences all number
    14
    24
    Back pain
         subjects affected / exposed
    26 / 177 (14.69%)
    12 / 87 (13.79%)
         occurrences all number
    36
    16
    Muscle spasms
         subjects affected / exposed
    3 / 177 (1.69%)
    5 / 87 (5.75%)
         occurrences all number
    3
    7
    Myalgia
         subjects affected / exposed
    5 / 177 (2.82%)
    5 / 87 (5.75%)
         occurrences all number
    8
    6
    Neck pain
         subjects affected / exposed
    2 / 177 (1.13%)
    6 / 87 (6.90%)
         occurrences all number
    2
    7
    Pain in extremity
         subjects affected / exposed
    11 / 177 (6.21%)
    6 / 87 (6.90%)
         occurrences all number
    19
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 177 (4.52%)
    6 / 87 (6.90%)
         occurrences all number
    9
    7
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 177 (3.39%)
    5 / 87 (5.75%)
         occurrences all number
    6
    5
    Urinary tract infection
         subjects affected / exposed
    19 / 177 (10.73%)
    11 / 87 (12.64%)
         occurrences all number
    26
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    63 / 177 (35.59%)
    24 / 87 (27.59%)
         occurrences all number
    115
    37
    Dehydration
         subjects affected / exposed
    10 / 177 (5.65%)
    7 / 87 (8.05%)
         occurrences all number
    13
    10
    Hyperglycaemia
         subjects affected / exposed
    8 / 177 (4.52%)
    5 / 87 (5.75%)
         occurrences all number
    13
    6
    Hypokalaemia
         subjects affected / exposed
    20 / 177 (11.30%)
    13 / 87 (14.94%)
         occurrences all number
    25
    21
    Hypomagnesaemia
         subjects affected / exposed
    12 / 177 (6.78%)
    2 / 87 (2.30%)
         occurrences all number
    17
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2011
    The interim analysis for futility was added to allow for the early stopping of the study if clinical benefit was not observed. An adjustment to the study power due to the addition of the interim analysis was noted.
    01 Nov 2011
    The collection of a pharmacokinetic sample was added postdose on day 1 of cycle 1 and the postdose timing of pharmacokinetic sample collection was clarified to ensure pharmacokinetic samples were collected during the Cmax period and during steady state. A postdose electrocardiogram (ECG) on day 1 of cycle 1 and a second ECG on day 15 of cycle 2 were added based on regulatory agency feedback. A section and an appendix were added describing the monitoring of common serious adverse events (SAEs) that could be anticipated to occur in the study population. Text was added to describe the recommended imaging modalities for the performance of the study CT and MRI scans. Life expectancy of ≥ 3 months was removed from the inclusion criteria as it is subsumed within the performance status and overall health status criteria. Language was added in the introduction noting that when tivozanib is administered with the mFOLFOX6 regimen, the expectedness determination should take into account the labeling of each specific marketed drug.
    07 Feb 2012
    The exclusion criterion for absolute neutrophil count (ANC) was revised from < 1500/mm^3 to < 2000/mm^3 based on regulatory agency feedback and to align with oxaliplatin product labeling. The exclusion criterion for the number of weeks required between major surgery and the first dose of study medication was reduced to align with bevacizumab product labeling. The description of the screening physical examination was revised to include a neurologic and dental examination, and a neurologic examination was specified as part of the directed physical examination on day 1 of each treatment cycle. The revisions were made based on regulatory agency feedback and to align with bevacizumab and oxaliplatin product labeling. The risks associated with treatment of bevacizumab and intravenous bisphosphonates were more clearly specified based regulatory agency feedback and to align with bevacizumab product labeling. In assessing central nervous system (CNS) symptoms in the context of dose reductions, text was added to clarify that a brain MRI should be performed to confirm the diagnosis if reversible posterior leukoencephalopathy syndrome (RPLS) was suspected. The revision was made based on regulatory agency feedback and to align with bevacizumab and oxaliplatin product labeling. Language was added to allow for randomization to occur up to 72 hours prior to the first dose of study drug due to logistics in obtaining components of the mFOLFOX6 chemotherapy backbone and/or bevacizumab. The criteria for starting the next cycle was revised with a lower platelet count to better reflect local practice and additional retreatment criteria relating to RPLS and proteinuria were added to align with bevacizumab and oxaliplatin product labeling.
    04 Sep 2012
    An analysis of PFS at 6 months comparing the 2 treatment arms was added due to toxicities associated with the mFOLFOX6 component of treatment with patients discontinuing the use of 1 or all components of the therapy after 6 months of use. The text relating to OS was revised to note patients could be contacted by site staff to collect long-term survival data to support key analyses. The decision criteria relating to the initiation of a phase 3 study was added to the sample size discussion for further transparency. The discontinuation criteria were revised to allow patients who became a candidate for surgical resection while on the study to resume study treatment after discussion with the Medical Monitor. The inclusion criteria for target lesions were clarified to note that for patients who had received prior radiotherapy, a target lesion could only be counted if it had progressed since the radiotherapy. The inclusion criteria for women and men of childbearing potential were updated to reduce the risk of pregnancy during the study. Language was added to clarify the actions needed for potential discontinuations from study treatment due to dose interruptions and to remind investigators of tivozanib’s long half-life when determining subsequent therapy. Language was added to clarify other investigational drugs were prohibited during the study and to add agents that affect gastric pH to the list of prohibited concomitant medications as these agents may affect absorption of tivozanib.
    17 Oct 2012
    The appendix listing events that were to always be considered as serious events was removed as this related to an internal activity that the Sponsor would perform based on the events reported. The definition of postmenopausal and the use of effective birth control in sexually active patients were clarified.
    05 Sep 2013
    Language was added to provide clarification for continuing treatment with study treatment as randomized if enrollment was completed prior to the interim analysis for futility. Necrotizing fasciitis was added to the criteria for the discontinuation of bevacizumab to align with updated bevacizumab product labeling. Language was added to provide clarification concerning the investigators’ reporting obligations relating to events that the Sponsor classified as always serious. Given the potential for the censoring of patients for PFS events due to patients having discontinued treatment without radiographic evidence of progression, a modified definition of PFS was introduced for the determination of the timing of the final data analysis. The text for the analysis of TTF was corrected to indicate TTF was to be censored at the date of last dose of study drug. Language was added to clarify that a systematic process would be utilized for identifying and summarizing protocol deviations. A brief section was added to ensure the end of trial was clearly defined in accordance with relevant regulations and guidelines.
    03 Mar 2014
    The study was terminated due to the results of the interim futility analysis. As such, only those patients who continued to derive benefit from the treatment remained on study drug until 1 of the discontinuation criteria were met. Closure of the study was initiated on 21 Feb 2014 via a letter to the investigators and the protocol was updated to reflect the study termination. Patients who, in the opinion of the investigator and in consultation with the Sponsor’s Medical Monitor, were continuing to derive benefit were allowed to continue to receive study treatment as randomized. The requirement for patients to follow the tumor assessment schedule if they discontinued treatment without radiological evidence of progression was removed. The requirement for patients to be followed for survival following the end-of-treatment visit was also removed. Termination language was added to clarify that only those patients who continued to derive benefit from the treatment were to remain on study. The discontinuation criteria were updated to indicate that all patients in the posttreatment tumor assessment and survival follow-up periods were to be discontinued from the study. The schedule of assessments was updated, including the clarification that HRQoL questionnaires need not be completed. Language was added to clarify that vital signs assessments, laboratory evaluations (hematology chemistry and urinalysis) and physical examinations should follow the local standard of care for patients who remained on study. The safety profile obtained from the interim futility analysis was reviewed and the risk/benefit text was updated to reflect this review.

    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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