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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blind, Placebo-Controlled, 2-Arm, Multi-Center Study Comparing Tivozanib Hydrochloride In Combination With Paclitaxel Versus Placebo In Combination With Paclitaxel in the Treatment of Subjects With Locally Recurrent and/or Metastatic Triple Negative Breast Cancer

    Summary
    EudraCT number
    		 2012-003507-35
    Trial protocol
    		 IT   ES  
    Global end of trial date
    13 Apr 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    AV-951-12-204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01745367
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aveo Pharmaceuticals, Inc.
    Sponsor organisation address
    30 Winter Street, Boston, United States, MA 02108
    Public contact
    Chief Medical Officer, AVEO Pharmaceuticals, Inc, 857 400-0101, clinical@aveooncology.com
    Scientific contact
    Chief Medical Officer, AVEO Pharmaceuticals, Inc, 857 400-0101, clinical@aveooncology.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare progression free survival (PFS) of subjects treated with tivozanib hydrochloride in combination with paclitaxel vs subjects treated with placebo in combination with paclitaxel.
    Protection of trial subjects
    Prior to the initiation of the study at each study center, the clinical study protocol, subject information sheet, informed consent form (ICF), and all other relevant study documentation were submitted to and approved by the responsible national Independent Ethics Committee (IEC) / Institutional Review Board (IRB).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Bahamas: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Ukraine: 7
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 1
    Country: Number of subjects enrolled
    Australia: 2
    Worldwide total number of subjects
    30
    EEA total number of subjects
    0
    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)
    24
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants who met all the inclusion and none of the exclusion criteria were enrolled.

    Pre-assignment
    Screening details
    		 Subjects attended a screening visit maximum of 4 weeks before receiving their first dose. All participants underwent inclusion exclusion criteria assessment and all eligible participants signed the informed consent before undergoing any study-related procedures.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo in Combination With Paclitaxel
    Arm description
    		 Participants received placebo orally once daily with 90 mg/m^2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching AV-951
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 1.5 mg placebo orally once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle of tivozanib hydrochloride or placebo was defined as 4 weeks.

    Arm title
    		 Tivozanib Hydrochloride in Combination With Paclitaxel
    Arm description
    		 Participants received 1.5 mg tivozanib hydrochloride orally once daily with 90 mg/m^2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tivozanib hydrochloride (AV-951)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 1.5 mg tivozanib hydrochloride orally once daily beginning on Day 1 for 3 weeks followed by 1 week off treatment. One cycle of tivozanib hydrochloride or placebo was defined as 4 weeks.

    Number of subjects in period 1
    		Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Started
    8
    22
    Treated
    8
    21
    Completed
    0
    0
    Not completed
    8
    22
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    1
    2
         Termination of The Study by The Sponsor
    6
    18
         Other Reasons Unspecified
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo in Combination With Paclitaxel
    Reporting group description
    		 Participants received placebo orally once daily with 90 mg/m^2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment.

    Reporting group title
    Tivozanib Hydrochloride in Combination With Paclitaxel
    Reporting group description
    		 Participants received 1.5 mg tivozanib hydrochloride orally once daily with 90 mg/m^2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment.

    Reporting group values
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel Total
    Number of subjects
    		 8 22 30
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 4 20 24
        From 65-84 years
    		 4 2 6
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 8 22 30
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 8 14 22
        Black
    		 0 5 5
        Asian
    		 0 2 2
        Dominican
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo in Combination With Paclitaxel
    Reporting group description
    		 Participants received placebo orally once daily with 90 mg/m^2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment.

    Reporting group title
    Tivozanib Hydrochloride in Combination With Paclitaxel
    Reporting group description
    		 Participants received 1.5 mg tivozanib hydrochloride orally once daily with 90 mg/m^2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment.

    Primary: Comparison of Progression-free Survival (PFS) of Subjects

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    End point title
    		 Comparison of Progression-free Survival (PFS) of Subjects [1]
    End point description
    PFS is defined as the time from randomization to progressive disease (PD) or death. The PFS comparison was to be performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
    End point type
    Primary
    End point timeframe
    approximately 24 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    End point values
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Subjects
        number (not applicable)
    Notes
    [2] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    [3] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Comparison of Objective Response Rate (ORR) and Duration of Response (DoR) of Subjects

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    End point title
    		 Comparison of Objective Response Rate (ORR) and Duration of Response (DoR) of Subjects
    End point description
    ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. DoR is defined as the length of time that a tumor continues to respond to treatment without the cancer growing or spreading. The ORR and DoR comparison was to be performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
    End point type
    Secondary
    End point timeframe
    approximately 24 months
    End point values
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Subjects
        number (not applicable)
    Notes
    [4] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    [5] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Comparison of Overall Survival (OS) of Subjects

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    End point title
    		 Comparison of Overall Survival (OS) of Subjects
    End point description
    OS measures how long subjects, who undergo a certain treatment regimen, live compared to subjects who are in a control group (i.e., taking either another drug or an inactive treatment, known as a placebo). OS comparison was to be performed for subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
    End point type
    Secondary
    End point timeframe
    approximately 24 months
    End point values
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Subjects
        number (not applicable)
    Notes
    [6] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    [7] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Safety and Tolerability of Tivozanib Hydrochloride in Combination With Paclitaxel vs Placebo in Combination With Paclitaxel

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    End point title
    		 Safety and Tolerability of Tivozanib Hydrochloride in Combination With Paclitaxel vs Placebo in Combination With Paclitaxel
    End point description
    Number of subjects with serious and non-serious adverse events. Descriptive statistical analyses were to be performed for a limited set of data (disposition, demographics, and adverse events).
    End point type
    Secondary
    End point timeframe
    approximately 24 months
    End point values
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Number of subjects analysed
    8
    21
    Units: Subjects
        Subjects with serious adverse events
    1
    1
        Subjects with non-serious adverse events
    8
    19
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) of Tivozanib Hydrochloride and Paclitaxel When Administered in Combination

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    End point title
    		 Pharmacokinetics (PK) of Tivozanib Hydrochloride and Paclitaxel When Administered in Combination
    End point description
    PK is defined as the study of the bodily absorption, distribution, metabolism, and excretion of drugs.
    End point type
    Secondary
    End point timeframe
    approximately 24 months
    End point values
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: not applicable
        number (not applicable)
    Notes
    [8] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    [9] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Identification of Hypoxia Gene Signature

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    End point title
    		 Identification of Hypoxia Gene Signature
    End point description
    Evaluation of hypoxia gene signature as a predictive biomarker of tivozanib hydrochloride response and establish the optimal cut-off to identify biomarker positive and negative subgroups. The genes comprising the hypoxia gene signature was to be analyzed in tumor tissue from subjects.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1: Pre-dose and 2, 4 and 24 hours post dose; Cycle 1, Day 8: Predose; Cycle 1, Day 21: Pre-dose and 2, 4, 24, 48, and 96 hours post dose; Cycle 2 (Day 1): Pre-dose
    End point values
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Subjects
        number (not applicable)
    Notes
    [10] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    [11] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Secondary: Measurement of Subjects' Quality of Life (QoL)

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    End point title
    		 Measurement of Subjects' Quality of Life (QoL)
    End point description
    The Functional Assessment of Cancer Therapy-Breast (FACT-B) and Euro Quality of Life - 5 Dimensions (EQ-5D) questionnaires was used throughout the study to measure subjects' health-related QoL.
    End point type
    Secondary
    End point timeframe
    approximately 24 months
    End point values
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: score on a scale
        number (not applicable)
    Notes
    [12] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    [13] - The study was terminated prior to complete enrollment; due to low enrollment, no data was collected.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    14 months
    Adverse event reporting additional description
    Serious treatment-emergent adverse events and treatment emergent adverse events in Safety Population was reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo in Combination With Paclitaxel
    Reporting group description
    		 Participants received placebo orally once daily with 90 mg/m^2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment.

    Reporting group title
    Tivozanib Hydrochloride in Combination With Paclitaxel
    Reporting group description
    		 Participants received 1.5 mg tivozanib hydrochloride orally once daily with 90 mg/m^2 of paclitaxel administered intravenously beginning on Day 1 for 3 weeks followed by 1 week off treatment.

    Serious adverse events
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain cancer metastatic
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (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
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo in Combination With Paclitaxel Tivozanib Hydrochloride in Combination With Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    19 / 21 (90.48%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastasis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 21 (33.33%)
         occurrences all number
    0
    8
    Poor venous access
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    4 / 8 (50.00%)
    11 / 21 (52.38%)
         occurrences all number
    6
    15
    Oedema peripheral
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    9 / 21 (42.86%)
         occurrences all number
    0
    9
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3
    Epistaxis
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    6
    Rhinitis allergic
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    Lipase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Liver function test abnormal
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    6
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         occurrences all number
    2
    9
    Platelet count increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Laceration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    Dysgeusia
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 21 (19.05%)
         occurrences all number
    1
    8
    Hypoaesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    Neuropathy peripheral
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 21 (23.81%)
         occurrences all number
    1
    6
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 21 (19.05%)
         occurrences all number
    3
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 8 (37.50%)
    5 / 21 (23.81%)
         occurrences all number
    11
    5
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    8
    Neutropenia
         subjects affected / exposed
    2 / 8 (25.00%)
    8 / 21 (38.10%)
         occurrences all number
    3
    17
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Constipation
         subjects affected / exposed
    3 / 8 (37.50%)
    6 / 21 (28.57%)
         occurrences all number
    5
    6
    Dyspepsia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    Nausea
         subjects affected / exposed
    4 / 8 (50.00%)
    9 / 21 (42.86%)
         occurrences all number
    6
    12
    Oral pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    4
    Stomatitis
         subjects affected / exposed
    1 / 8 (12.50%)
    6 / 21 (28.57%)
         occurrences all number
    1
    7
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 21 (23.81%)
         occurrences all number
    1
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 8 (50.00%)
    7 / 21 (33.33%)
         occurrences all number
    5
    12
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Pruritis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Pruritis Generalized
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 21 (19.05%)
         occurrences all number
    1
    6
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Haematuria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 21 (14.29%)
         occurrences all number
    4
    3
    Back Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Muscular weakness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         occurrences all number
    1
    4
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Rash pustular
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    Sinusitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 21 (14.29%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 21 (23.81%)
         occurrences all number
    2
    7
    Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    Hypomagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2013
    1. Section 5.1, Introduction, Background; Section 5.6 Previous human experience with tivozanib hydrochloride: text in this section was modified to include additional data on other vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors in second line setting. Information regarding rationale for study design was also updated. Pharmacokinetics in subjects with solid tumors section was updated to include more recent data. Order of sections was rearranged. 2. Section 5.7.3, Potential Risks/Benefits of Tivozanib Hydrochloride: Section number has changed from 5.7.4 to 5.7.3. The following text was removed: Tivozanib hydrochloride should not be administered to pregnant women, as it is known that angiogenesis plays an important role in reproductions and embryonic development. It is required that women of childbearing potential undergo a pregnancy test before treatment and must use adequate contraceptive measures while on study and for at least 30 days after the last dose of study drug. 3. Section 6.2, Secondary Objectives: The following objective was removed- to evaluate QoL. 4. Section 8.2, Subject Exclusion Criteria: New exclusion criteria #2 was added as follows: 2. Subjects who have received any prior treatment with any investigational or licensed drug that targets VEGF, VEGFR or the VEGF pathway. 5. Section 8.3, Concomitant Medications and Procedures During the Study Treatment: The following prohibited medication was added: Steroid therapy equivalent to prednisone >10 mg/day and Denosumab is allowed for the prevention of skeletal-related events in subjects with bone metastases.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    29 Jan 2014
    The Sponsor terminated Study AV-951-12-204 before enrollment was completed after determining that enrollment of subjects was much lower than expected, and that timely completion of the study was not feasible.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The Sponsor terminated Study AV-951-12-204 before enrollment was completed after determining that enrollment of subjects was much lower than expected, and that timely completion of the study was not feasible.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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