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    Clinical Trial Results:
    A randomised phase II Trial of carboplatin and gemcitabine +/- vandetanib in first line treatment Of advanced Urothelial cell Cancer in patients who are not suitable to receive cisplatin

    Summary
    EudraCT number
    		 2009-010140-33
    Trial protocol
    		 GB  
    Global end of trial date
    05 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Aug 2017
    First version publication date
    23 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPON672-09
    Additional study identifiers
    ISRCTN number
    		 ISRCTN68146831
    US NCT number
    		 NCT01191892
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cardiff University
    Sponsor organisation address
    30-36 Newport Road, Cardiff, United Kingdom, CF24 0DE
    Public contact
    Tracie Madden, Wales Cancer Trials Unit, 0044 02920687953, MaddenTA1@cf.ac.uk
    Scientific contact
    Tracie Madden, Wales Cancer Trials Unit, 0044 02920687953, MaddenTA1@cf.ac.uk
    Sponsor organisation name
    Cardiff University
    Sponsor organisation address
    7th Floor, McKenzie House, Cardiff University, Cardiff, United Kingdom, CF14 4YS
    Public contact
    Tracie-Ann Madden, Centre for Trials Research, +44 2920687953, MaddenTA1@cardiff.ac.uk
    Scientific contact
    Tracie-Ann Madden, Centre for Trials Research, +44 2920687953, MaddenTA1@cardiff.ac.uk
    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
    27 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to assess whether the addition of vandetanib to standard carboplatin/gemcitabine cancer chemotherapy improves the clinical outcome for participants with advanced cancer of the urinary system (urothelial cancer).
    Protection of trial subjects
    Toxicity data were reviewed by the IDMC after 20 and 40 patients had been randomised. This was to ensure patients receiving vandetanib were not experiencing excessive toxicity early on compared those on placebo.
    Background therapy
    		 Patients received up to 6 cycles of carboplatin (AUC=4.5 using Calvert formula) IV over 30 minutes on day 1 and gemcitabine (1000mg/m^2) IV over 30 minutes days 1 and 8 of a 21 day cycle.
    Evidence for comparator
    		 N/A - A placebo tablet was used as the comparator.
    Actual start date of recruitment
    20 Jul 2010
    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
    United Kingdom: 82
    Worldwide total number of subjects
    82
    EEA total number of subjects
    82
    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)
    15
    From 65 to 84 years
    65
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 21 sites were opened between June 2010 and April 2013, and of these, 16 UK sites recruited at least one or more participants. 82 patients were recruited and randomised, during the recruitment period from July 2010 to December 2014.

    Pre-assignment
    Screening details
    		 The patient’s written informed consent was obtained. The patient’s medical history was reviewed against the participant eligibility criteria. Physical examination, including ECOG performance status, a 12 lead ECG with measurement of QTc, and blood pressure were performed. 212 patients were screened.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Patients were allocated treatment through a central interactive web response system. The packaging and tablets appeared identical for both active and matching placebo treatments. The label attached to each package of blinded study material had a unique treatment kit number that was linked to the randomisation scheme. Upon randomisation, a label number was provided, and the package with a matching label number was dispensed to the patient.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    Other name
    Zactima, Caprelsa
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 100mg oral tablet once a day to be taken by mouth until 21 days after the last dose of carboplatin.

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One oral tablet once a day to be taken by mouth until 21 days after the last dose of carboplatin.

    Number of subjects in period 1
    		Experimental Control
    Started
    40
    42
    Completed
    8
    17
    Not completed
    32
    25
         death
    2
    1
         Adverse event, non-fatal
    22
    14
         disease progression
    3
    7
         Patient choice
    3
    1
         Other unknown reason
    2
    2

    Baseline characteristics

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

    Reporting group title
    Control
    Reporting group description
    		 -

    Reporting group values
    		 Experimental Control Total
    Number of subjects
    		 40 42 82
    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)
    		 9 6 15
        From 65-84 years
    		 31 34 65
        85 years and over
    		 0 2 2
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 73.5 (65.5 to 77) 73.5 (67 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 8 7 15
        Male
    		 32 35 67
    Location of primary disease
    Units: Subjects
        Bladder
    		 28 34 62
        Other
    		 12 8 20

    End points

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

    Reporting group title
    Control
    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
    The time in months from randomisation until disease progression or death.
    End point values
    		 Experimental Control
    Number of subjects analysed
    40
    42
    Units: months
        median (confidence interval 95%)
    6.8 (4.6 to 8.5)
    8.8 (5.7 to 9)
    Attachments
    		 Progression free survival
    Statistical analysis title
    		 One-sided log rank test
    Comparison groups
    Experimental v Control
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.71
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Months from randomisation until death
    End point values
    		 Experimental Control
    Number of subjects analysed
    40
    42
    Units: months
        median (confidence interval 95%)
    10.8 (8 to 13)
    13.8 (11.1 to 16.6)
    Attachments
    		 Overall survival
    Statistical analysis title
    		 Overall survival
    Comparison groups
    Experimental v Control
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.416

    Secondary: Objective response

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    End point title
    		 Objective response
    End point description
    Best disease response, measured at each RECIST assessment of CT scans.
    End point type
    Secondary
    End point timeframe
    Best response seen during treatment and follow-up.
    End point values
    		 Experimental Control
    Number of subjects analysed
    40
    42
    Units: subjects
        Complete Response
    2
    2
        Partial response
    18
    21
        Stable disease
    10
    12
        Progressive disease
    2
    3
    No statistical analyses for this end point

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    The number of patients reporting complete response or partial response as their best response.
    End point type
    Secondary
    End point timeframe
    During treatment and follow-up.
    End point values
    		 Experimental Control
    Number of subjects analysed
    40
    42
    Units: subjects
    20
    23
    No statistical analyses for this end point

    Secondary: Waterfall plot

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    End point title
    		 Waterfall plot
    End point description
    Change of size of measurable lesions 9 weeks after start of chemotherapy (using Waterfall plots).
    End point type
    Secondary
    End point timeframe
    Between start of chemotherapy (baseline CT scan) and 9 weeks after the start of chemotherapy (9 week CT scan).
    End point values
    		 Experimental Control
    Number of subjects analysed
    30 [1]
    34 [2]
    Units: mm
        arithmetic mean (standard deviation)
    -0.373 ( 0.32 )
    -0.277 ( 0.29 )
    Attachments
    		 Waterfall plot
    Notes
    [1] - 30 patients had RECIST data at 9 weeks.
    [2] - 34 patients had RECIST data at 9 weeks.
    No statistical analyses for this end point

    Other pre-specified: Per protocol Progression-free survival

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    End point title
    		 Per protocol Progression-free survival
    End point description
    End point type
    Other pre-specified
    End point timeframe
    The time in months from randomisation until disease progression or death.
    End point values
    		 Experimental Control
    Number of subjects analysed
    33 [3]
    37 [4]
    Units: months
        median (confidence interval 95%)
    6.8 (5.1 to 8.5)
    8.3 (5.7 to 9)
    Notes
    [3] - Per protocol population. Patients confirmed to be eligible who started trial treatment.
    [4] - Per protocol population. Patients confirmed to be eligible who started trial treatment.
    Statistical analysis title
    		 Progression-free survival
    Comparison groups
    Experimental v Control
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.268

    Other pre-specified: Per protocol overall survival

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    End point title
    		 Per protocol overall survival
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Months from randomisation until death
    End point values
    		 Experimental Control
    Number of subjects analysed
    33 [5]
    37 [6]
    Units: months
        median (confidence interval 95%)
    10.5 (8 to 13)
    15.8 (15.8 to 17.9)
    Notes
    [5] - Per protocol population. Patients confirmed to be eligible who started trial treatment.
    [6] - Per protocol population. Patients confirmed to be eligible who started trial treatment.
    Statistical analysis title
    		 Overall survival
    Comparison groups
    Control v Experimental
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 2.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.431

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation until data lock
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Experimental
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Serious adverse events
    		 Experimental Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 40 (70.00%)
    22 / 42 (52.38%)
         number of deaths (all causes)
    24
    24
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    Arterial ischemia
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain - ischemic
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial swelling and redness
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Edema limbs
    Additional description: swollen right leg
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions - Other, symptom control
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspergillus pneumonia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest infection
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusion
    Additional description: confusion due to hydronephrosis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Creatinine increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    7 / 40 (17.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    8 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
    Additional description: hydronephrosis (urostomy tube inserted)
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (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
    Collapse
    Additional description: Syncope
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bleed
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Photosensitivity
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute renal failure
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other, viral infection
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Experimental Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 40 (90.00%)
    41 / 42 (97.62%)
    Investigations
    Alkaline phosphatase increased
         subjects affected / exposed
    9 / 40 (22.50%)
    9 / 42 (21.43%)
         occurrences all number
    17
    15
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 40 (32.50%)
    12 / 42 (28.57%)
         occurrences all number
    33
    34
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 40 (15.00%)
    5 / 42 (11.90%)
         occurrences all number
    11
    7
    Blood bilirubin increased
         subjects affected / exposed
    3 / 40 (7.50%)
    4 / 42 (9.52%)
         occurrences all number
    10
    6
    Lymphocyte count decreased
         subjects affected / exposed
    18 / 40 (45.00%)
    12 / 42 (28.57%)
         occurrences all number
    49
    31
    Platelet count decreased
         subjects affected / exposed
    23 / 40 (57.50%)
    19 / 42 (45.24%)
         occurrences all number
    55
    49
    Weight loss
         subjects affected / exposed
    5 / 40 (12.50%)
    6 / 42 (14.29%)
         occurrences all number
    10
    9
    White blood cell count decreased
         subjects affected / exposed
    19 / 40 (47.50%)
    21 / 42 (50.00%)
         occurrences all number
    49
    53
    Creatinine increased
         subjects affected / exposed
    6 / 40 (15.00%)
    7 / 42 (16.67%)
         occurrences all number
    27
    13
    Neutrophil count decreased
         subjects affected / exposed
    16 / 40 (40.00%)
    15 / 42 (35.71%)
         occurrences all number
    27
    25
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 40 (15.00%)
    6 / 42 (14.29%)
         occurrences all number
    11
    13
    Nervous system disorders
    Insomnia
         subjects affected / exposed
    6 / 40 (15.00%)
    3 / 42 (7.14%)
         occurrences all number
    11
    8
    Dizziness
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 42 (9.52%)
         occurrences all number
    5
    5
    Dysgeusia
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    Paraesthesia
         subjects affected / exposed
    3 / 40 (7.50%)
    3 / 42 (7.14%)
         occurrences all number
    6
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 40 (65.00%)
    25 / 42 (59.52%)
         occurrences all number
    76
    96
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    24 / 40 (60.00%)
    30 / 42 (71.43%)
         occurrences all number
    73
    59
    Oedema limbs
         subjects affected / exposed
    3 / 40 (7.50%)
    7 / 42 (16.67%)
         occurrences all number
    6
    23
    Fever
         subjects affected / exposed
    3 / 40 (7.50%)
    5 / 42 (11.90%)
         occurrences all number
    3
    6
    Pain
         subjects affected / exposed
    14 / 40 (35.00%)
    14 / 42 (33.33%)
         occurrences all number
    52
    37
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 40 (12.50%)
    9 / 42 (21.43%)
         occurrences all number
    14
    14
    Constipation
         subjects affected / exposed
    6 / 40 (15.00%)
    11 / 42 (26.19%)
         occurrences all number
    17
    17
    Diarrhoea
         subjects affected / exposed
    15 / 40 (37.50%)
    10 / 42 (23.81%)
         occurrences all number
    20
    18
    Nausea
         subjects affected / exposed
    14 / 40 (35.00%)
    12 / 42 (28.57%)
         occurrences all number
    32
    22
    Vomiting
         subjects affected / exposed
    7 / 40 (17.50%)
    13 / 42 (30.95%)
         occurrences all number
    10
    21
    Dyspepsia
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 42 (4.76%)
         occurrences all number
    5
    3
    Mucositis oral
         subjects affected / exposed
    7 / 40 (17.50%)
    7 / 42 (16.67%)
         occurrences all number
    10
    9
    Respiratory, thoracic and mediastinal disorders
    Lung infection
         subjects affected / exposed
    5 / 40 (12.50%)
    3 / 42 (7.14%)
         occurrences all number
    8
    4
    Cough
         subjects affected / exposed
    10 / 40 (25.00%)
    4 / 42 (9.52%)
         occurrences all number
    15
    8
    Dyspnoea
         subjects affected / exposed
    11 / 40 (27.50%)
    7 / 42 (16.67%)
         occurrences all number
    28
    11
    Epistaxis
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 42 (4.76%)
         occurrences all number
    6
    2
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    6 / 40 (15.00%)
    0 / 42 (0.00%)
         occurrences all number
    11
    0
    Pruritus
         subjects affected / exposed
    3 / 40 (7.50%)
    4 / 42 (9.52%)
         occurrences all number
    6
    6
    Rash
         subjects affected / exposed
    19 / 40 (47.50%)
    11 / 42 (26.19%)
         occurrences all number
    57
    16
    Alopecia
         subjects affected / exposed
    3 / 40 (7.50%)
    5 / 42 (11.90%)
         occurrences all number
    3
    8
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    7 / 40 (17.50%)
    1 / 42 (2.38%)
         occurrences all number
    13
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    6 / 40 (15.00%)
    4 / 42 (9.52%)
         occurrences all number
    16
    7
    Haematuria
         subjects affected / exposed
    10 / 40 (25.00%)
    8 / 42 (19.05%)
         occurrences all number
    17
    20
    Urinary tract infection
         subjects affected / exposed
    6 / 40 (15.00%)
    4 / 42 (9.52%)
         occurrences all number
    14
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 40 (12.50%)
    2 / 42 (4.76%)
         occurrences all number
    13
    3
    Infections and infestations
    Skin infection
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 42 (9.52%)
         occurrences all number
    1
    4
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    11 / 40 (27.50%)
    8 / 42 (19.05%)
         occurrences all number
    20
    14
    Hypokalaemia
         subjects affected / exposed
    7 / 40 (17.50%)
    2 / 42 (4.76%)
         occurrences all number
    11
    2
    Hypomagnesaemia
         subjects affected / exposed
    8 / 40 (20.00%)
    8 / 42 (19.05%)
         occurrences all number
    19
    22
    Hypophosphataemia
         subjects affected / exposed
    9 / 40 (22.50%)
    3 / 42 (7.14%)
         occurrences all number
    18
    5
    Dehydration
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 42 (7.14%)
         occurrences all number
    3
    4
    Hyperglycaemia
         subjects affected / exposed
    2 / 40 (5.00%)
    4 / 42 (9.52%)
         occurrences all number
    2
    6
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 42 (4.76%)
         occurrences all number
    4
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2010
    Change of PI at Southampton General Hospital: Dr Ben Mead replaced by Dr Simon Crabb Addition of new Principal Investigator/research sites: Kent and Canterbury Hospital, Canterbury – Dr Natasha Mithal William Harvey Hospital, Ashford – Dr Natasha Mithal Queen Elizabeth The Queen Mother Hospital, Margate – Dr Natasha Mithal Charing Cross Hospital, London – Dr Simon Stewart Hammersmith Hospital, London – Dr Simon Stewart; Royal Lancashire Infirmary, Lancaster – Dr Alison Birtle Churchill Hospital, Headington – Dr Andrew Protheroe Royal Bournemouth Hospital, Bournemouth – Dr Tom Geldart
    16 Aug 2010
    Change of PI: Royal Bournemouth Hospital, Bournemouth – Dr Tom Geldart replaced by Dr Sue Brock Addition of new site and PI: Castle Hill Hospital, Cottingham – Dr Mohammed Butt
    21 Mar 2013
    To add a new site: The Clatterbridge Cancer Centre NHS Foundation Trust –Syed Hussain To close an existing site: Edinburgh Cancer Centre Western General Hospital –Duncan McLaren Amendment of trial documentation as follows: 1. Protocol V1.2 dated 20.10.2012 superseded by V2.0 dated 08 March 2013 (update of trial assessments, concomitant medications, adverse events, safety reports, and withdrawal levels) 2. GP Letter V 1.0 dated 06.08.2009 superseded by v2.0 dated 14 March 2013 (update of concomitant medications) 3. PIS V1.2 dated 20.10.2009 superseded by V2.0 dated 14 March 2013 (sections re-written and simplified for a more user-friendly document) 4. Consent Form V1.2 dated 20.10.2009 superseded by V2.0 dated 14 March 2013 (inclusion of sub-sections for make clear difference between main and optional study) 5. Pregnancy PIS V1.0 dated 06 August 2009 superseded by V2.0 dated 14 March 2013 (inclusion of ISRCTN reference)
    28 Jul 2014
    Amendment of trial documentation as follows: Protocol v3.0 dated 13 December 2013 superseded by v4.0 dated12 June 2013 (change of sample size from 122 to 82) To add new sites and PIs: Queen Elizabeth Hospital, Norfolk-Gail Horan Royal Derby Hospital-Pabir Chakaraboti Queens Hospital (Staffordshire)-Pugazhenthi Pattu Mount Vernon Hospital-Peter Hoskin Charing Cross Hospital-Steve Nicholson Weston Park Hospital-Linda Evans Ayr Hospital-Hilary Glen Royal Free Hospital-Maria Vilarino Varela West Suffolk NHS Trust-Cathryn Woodward Calderdale Royal Hospital-Uschi Hofmann Huddersfield Royal Infirmary-Uschi Hofmann Bristol Haematology and Oncology Centre-Mark Beresford Royal United Hospital-Olivia Firm To make minor details to the CTA: Update contact for Fisher Clinical Services Clarify duties performed by FCS Add sources of monetary or material support Add contact point for sponsor To inform the MHRA of the non-substantial changes that were made to protocol V 2.0 08/03/2013 to generate v3.0 13/12/13.

    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.
    Neither limitations nor caveats are applicable to this summary of the results.
    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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