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    Clinical Trial Results:
    Regorafenib Assessment in Refractory advanced Colorectal cancer

    Summary
    EudraCT number
    		 2012-005655-16
    Trial protocol
    		 BE  
    Global end of trial date
    26 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Sep 2021
    First version publication date
    19 Sep 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Regard-CrC_2012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01929616
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut Jules Bordet
    Sponsor organisation address
    rue Héger Bordet 1, Brussels, Belgium, 1000
    Public contact
    Hendlisz, Dr Alain, 0032 25413196, alain.hendlisz@bordet.be
    Scientific contact
    Alain Hendlisz, Institut Jules Bordet, 32 25413196, alain.hendlisz@bordet.be
    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
    17 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    As a primary objective : - To identify in a population of patients bearing advanced, refractory colorectal cancers, those who draw no benefit from treatment with regorafenib. As secondary objectives : - To analyse PFS and response rate (RR) in relationship with the same covariates as for OS - To assess regorafenib efficacy (OS, PFS, RR) and safety profile in this study population. - To assess the Disease control rate (DCR = Complete response [CR] + partial response [PR] + stable disease [SD]) -To compare the relative benefit (OS, PFS) of regorafenib according to history of treatment with bevacizumab. - To validate the relationship that was found, in a previous study (the SoMore) conducted in the same patients population treated with Sorafenib, between overall survival and early metabolic homogeneous response (all lesions responding, yes or no)
    Protection of trial subjects
    Some of the eligibility criteria that the subjects had to meet to be entered in the trial were chosen in order to minimize the risk of severe adverse events. In addition, the protocol planned rules for treatment modifications in case of the occurrence of specific adverse events. All subjects were free to withdraw from the clinical trial at any time for any reason given and the study was conducted in agreement with the declaration of Helsinki. It was controlled that the patients received before inclusion in the trial all standard medications that could be of benefit for them.
    Background therapy
    		 Regorafenib (BAY 73-4506) is a novel oral diphenylurea-based multikinase inhibitor with both a distinct profile of biochemical kinase inhibition and distinct pharmacological characteristics. Preclinical studies have shown that regorafenib is a potent inhibitor of several angiogenic and stromal receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor (VEGFR)-1, -2, -3, platelet-derived growth factor receptor (PDGFR)-β, fibroblast growth factor receptor (FGFR)-1 , and TIE2. In addition, regorafenib inhibits various oncogenic receptor tyrosine kinases (RTKs) (c-KIT and RET) and intracellular signalling kinases (cRAF/RAF-1, BRAF, and B-RAF V600E mutant).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Aug 2013
    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
    Belgium: 141
    Worldwide total number of subjects
    141
    EEA total number of subjects
    141
    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)
    62
    From 65 to 84 years
    79
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 There were 141 subjects registered between 06/08/2013 and 29/10/2014. 138 subjects were eligible to receive regorafenib. 136 subjects completed the trial and 2 subjects did not complete the trial.

    Pre-assignment
    Screening details
    		 During the conduct of the study, the strategy was changed for the timing of the baseline PET: first, it was not required to have it done at the time of registration and afterwards, it was required (as the result of this PET impacts on the eligibility status).

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

    Arms
    Arm title
    		 Regorafenib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Regorafenib was administered every day orally at a dose of 160 mg, 3 weeks/4 (where a cycle was defined by a 28 day-period).

    Number of subjects in period 1
    		Regorafenib
    Started
    141
    Completed
    136
    Not completed
    5
         Not eligible
    3
         Lost to follow-up
    1
         Subject never treated
    1

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 141 141
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 62 62
        From 65-84 years
    		 79 79
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 66 (31 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 59 59
        Male
    		 82 82
    ECOG performance status
    Units: Subjects
        Score 0
    		 66 66
        Score 1
    		 72 72
        Ineligible
    		 3 3
    KRas status
    Units: Subjects
        Wild
    		 63 63
        Mutated
    		 74 74
        Missing
    		 1 1
        Ineligible
    		 3 3
    Delay from diagnosis
    Units: months
        median (full range (min-max))
    		 -
    Delay from last chemotherapy
    Units: weeks
        median (full range (min-max))
    		 -
    Subject analysis sets

    Subject analysis set title
    Eligible patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who satisfied all the eligibility criteria including measurable metabolic lesions seen on the baseline PET

    Subject analysis set title
    Evaluable patients
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects that underwent second PET (day 14)

    Subject analysis set title
    Metabolic responder
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who responded to treatment based on the second PET

    Subject analysis set title
    Metabolic non-responder
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who did not respond to treatment based on the second PET

    Subject analysis sets values
    		 Eligible patients Evaluable patients Metabolic responder Metabolic non-responder
    Number of subjects
    138
    113
    69
    44
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    67 (31 to 84)
    67 (31 to 83)
    Gender categorical
    Units: Subjects
        Female
    58
    44
        Male
    80
    69
    ECOG performance status
    Units: Subjects
        Score 0
    66
    58
        Score 1
    72
    55
        Ineligible
    0
    0
    KRas status
    Units: Subjects
        Wild
    63
    50
        Mutated
    74
    62
        Missing
    1
    1
        Ineligible
    0
    0
    Delay from diagnosis
    Units: months
        median (full range (min-max))
    40 (2 to 155)
    40 (2 to 155)
    Delay from last chemotherapy
    Units: weeks
        median (full range (min-max))
    6 (3 to 54)
    6 (3 to 54)

    End points

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

    Subject analysis set title
    Eligible patients
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients who satisfied all the eligibility criteria including measurable metabolic lesions seen on the baseline PET

    Subject analysis set title
    Evaluable patients
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects that underwent second PET (day 14)

    Subject analysis set title
    Metabolic responder
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who responded to treatment based on the second PET

    Subject analysis set title
    Metabolic non-responder
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who did not respond to treatment based on the second PET

    Primary: Overall survival from second PET

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    End point title
    		 Overall survival from second PET
    End point description
    End point type
    Primary
    End point timeframe
    From subject's second PET until death or drop out
    End point values
    		 Evaluable patients Metabolic responder Metabolic non-responder
    Number of subjects analysed
    113
    69
    44
    Units: Time from second PET to death (months)
        median (confidence interval 95%)
    6.7 (5.4 to 8.8)
    7.5 (5.0 to 10.1)
    5.4 (2.9 to 6.5)
    Attachments
    		 Untitled (Filename: Overall Survival by Metabolic Response.docx)
    Statistical analysis title
    		 Overall Survival by metabolic response
    Statistical analysis description
    Comparison of Overall Survival between metabolic responders and non-responders
    Comparison groups
    Metabolic non-responder v Metabolic responder
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.04

    Secondary: Overall survival from the time of registration

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    End point title
    		 Overall survival from the time of registration
    End point description
    End point type
    Secondary
    End point timeframe
    Time from subject's registration until death or drop out
    End point values
    		 Eligible patients
    Number of subjects analysed
    138
    Units: Time from registration to death (months)
        median (confidence interval 95%)
    6.3 (4.4 to 7.1)
    No statistical analyses for this end point

    Secondary: Progression free survival from the time of registration

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    End point title
    		 Progression free survival from the time of registration
    End point description
    End point type
    Secondary
    End point timeframe
    Time from registration until progression, death or drop out
    End point values
    		 Eligible patients
    Number of subjects analysed
    138
    Units: Time from regr to progression (months)
        median (confidence interval 95%)
    2.1 (1.8 to 3.3)
    No statistical analyses for this end point

    Secondary: Progression free survival from second PET

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    End point title
    		 Progression free survival from second PET
    End point description
    End point type
    Secondary
    End point timeframe
    Time from second PET to disease progression, death or drop out
    End point values
    		 Evaluable patients Metabolic responder Metabolic non-responder
    Number of subjects analysed
    113
    69
    44
    Units: Time to progression (months)
    median (confidence interval 95%)
        Metabolic response
    2.1 (1.3 to 3.0)
    3.1 (1.4 to 4.3)
    1.3 (1.1 to 2.2)
    Statistical analysis title
    		 PFS from second PET by metabolic response
    Statistical analysis description
    Comparison of time to progression from second PET between metabolic responders and non-responders
    Comparison groups
    Metabolic responder v Metabolic non-responder
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.94

    Secondary: One year overall survival rate from the time of registration

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    End point title
    		 One year overall survival rate from the time of registration
    End point description
    Percent of patients who were still alive at one year after the time of registration
    End point type
    Secondary
    End point timeframe
    Time from registration to time of death or drop out
    End point values
    		 Eligible patients
    Number of subjects analysed
    138
    Units: Percent of patients
        number (confidence interval 95%)
    24.8 (17.3 to 32.3)
    No statistical analyses for this end point

    Secondary: One year overall survival rate from the time of second PET

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    End point title
    		 One year overall survival rate from the time of second PET
    End point description
    Percent of patients who were still alive at one year after second PET
    End point type
    Secondary
    End point timeframe
    Time of patient's registration until death or drop out
    End point values
    		 Evaluable patients Metabolic responder Metabolic non-responder
    Number of subjects analysed
    113
    69
    44
    Units: Percent of patients
        number (confidence interval 95%)
    27.4 (18.9 to 35.9)
    32.8 (21.6 to 44.0)
    14.2 (3.4 to 25.0)
    No statistical analyses for this end point

    Secondary: Six-month PFS rate from the time of registration

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    End point title
    		 Six-month PFS rate from the time of registration
    End point description
    Percent of patients without progression disease or death six months after the time of registration
    End point type
    Secondary
    End point timeframe
    Time of patients' registration to time of death or drop out
    End point values
    		 Eligible patients
    Number of subjects analysed
    138
    Units: Percent of patients
        number (confidence interval 95%)
    12.4 (7.4 to 19.2)
    No statistical analyses for this end point

    Secondary: Six-month PFS rate from the second PET

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    End point title
    		 Six-month PFS rate from the second PET
    End point description
    Percent of patients without disease progression or death at six month after the second PET
    End point type
    Secondary
    End point timeframe
    Time of patients' second PET to progression or death
    End point values
    		 Evaluable patients Metabolic responder Metabolic non-responder
    Number of subjects analysed
    113
    69
    44
    Units: Percent of patients
        number (confidence interval 95%)
    13.3 (6.9 to 19.7)
    14.5 (6.0 to 23.0)
    11.4 (1.8 to 21.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from ICF signature until 28 days after the last administration of regorafenib. After this period, only SAEs which have a reasonable possibility to be related to regorafenib.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Safety analysis
    Reporting group description
    		 -

    Serious adverse events
    		 Safety analysis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 137 (30.66%)
         number of deaths (all causes)
    6
         number of deaths resulting from adverse events
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 4
    Mucosal inflammation
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 137 (4.38%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radicular pain
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 137 (2.92%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety analysis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 137 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Haemorrhage
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Hypertension
         subjects affected / exposed
    44 / 137 (32.12%)
         occurrences all number
    69
    Hypotension
         subjects affected / exposed
    5 / 137 (3.65%)
         occurrences all number
    5
    Pallor
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Peripheral coldness
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Phlebitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 137 (5.11%)
         occurrences all number
    8
    Chest pain
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Chills
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    106 / 137 (77.37%)
         occurrences all number
    119
    General physical health deterioration
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Hypothermia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Influenza like illness
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Mucosal inflammation
         subjects affected / exposed
    8 / 137 (5.84%)
         occurrences all number
    15
    Oedema
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    4
    Oedema peripheral
         subjects affected / exposed
    14 / 137 (10.22%)
         occurrences all number
    14
    Pain
         subjects affected / exposed
    6 / 137 (4.38%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    27 / 137 (19.71%)
         occurrences all number
    31
    Secretion discharge
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Thirst
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Genital tract inflammation
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    2
    Pelvic pain
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Prostatitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Scrotal oedema
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    13 / 137 (9.49%)
         occurrences all number
    17
    Dysphonia
         subjects affected / exposed
    31 / 137 (22.63%)
         occurrences all number
    33
    Dyspnoea
         subjects affected / exposed
    25 / 137 (18.25%)
         occurrences all number
    28
    Dyspnoea exertional
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    3
    Epistaxis
         subjects affected / exposed
    4 / 137 (2.92%)
         occurrences all number
    4
    Haemoptysis
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Hiccups
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Lung disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Nasal dryness
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Oropharyngeal discomfort
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Pneumonitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    15 / 137 (10.95%)
         occurrences all number
    15
    Confusional state
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Depression
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    9 / 137 (6.57%)
         occurrences all number
    9
    Personality change
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Blood bilirubin increased
         subjects affected / exposed
    5 / 137 (3.65%)
         occurrences all number
    5
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Blood iron decreased
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    2
    Blood pressure orthostatic decreased
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    4 / 137 (2.92%)
         occurrences all number
    4
    International normalised ratio increased
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Liver function test abnormal
         subjects affected / exposed
    7 / 137 (5.11%)
         occurrences all number
    7
    Thyroxine increased
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    17 / 137 (12.41%)
         occurrences all number
    17
    Hyperglycaemia
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Humerus fracture
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Stoma complication
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    2
    Stoma site irritation
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Cyanosis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Intracardiac mass
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 137 (4.38%)
         occurrences all number
    6
    Dysaesthesia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Dysgeusia
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    14 / 137 (10.22%)
         occurrences all number
    20
    Language disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Motor dysfunction
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Nervous system disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Paraesthesia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    14 / 137 (10.22%)
         occurrences all number
    16
    Sciatica
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Spinal cord compression
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 137 (11.68%)
         occurrences all number
    21
    Haemolysis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Thrombocytopenia
         subjects affected / exposed
    8 / 137 (5.84%)
         occurrences all number
    10
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Dry eye
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Eye disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Eyelid oedema
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    25 / 137 (18.25%)
         occurrences all number
    28
    Abdominal pain upper
         subjects affected / exposed
    15 / 137 (10.95%)
         occurrences all number
    19
    Anal incontinence
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Anal inflammation
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Ascites
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Colonic fistula
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    24 / 137 (17.52%)
         occurrences all number
    25
    Diarrhoea
         subjects affected / exposed
    56 / 137 (40.88%)
         occurrences all number
    92
    Dry mouth
         subjects affected / exposed
    7 / 137 (5.11%)
         occurrences all number
    7
    Dyspepsia
         subjects affected / exposed
    4 / 137 (2.92%)
         occurrences all number
    5
    Dysphagia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Enteritis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Gastrointestinal pain
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Glossitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Intestinal dilatation
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    25 / 137 (18.25%)
         occurrences all number
    29
    Oesophagitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Periodontal disease
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Proctalgia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    4
    Rectal haemorrhage
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    44 / 137 (32.12%)
         occurrences all number
    58
    Toothache
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Varices oesophageal
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    15 / 137 (10.95%)
         occurrences all number
    19
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Hepatic failure
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Hepatomegaly
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Jaundice
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Liver disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Portal hypertension
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 137 (5.84%)
         occurrences all number
    8
    Blister
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Dermatitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    8 / 137 (5.84%)
         occurrences all number
    8
    Eczema
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    4 / 137 (2.92%)
         occurrences all number
    4
    Hyperhidrosis
         subjects affected / exposed
    4 / 137 (2.92%)
         occurrences all number
    4
    Onycholysis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Pain of skin
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    63 / 137 (45.99%)
         occurrences all number
    88
    Petechiae
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    21 / 137 (15.33%)
         occurrences all number
    23
    Skin exfoliation
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Skin induration
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Skin reaction
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Skin ulcer
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Xeroderma
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Haematoma
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Bladder disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Haematuria
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Hydronephrosis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Polyuria
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Proteinuria
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Renal failure
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Vesical fistula
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Hypothyroidism
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 137 (4.38%)
         occurrences all number
    7
    Back pain
         subjects affected / exposed
    19 / 137 (13.87%)
         occurrences all number
    19
    Bone pain
         subjects affected / exposed
    4 / 137 (2.92%)
         occurrences all number
    6
    Flank pain
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    2
    Joint swelling
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Muscle fatigue
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    10 / 137 (7.30%)
         occurrences all number
    11
    Muscle twitching
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Muscular weakness
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Musculoskeletal pain
         subjects affected / exposed
    7 / 137 (5.11%)
         occurrences all number
    7
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Neck pain
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Osteoarthritis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    8 / 137 (5.84%)
         occurrences all number
    8
    Tendonitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Torticollis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    6 / 137 (4.38%)
         occurrences all number
    8
    Candida infection
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Cystitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Furuncle
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Gastrointestinal fungal infection
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Gingivitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    2
    Herpes infection
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Lung infection
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    3
    Mucosal infection
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Oral fungal infection
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Oral herpes
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Paronychia
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    2
    Respiratory tract infection
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Tooth abscess
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 137 (1.46%)
         occurrences all number
    2
    Urinary tract infection
         subjects affected / exposed
    8 / 137 (5.84%)
         occurrences all number
    8
    Viral skin infection
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Cell death
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Decreased appetite
         subjects affected / exposed
    74 / 137 (54.01%)
         occurrences all number
    81
    Dehydration
         subjects affected / exposed
    4 / 137 (2.92%)
         occurrences all number
    4
    Folate deficiency
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Hyperammonaemia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    2
    Hypocalcaemia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    3
    Hypomagnesaemia
         subjects affected / exposed
    3 / 137 (2.19%)
         occurrences all number
    4
    Hypophosphataemia
         subjects affected / exposed
    17 / 137 (12.41%)
         occurrences all number
    22
    Hypovitaminosis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1
    Iron deficiency
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Aug 2013
    Making the initial frozen biopsy optional (because of the bias risk of limiting the study for patients bearing liver metastasis only due to many contraindications and limitations for biopsies outside the liver) along with making mandatory the collection of previously obtained tumoral tissue material (frozen of FFPE). Making other minor changes in the protocol wording and contact details Changing the ICF in order to reflect the changes of making initial frozen biopsy optional Adding secondary objective to validate the relationship that was found, in a previous study (the SoMore study) conducted in the same patients population treated with Sorafenib, between overall survival and early metabolic homogeneous response (all lesions responding, yes or no).
    15 Jan 2014
    Modifications in the inclusion criteria The clarification on Imaging Time Point o Subjects should have been on Regorafenib at least 4 days priortheir second PET scan. o Latest time point for the second PET scan is 21 calendar days after the start of treatment Study call to patients by Research Nurse at J10 instead of J8. This will allow to reduce the dose and not to interrupt it. Translational : Research Recommended to collect the tissue block. In the event that the tissue block cannot be provided, slides (20-25 slides of approximately 5up) will suffice. Precision about the estimated sample: between 124 and 140 patients will be accrued. It will be eventually adapted according to the observed drop out rate, in order to reach the number of 105 evaluable patients.
    10 Apr 2014
    Modifications in the inclusion criteria : -Precision of previsous use for the oxaliplatin - Bilirubin ( in order to reflect Gilbert’s syndrome) - P-ALK level New exclusion criterion Safety : modifications in the report procedure Precision for the FDG PET-CT
    05 Aug 2014
    Making the initial biopsies mandatory Changing the ICF in order to reflect the changes of making initial frozen biopsy mandatory New inclusion criteria ( related to the biopsy) New exclusion criteria ( related to the biopsy) Addition of tumour markers CEA and CA19 9 in the protocol and in the CRF (Case Report Form)
    18 Sep 2014
    Modification in the inclusion criterion # 9 o Clarification on the collection of tissue New exclusion criteria o Venous thrombosis o Proteinuria Update in the concomitant medication section Modification for the blood pressure monitoring Precision on the liver function test Precisions on statistical points

    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.
    Non-randomized nature forbides any differentiation between the prognostic and the predictive value of biomarkers limited information of progressive disease for patients with “clinically-only” progressive disease without radiological demonstration
    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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