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    Clinical Trial Results:
    A Phase 3, Randomized, Controlled Study of Cabozantinib (XL184) vs Everolimus in Subjects with Metastatic Renal Cell Carcinoma that has Progressed after Prior VEGFR Tyrosine Kinase Inhibitor Therapy

    Summary
    EudraCT number
    		 2013-001010-14
    Trial protocol
    		 HU   AT   SE   BE   CZ   PT   IE   IT   NL   SK   GB   ES   DE   DK   FR   FI   PL  
    Global end of trial date
    19 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2022
    First version publication date
    25 Apr 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    XL184-308
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01865747
    WHO universal trial number (UTN)
    		 U1111-1144-7394
    Sponsors
    Sponsor organisation name
    Exelixis, Inc.
    Sponsor organisation address
    1851 Harbor Bay Parkway, Alameda, United States, 94502
    Public contact
    Exelixis Medical Affairs, Exelixis, Inc., +1 8883935494, druginfo@exelixis.com
    Scientific contact
    Exelixis Medical Affairs, Exelixis, Inc., +1 8883935494, druginfo@exelixis.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
    22 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to evaluate the effect of cabozantinib compared with everolimus on progression-free survival (PFS) and overall survival (OS) in subjects with advanced renal cell cancer that has progressed after prior VEGFR tyrosine kinase inhibitor therapy.
    Protection of trial subjects
    Study protocol, informed consent form, and other study documents reviewed and approved by ethics committees and regulatory agencies, as required. All subjects signing informed consent prior to study related procedures (including screening assessments), and throughout the study as new information became available. An IDMC was established to review safety data on an ongoing basis and make recommendations to the Sponsor if deemed warranted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Denmark: 20
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    France: 57
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    United States: 200
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Australia: 49
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Chile: 12
    Worldwide total number of subjects
    658
    EEA total number of subjects
    275
    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)
    394
    From 65 to 84 years
    263
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening evaluations were completed within 28 days prior to randomization to determine eligibility of subjects.

    Period 1
    Period 1 title
    Treatment 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
    		 Cabozantinib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cabozantinib administered once daily

    Arm title
    		 Everolimus
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus administered orally once daily

    Number of subjects in period 1
    		Cabozantinib Everolimus
    Started
    330
    328
    Completed
    330
    328

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cabozantinib
    Reporting group description
    		 -

    Reporting group title
    Everolimus
    Reporting group description
    		 -

    Reporting group values
    		 Cabozantinib Everolimus Total
    Number of subjects
    		 330 328 658
    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)
    		 196 198 394
        From 65-84 years
    		 133 130 263
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 62.5 (32 to 86) 62.0 (31 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 77 86 163
        Male
    		 253 241 494
        Missing (not recorded)
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Cabozantinib
    Reporting group description
    		 -

    Reporting group title
    Everolimus
    Reporting group description
    		 -

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    End point type
    Primary
    End point timeframe
    assessed until 247 PFS events were observed in the first 375 randomized subjects
    End point values
    		 Cabozantinib Everolimus
    Number of subjects analysed
    187
    188
    Units: months
        median (confidence interval 95%)
    7.4 (3.7 to 13.5)
    3.8 (3.7 to 5.4)
    Statistical analysis title
    		 PFS analysis
    Comparison groups
    Cabozantinib v Everolimus
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.76

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at a pre-specified secondary interim analysis (320 deaths observed)
    End point values
    		 Cabozantinib Everolimus
    Number of subjects analysed
    330
    328
    Units: months
        median (confidence interval 95%)
    21.4 (18.7 to 21.4)
    16.5 (7.5 to 16.5)
    Statistical analysis title
    		 OS analysis
    Comparison groups
    Cabozantinib v Everolimus
    Number of subjects included in analysis
    658
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.83

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Analyzed at the time of the PFS analysis, in all subjects
    End point values
    		 Cabozantinib Everolimus
    Number of subjects analysed
    330
    328
    Units: percentage of patients
    17
    3
    Statistical analysis title
    		 ORR Analysis
    Comparison groups
    Cabozantinib v Everolimus
    Number of subjects included in analysis
    658
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    reported through the primary PFS analysis
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Cabozantinib
    Reporting group description
    		 -

    Reporting group title
    Everolimus
    Reporting group description
    		 -

    Serious adverse events
    		 Cabozantinib Everolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    131 / 331 (39.58%)
    139 / 322 (43.17%)
         number of deaths (all causes)
    15
    23
         number of deaths resulting from adverse events
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to bone
         subjects affected / exposed
    2 / 331 (0.60%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 331 (0.30%)
    5 / 322 (1.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    2 / 331 (0.60%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    4 / 331 (1.21%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 331 (1.21%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    6 / 331 (1.81%)
    5 / 322 (1.55%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 331 (1.21%)
    6 / 322 (1.86%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Generalised oedema
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    local swelling
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (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
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multi-organ failure
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    5 / 331 (1.51%)
    4 / 322 (1.24%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
         subjects affected / exposed
    3 / 331 (0.91%)
    4 / 322 (1.24%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 331 (1.81%)
    13 / 322 (4.04%)
         occurrences causally related to treatment / all
    0 / 6
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 331 (0.00%)
    3 / 322 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    10 / 331 (3.02%)
    6 / 322 (1.86%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 331 (0.00%)
    3 / 322 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 331 (0.00%)
    8 / 322 (2.48%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    4 / 331 (1.21%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 331 (1.81%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 331 (0.60%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Decreased appetite
         subjects affected / exposed
    2 / 331 (0.60%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 331 (0.91%)
    7 / 322 (2.17%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    4 / 331 (1.21%)
    4 / 322 (1.24%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 331 (0.60%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    4 / 331 (1.21%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 331 (1.21%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 331 (0.30%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 331 (0.60%)
    3 / 322 (0.93%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    convulsion
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 331 (0.60%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 331 (0.30%)
    4 / 322 (1.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Abdominal lymphadenopathy
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (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
    6 / 331 (1.81%)
    12 / 322 (3.73%)
         occurrences causally related to treatment / all
    2 / 6
    7 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhagic anaemia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 331 (3.02%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    3 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 331 (2.11%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    6 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    7 / 331 (2.11%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal pain
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 331 (0.60%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestine obstruction
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    small intestine perforation
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swollen tongue
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 331 (1.81%)
    4 / 322 (1.24%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct obstruction
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 331 (0.30%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure acute
         subjects affected / exposed
    0 / 331 (0.00%)
    5 / 322 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 331 (1.81%)
    4 / 322 (1.24%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 331 (0.30%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchitis
         subjects affected / exposed
    1 / 331 (0.30%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 331 (0.30%)
    3 / 322 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung infection
         subjects affected / exposed
    2 / 331 (0.60%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 331 (1.81%)
    13 / 322 (4.04%)
         occurrences causally related to treatment / all
    0 / 6
    2 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 331 (0.30%)
    3 / 322 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fall
         subjects affected / exposed
    3 / 331 (0.91%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    2 / 331 (0.60%)
    0 / 322 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 322 (0.31%)
         occurrences causally related to treatment / all
    0 / 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
    		 Cabozantinib Everolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    328 / 331 (99.09%)
    270 / 322 (83.85%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    53 / 331 (16.01%)
    19 / 322 (5.90%)
         occurrences all number
    53
    19
    Aspartate aminotransferase increased
         subjects affected / exposed
    58 / 331 (17.52%)
    18 / 322 (5.59%)
         occurrences all number
    58
    18
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    23 / 331 (6.95%)
    3 / 322 (0.93%)
         occurrences all number
    23
    3
    Weight decreased
         subjects affected / exposed
    104 / 331 (31.42%)
    39 / 322 (12.11%)
         occurrences all number
    104
    39
    Vascular disorders
    Hypertension
         subjects affected / exposed
    122 / 331 (36.86%)
    23 / 322 (7.14%)
         occurrences all number
    122
    23
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    78 / 331 (23.56%)
    30 / 322 (9.32%)
         occurrences all number
    78
    30
    General disorders and administration site conditions
    fatigue
         subjects affected / exposed
    185 / 331 (55.89%)
    149 / 322 (46.27%)
         occurrences all number
    185
    149
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    50 / 331 (15.11%)
    30 / 322 (9.32%)
         occurrences all number
    50
    30
    Abdominal pain upper
         subjects affected / exposed
    26 / 331 (7.85%)
    7 / 322 (2.17%)
         occurrences all number
    26
    7
    Constipation
         subjects affected / exposed
    83 / 331 (25.08%)
    61 / 322 (18.94%)
         occurrences all number
    83
    61
    Diarrhoea
         subjects affected / exposed
    245 / 331 (74.02%)
    88 / 322 (27.33%)
         occurrences all number
    245
    88
    Dyspepsia
         subjects affected / exposed
    40 / 331 (12.08%)
    15 / 322 (4.66%)
         occurrences all number
    40
    15
    Flatulence
         subjects affected / exposed
    32 / 331 (9.67%)
    6 / 322 (1.86%)
         occurrences all number
    32
    6
    Nausea
         subjects affected / exposed
    164 / 331 (49.55%)
    89 / 322 (27.64%)
         occurrences all number
    164
    89
    Vomiting
         subjects affected / exposed
    105 / 331 (31.72%)
    44 / 322 (13.66%)
         occurrences all number
    105
    44
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    66 / 331 (19.94%)
    12 / 322 (3.73%)
         occurrences all number
    66
    12
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    139 / 331 (41.99%)
    19 / 322 (5.90%)
         occurrences all number
    139
    19
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    68 / 331 (20.54%)
    2 / 322 (0.62%)
         occurrences all number
    68
    2
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    42 / 331 (12.69%)
    16 / 322 (4.97%)
         occurrences all number
    42
    16
    Pain in extremity
         subjects affected / exposed
    46 / 331 (13.90%)
    25 / 322 (7.76%)
         occurrences all number
    46
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    152 / 331 (45.92%)
    108 / 322 (33.54%)
         occurrences all number
    152
    108
    Hypomagnesaemia
         subjects affected / exposed
    50 / 331 (15.11%)
    5 / 322 (1.55%)
         occurrences all number
    50
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Apr 2014
    The amendment added details around study assessments and procedures after the study objectives were completed. Additional clarifications were added.

    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.
    Presentation of SAEs limited to those observed >2 subjects across arms. Efficacy results: based on initial statistical analyses that may differ from product labeling. Upper limits of confidence intervals not reached shown as median values.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26406150
    http://www.ncbi.nlm.nih.gov/pubmed/27279544
    For support, Contact us.
    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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