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    Clinical Trial Results:
    A randomised phase II study of sunitinib versus dacarbazine in the treatment of patients with metastatic uveal melanoma

    Summary
    EudraCT number
    		 2008-008794-55
    Trial protocol
    		 GB  
    Global end of trial date
    17 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Feb 2019
    First version publication date
    28 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RDD299
    Additional study identifiers
    ISRCTN number
    		 ISRCTN75033520
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Clatterbridge Cancer Centre NHS Foundation Trust
    Sponsor organisation address
    Clatterbridge Road, Wirral, United Kingdom, CH63 4JY
    Public contact
    Ms Charlotte Rawcliffe, Liverpool Cancer Trials Unit, University of Liverpool, 0151 794 8167, C.Rawcliffe@liverpool.ac.uk
    Scientific contact
    Dr Victoria Shaw, GCLP Labs, University of Liverpool, 0151 706 4180, Victoria.Shaw@liverpool.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
    18 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Can the progression free survival time of patients with metastatic Uveal Melanoma be extended by treatment with Sunitinib, compared with the treatment by Dacarbazine?
    Protection of trial subjects
    Consent should be obtained prior to each patient participating in the trial, after a full explanation has been given of the treatment options, including the conventional and generally accepted methods of treatment. The right of patients to refuse their consent to participate in the trial without providing a reason must be respected. Verification of appropriate informed consent will be enabled by the provision of copies of participants‟ signed informed consent form being supplied to the LCTU by recruiting centres. This requires that name data will be transferred to the LCTU, which is explained in the PIS. The LCTU will preserve the confidentiality of participants taking part in the study and the University of Liverpool is a Data Controller registered with the Information Commissioners Office. Individual participant medical information obtained as a result of this study is considered confidential and disclosure to third parties is prohibited. CRFs will be labelled with patient initials and unique trial screening and/or randomisation number. Blood and paraffin blocks will be transferred to the LECMC GCLP laboratory and will be identifiable by unique trial randomisation number only. Consent forms sent to the LCTU as part of the randomisation process may contain patient identifiers for the purpose of monitoring as described in the trial risk assessment. Such information will be stored in secure, locked cabinets. The LCTU will request consent from all patients to obtain information from the NHS Information Centre (Medical Research Information Service) to follow patient progress if this is not available from their hospital or General Practitioner (GP).
    Background therapy
    		 -
    Evidence for comparator
    		 Relapsed uveal melanoma carries a dismal prognosis and to date no systemic or regional therapy has shown a survival advantage over best supportive care. As a consequence there is an urgent need to investigate novel therapies in this disease. Presently, patients with metastatic uveal melanoma have few treatment options given the limited available evidence base for systemic therapy. In the UK, the majority of patients are managed with symptomatic measures, DTIC chemotherapy or entry into phase I clinical programmes. Preliminary evidence suggests that C-Kit and angiogenesis may both play a role in disease progression and that Imatinib may have limited activity irrespective of C-Kit expression. Sunitinib is a multi-targeted TKI which has shown significant activity both in Imatinib resistant GIST but also in a range of malignancies by virtue of its anti-angiogenic effects. A preliminary report of efficacy in uveal melanoma requires confirmation in a larger randomised controlled setting. The heterogeneous nature of the disease and variable prognosis according to tumour volume at relapse limit the utility of further small single arm pilot phase II studies. Currently, DTIC represents a standard of care in the absence of evidence based protocols and thus Sunitinib will be investigated in a randomised phase II setting with the opportunity for cross-over on first progression. For the purposes of this trial and potential future phase III comparison, DTIC will be administered at an internationally recognised standard dose of 1000mg/m2.
    Actual start date of recruitment
    22 Oct 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: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    48
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 UK; First patient randomised: 22/10/2010; Last patient randomised: 07/08/2012; Cut off date: 30/11/2012; Total number randomised to Cut‐off date: 84 Total number withdrawn from study to Cut‐off date: 75/84 before crossover (62 due to progression); 19/35 after crossover (12 due to progression) Total number of deaths to Cut‐off date: 54

    Pre-assignment
    Screening details
    		 ECOG performance status (see Appendix B); Physical Examination (including weight); Urine pregnancy test; 12 lead ECG; Vital Signs; Haematology; Biochemistry; CT scan; Additional MRI Scan; Identification of target lesions; CT Scan; Blood Sample Cut‐off date: 30/11/2012 - Total number screened to Cut‐off date: 110

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dacarbazine
    Arm description
    		 Patients will receive 1000mg/m2 every 21 days by IV until progression or unacceptable toxicity
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dacarbazine will be administered as an open-label by IV infusion 1000mg/m2 over 30 to 60 minutes, starting on Week 1 and repeated every 3 weeks until disease progression or unacceptable toxicity.

    Arm title
    		 Sunitinib
    Arm description
    		 Sunitinib 50mg to be taken orally once a day for 28 days followed by 14 day break, until progression or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Individual patients will receive 28 days supply, dispensed at every other 3-weekly clinic visit (i.e. every 6 weeks) according to locally defined policy. 50mg of Sunitinib to be taken by mouth once a day for 28 days followed by a 14 day break (4/2 schedule) until progression or unacceptable toxicity.

    Number of subjects in period 1
    		Dacarbazine Sunitinib
    Started
    40
    44
    Cross Over
    24
    11
    Completed
    24
    11
    Not completed
    16
    33
         Withdrew between cross-over of treatments
    16
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dacarbazine
    Reporting group description
    		 Patients will receive 1000mg/m2 every 21 days by IV until progression or unacceptable toxicity

    Reporting group title
    Sunitinib
    Reporting group description
    		 Sunitinib 50mg to be taken orally once a day for 28 days followed by 14 day break, until progression or unacceptable toxicity.

    Reporting group values
    		 Dacarbazine Sunitinib Total
    Number of subjects
    		 40 44 84
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 62.6 (53.1 to 68.1) 66.6 (59.4 to 71.9) -
    Gender categorical
    Units: Subjects
        Female
    		 26 20 46
        Male
    		 14 24 38
    ECOG Performance
    ECOG Performance Status
    Units: Subjects
        ECOG 0
    		 22 27 49
        ECOG 1
    		 18 14 32
        ECOG 2
    		 0 3 3
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In order to follow the Intention to Treat (ITT) principle this will consist of all randomised patients excepting for: a) patients withdrawing consent between randomisation and starting therapy b) patients withdrawn from the study after randomisation because of irregularities with the consent process c) patients whose information determining ineligibility existed before randomisation but was not read until after randomisation.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received any trial treatment.

    Subject analysis sets values
    		 Full Analysis Set Safety Set
    Number of subjects
    84
    84
    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 (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
    46
    46
        Male
    38
    38
    ECOG Performance
    ECOG Performance Status
    Units: Subjects
        ECOG 0
    49
    49
        ECOG 1
    32
    32
        ECOG 2
    3
    3

    End points

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    End points reporting groups
    Reporting group title
    Dacarbazine
    Reporting group description
    		 Patients will receive 1000mg/m2 every 21 days by IV until progression or unacceptable toxicity

    Reporting group title
    Sunitinib
    Reporting group description
    		 Sunitinib 50mg to be taken orally once a day for 28 days followed by 14 day break, until progression or unacceptable toxicity.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In order to follow the Intention to Treat (ITT) principle this will consist of all randomised patients excepting for: a) patients withdrawing consent between randomisation and starting therapy b) patients withdrawn from the study after randomisation because of irregularities with the consent process c) patients whose information determining ineligibility existed before randomisation but was not read until after randomisation.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received any trial treatment.

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    Progression will be defined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (see Appendix C) and will be captured by 12 weekly imaging, or imaging in the event of a clinical deterioration. Patients still alive with no evidence of progression at the time of their last visit are censored at the time of the most recent information. That is, PFS (months) = (min(censoring date, date of death) – date of randomisation)/30.4. The protocol specified that the analysis would take place once all patients have been followed up for at least 3 months. Because of the early termination (which might affect willingness to switch treatments) a common administrative) censoring date was taken as the date of the TSC letter suspending randomisation (referred to as the “cut‐off” date). Time to progression on first‐line treatment (TTP1) will be compared to time to progression on second‐line treatment (TTP2) for patients who receive crossover therapy
    End point type
    Primary
    End point timeframe
    Measured as days from randomisation to progression or death.
    End point values
    		 Dacarbazine Sunitinib Full Analysis Set
    Number of subjects analysed
    40
    44
    84
    Units: Subjects
        median (confidence interval 95%)
    2.8 (2.6 to 2.9)
    2.8 (2.6 to 3.5)
    2.8 (2.6 to 2.9)
    Statistical analysis title
    		 PFS Analysis
    Comparison groups
    Dacarbazine v Sunitinib
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7658
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.39

    Secondary: AEs

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    End point title
    		 AEs
    End point description
    Classified using the NCI CTCAE version 4. Measured as the number of patients to experience at least 1 grade 3 adverse event.
    End point type
    Secondary
    End point timeframe
    AEs experienced following randomisation
    End point values
    		 Dacarbazine Sunitinib
    Number of subjects analysed
    40
    44
    Units: Subjects
    27
    23
    No statistical analyses for this end point

    Secondary: Progression Free Survival of Crossover Patients

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    End point title
    		 Progression Free Survival of Crossover Patients
    End point description
    Time to progression on first-line treatment (TTP1) compared to time to progression on second-line treatment (TTP2) for patients who receive cross-over therapy
    End point type
    Secondary
    End point timeframe
    Measured as days from randomisation to progression or death
    End point values
    		 Dacarbazine Sunitinib
    Number of subjects analysed
    40
    44
    Units: Subjects
        median (full range (min-max))
    2.5 (0 to 12)
    2.5 (0 to 12)
    Statistical analysis title
    		 Second-line PFS
    Comparison groups
    Dacarbazine v Sunitinib
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 2.28

    Secondary: Overall survival to death from any cause

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    End point title
    		 Overall survival to death from any cause
    End point description
    Patients known to have survived past the cut‐off date (eg have attended for assessment after the cut‐off date) will be censored at the cut‐off date. Patients not known to have died but who have no record of attendance after the cut‐off date will censored at the last visit date before the cut‐off date.
    End point type
    Secondary
    End point timeframe
    Overall survival measured as months from randomisation to death from any cause
    End point values
    		 Dacarbazine Sunitinib Full Analysis Set
    Number of subjects analysed
    40
    44
    84
    Units: Subjects
        median (confidence interval 95%)
    7.4 (6.2 to 11.1)
    6.3 (3.3 to 8.4)
    7.4 (6.1 to 8.4)
    Statistical analysis title
    		 OS Analysis
    Comparison groups
    Dacarbazine v Sunitinib
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.208
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 2.61

    Secondary: Overall response according to RECIST

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    End point title
    		 Overall response according to RECIST
    End point description
    Overall response rate on first-line treatment (RR1) compared to overall response rate on second-line treatment (RR2) for patients who receive cross-over therapy
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date
    End point values
    		 Dacarbazine Sunitinib Full Analysis Set
    Number of subjects analysed
    40
    44
    84
    Units: Subjects
    3
    0
    3
    Statistical analysis title
    		 Difference in ORR
    Comparison groups
    Dacarbazine v Sunitinib
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.108
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Proportions
    Point estimate
    -0.075
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.01

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were reported from first patient first visit until 28 days after the last study treatment was administered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCTAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Dacarbazine
    Reporting group description
    		 Patients will receive 1000mg/m2 every 21 days by IV until progression or unacceptable toxicity This reporting group also includes patients who have crossed over to Dacarbazine from the original Sunitinib Arm

    Reporting group title
    Sunitinib
    Reporting group description
    		 Sunitinib 50mg to be taken orally once a day for 28 days followed by 14 day break, until progression or unacceptable toxicity. This also includes patients who have cross over from Dacarbazine

    Serious adverse events
    		 Dacarbazine Sunitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 51 (29.41%)
    10 / 68 (14.71%)
         number of deaths (all causes)
    26
    28
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleuritic Pain
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    infections and infestations - Other
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung infection
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alkaline phospate increased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine Increased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GGT increased
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil Count increased
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Phosphotase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (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
    		 Dacarbazine Sunitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 51 (78.43%)
    55 / 68 (80.88%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 51 (5.88%)
    10 / 68 (14.71%)
         occurrences all number
    4
    16
    Thromboembolic event
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 68 (5.88%)
         occurrences all number
    2
    4
    FATIGUE
         subjects affected / exposed
    23 / 51 (45.10%)
    34 / 68 (50.00%)
         occurrences all number
    43
    50
    FEVER
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 68 (2.94%)
         occurrences all number
    10
    2
    Flu like symptoms
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Localized edema
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    PAIN
         subjects affected / exposed
    7 / 51 (13.73%)
    9 / 68 (13.24%)
         occurrences all number
    7
    10
    General disorders and administration site conditions - Other, specify
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2
    Reproductive system and breast disorders
    Irregular menstruation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Menorrhagia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Vaginal hemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 68 (5.88%)
         occurrences all number
    2
    6
    DYSPNEA
         subjects affected / exposed
    4 / 51 (7.84%)
    8 / 68 (11.76%)
         occurrences all number
    5
    10
    Epistaxis
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 68 (5.88%)
         occurrences all number
    2
    5
    Hiccups
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders - Other, specify
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    3
    Restlessness
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Agitation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Alanine Aminotransferase increased
         subjects affected / exposed
    4 / 51 (7.84%)
    5 / 68 (7.35%)
         occurrences all number
    4
    8
    Alkaline Phosphatase Increased
         subjects affected / exposed
    6 / 51 (11.76%)
    7 / 68 (10.29%)
         occurrences all number
    6
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 51 (11.76%)
    10 / 68 (14.71%)
         occurrences all number
    8
    15
    Creatinine Increased
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences all number
    1
    3
    GGT increased
         subjects affected / exposed
    16 / 51 (31.37%)
    16 / 68 (23.53%)
         occurrences all number
    21
    22
    Haemoglobin increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Investigations - Other, specify
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 68 (5.88%)
         occurrences all number
    5
    4
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 51 (9.80%)
    6 / 68 (8.82%)
         occurrences all number
    8
    9
    neutrophil count decreased
         subjects affected / exposed
    12 / 51 (23.53%)
    6 / 68 (8.82%)
         occurrences all number
    22
    9
    platelet count decreased
         subjects affected / exposed
    9 / 51 (17.65%)
    10 / 68 (14.71%)
         occurrences all number
    16
    22
    WEIGHT LOSS
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 68 (5.88%)
         occurrences all number
    1
    5
    white blood cell decreased
         subjects affected / exposed
    10 / 51 (19.61%)
    6 / 68 (8.82%)
         occurrences all number
    13
    10
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 51 (0.00%)
    6 / 68 (8.82%)
         occurrences all number
    0
    7
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 68 (1.47%)
         occurrences all number
    2
    1
    Wound complication
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Venous injury
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Palpitations
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    dysgeusia
         subjects affected / exposed
    3 / 51 (5.88%)
    13 / 68 (19.12%)
         occurrences all number
    3
    16
    Headache
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 68 (2.94%)
         occurrences all number
    2
    3
    Lethargy
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 68 (2.94%)
         occurrences all number
    2
    6
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    9 / 51 (17.65%)
    6 / 68 (8.82%)
         occurrences all number
    13
    10
    Blood and lymphatic system disorders - Other, specify
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 68 (5.88%)
         occurrences all number
    7
    5
    Febrile neutropenia
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 68 (0.00%)
         occurrences all number
    2
    0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2
    Eye disorders
    Eye disorders - Other, specify
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    photophobia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    3 / 51 (5.88%)
    6 / 68 (8.82%)
         occurrences all number
    3
    7
    CONSTIPATION
         subjects affected / exposed
    7 / 51 (13.73%)
    7 / 68 (10.29%)
         occurrences all number
    15
    8
    DIARRHEA
         subjects affected / exposed
    7 / 51 (13.73%)
    12 / 68 (17.65%)
         occurrences all number
    8
    13
    Dry mouth
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    dyspepsia
         subjects affected / exposed
    1 / 51 (1.96%)
    10 / 68 (14.71%)
         occurrences all number
    1
    10
    Flatulence
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences all number
    1
    2
    Gastrointestinal disorders - Other, specify
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences all number
    1
    2
    Gastrointestinal pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Mucositis oral
         subjects affected / exposed
    2 / 51 (3.92%)
    11 / 68 (16.18%)
         occurrences all number
    3
    15
    NAUSEA
         subjects affected / exposed
    8 / 51 (15.69%)
    19 / 68 (27.94%)
         occurrences all number
    8
    25
    VOMITING
         subjects affected / exposed
    6 / 51 (11.76%)
    8 / 68 (11.76%)
         occurrences all number
    8
    9
    Oral pain
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 68 (7.35%)
         occurrences all number
    0
    5
    Bloating
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    3
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 68 (1.47%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences all number
    1
    3
    Erythema multiforme
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Pain of skin
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Photosensitivity
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Scalp pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Skin atrophy
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2
    Dry skin
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders - Other, specify
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2
    Nail discoloration
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2
    Skin hypopigmentation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 68 (4.41%)
         occurrences all number
    0
    3
    skin hyperpigmentation
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 68 (5.88%)
         occurrences all number
    0
    8
    Renal and urinary disorders
    urinary tract pain
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences all number
    1
    2
    Back pain
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 68 (0.00%)
         occurrences all number
    4
    0
    Bone pain
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences all number
    2
    2
    Flank pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Muscle weakness lower limb
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 68 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 68 (4.41%)
         occurrences all number
    1
    3
    Buttock pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Infections and infestations
    Infections and infestations - Other, specify
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences all number
    1
    2
    lung infection
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    Rhinitis infective
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 68 (1.47%)
         occurrences all number
    1
    1
    urinary tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 68 (4.41%)
         occurrences all number
    1
    3
    Mucosal infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Upper respiratory infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Bladder infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    ANOREXIA
         subjects affected / exposed
    4 / 51 (7.84%)
    8 / 68 (11.76%)
         occurrences all number
    6
    10
    HYPOALBUMINEMIA
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 68 (2.94%)
         occurrences all number
    5
    3
    Hypokalemia
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 68 (2.94%)
         occurrences all number
    1
    2
    HYPONATREMIA
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 68 (7.35%)
         occurrences all number
    4
    6
    HYPOPHOSPHATEMIA
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 68 (1.47%)
         occurrences all number
    2
    1
    Dehydration
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Hyperkalemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    Hypocalcemia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    3
    Hypercalcemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    HYPOMAGNESEMIA
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 68 (1.47%)
         occurrences all number
    0
    1
    HYPERNATREMIA
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 68 (2.94%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2010
    AMENDMENT 1 (Substantial 01) - Addition of sites (Beatson, Royal Devon & Exeter, Southampton, The Christie) - Change in PI (Royal Marsden) - Change of Institution (Hillingdon to East & North Hertfordshire)
    02 Nov 2010
    AMENDMENT 2 (Substantial 02) - Update to protocol (Version 1 to 2) * Inclusion criteria changes: to refer to randomisation correct units for platelets (Section 2 pages 12-13, Section 6 24-25) * Exclusion criteria changes: typographical error corrected reference to Coumadin removed (Section 2 pages 12-13, Section 6 24-25) * Trial Schematic updated: to reflect protocol changes (Section 2 15-16) * Clarification of withdrawal process (section 6.3 page 25, section 6.3.2 page 26) * Enrolment and randomisation details clarified (section 7, page 27-28)
    17 May 2011
    AMENDMENT 3 (Substantial 03) - Addition of New Site (Queen Elizabeth, Birmingham)
    07 Jun 2012
    AMENDMENT 4 (Substantial 04) - Addition of New Site (Velindre)
    30 Aug 2012
    AMENDMENT 5 (Substantial) - Change of Sponsor name (Clatterbridge Centre for Oncology NHS Foundation Trust to The Clatterbridge Cancer Centre NHS Foundation Trust
    14 Dec 2012
    AMENDMENT 6 (Substantial 05) - Protocol update (Version 2 to Version 3) * Administrative updates to trial management (adding new contacts, clearer instructions for dose modification and RECIST 1.1) * Expansion of window for Tumour Assessments (+/- 2 weeks rather than +/- 1 week) * Updated central monitoring procedures (closer monitoring of our primary endpoint of PFS by requesting CT scan reports be sent in to LCTU at all time points as previously only requested at Crossover) * Allowance for Dacarbazine administration in elderly patients (at PI discretion, can start at 850 mg/m2 rather than 1000mg/m2) * Updating inclusion criteria from transaminases < 5 x ULN to AST and ALT < 5 x ULN - PIS update (Version 2 to Version 3) - GP Letter update (Version 2 to Version 3) - Addition of New Site (St Barts)
    07 Jan 2013
    AMENDMENT 8 (Substantial 06) - Cessation to recruitment - Addendum to ICF Version 1 and Addendum to PIS Version 1 (explaining cessation of recruitment)
    02 Jul 2013
    AMENDMENT 9 (Substantial 07) - Update from Protocol Version 3 to Version 4 * Addition of a specific reference to the RSI to the Pharmacovigilance section - Changes in PI (Leicester and Weston Park)
    05 Sep 2013
    AMENDMENT 11 (Substantial 08) - Update to the Sunitinib SmPC Version 4 to Version 5
    04 Feb 2014
    AMENDMENT 12 (Substantial 09) - Update to Protocol Version 4 to Version 5 (update to the End of Trial definition - ‘If trial recruitment ends early due to harm or futility the end of trial will be 28 days after the first progression of the last patient currently treated with sunitinib, or 28 days after the second progression of the last patient currently treated with Sunitinib, whichever is later.’) - End date changed to 01/11/2014 (The study end date was amended to 22/10/2013. That date passed and there were still some patients receiving Sunitinib, therefore an extension to the study end date was required for patient to reach the end of trial under the definition above.)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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