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    Clinical Trial Results:
    A randomised double blind phase 2 trial of whole brain radiotherapy with or without vandetanib in metastatic melanoma with brain metastases

    Summary
    EudraCT number
    		 2011-000661-12
    Trial protocol
    		 GB  
    Global end of trial date
    27 Nov 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 May 2016
    First version publication date
    31 Mar 2016
    Other versions
    		 v1
    Version creation reason
    • Changes to summary attachments
    Attachment of Clinical Study Report following review by funder
    Summary report(s)
    		 RADVAN_ClinicalStudyReport_V3.0_20Apr2016

    Trial information

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    Trial identification
    Sponsor protocol code
    OCTO_022
    Additional study identifiers
    ISRCTN number
    		 ISRCTN20253034
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Oxford, Block 60, Churchill Hospital, Old Road, Headington, Oxford, United Kingdom, OX3 7LE
    Public contact
    RADVAN Trial Coordinator, Oncology Clinical Trials Office (OCTO), +44 01865617089, RADVAN@octo-oxford.org.uk
    Scientific contact
    RADVAN Trial Coordinator, Oncology Clinical Trials Office (OCTO), +44 01865617089, RADVAN@octo-oxford.org.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
    13 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The principal objective of this study is to evaluate how long whole brain radiotherapy plus vandetanib is able to control the progression of melanoma brain metastases, compared with radiotherapy alone.
    Protection of trial subjects
    The trial received ethical and regulatory approval, and was run in compliance with the Medicines for Human Use (Clinical Trials) Regulations 2004, and amendments thereafter, the guidelines for Good Clinical Practice, and the applicable policies of the Sponsor, the University of Oxford. Together, these regulations implement the ethical principles of the Declaration of Helsinki (2008) and the regulatory requirements for clinical trials of an investigational medicinal product as set out in the European Union (EU) Directives 001/20/EC (Clinical Trials) and 2005/28/EC (GCP). Patients also were seen for study assessments up to 30 days post end of treatment and thereafter every 2 months for clinical and radiological assessment up to a total of 12 months post randomisation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    14
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 6 eligible participants were recruited to the safety run-in phase of the trial between 1st February 2012 and 14th February 2013. Between 24th April 2013 and 17th April 2014, 18 eligible participants were recruited to the randomised phase. The TMG met on 30 April 2014 and agreed to close the RADVAN trial early to recruitment with immediate effect.

    Pre-assignment
    Screening details
    		 71 participants were screened. 47 patients were excluded/ineligible; 33 didn't meet the inclusion criteria (7 had poor performance status, 3 were unable to comply with protocol, 3 had a life expectancy <12 weeks, among other reasons), 12 patients declined to participate (of which 4 chose alternative treatment), and 2 patients did not give reasons.

    Period 1
    Period 1 title
    Baseline Randomised (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Vandetanib/placebo were both supplied as 100mg white film-coated tablets packed in high density polyethylene (HDPE) bottles.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Vandetanib plus WBRT
    Arm description
    		 Experimental treatment arm of Vandetanib followed by WBRT
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in the randomisation phase received vandetanib/placebo 100 mg once daily (OD), starting 4 days (+/- 1 day) before Whole Brain Radiotherapy (WBRT) and continuing for 21 days in total, in oral tablet form. No study treatment was to be given beyond day 21, even if any doses were missed during this period. The exposure to vandetanib is unchanged whether given in the fasted state or with food and thus a restriction on dosing with food was not required. The dose of study drug was repeated if emesis occurred within 30 minutes of taking the tablet. If the patient inadvertently did not take the dose in the morning, he or she may have taken that day’s dose any time up to 10pm that same day. The study drug could therefore be taken before or after radiotherapy treatment. However, if a patient missed taking the scheduled dose and was unable to take the missed dose on the same day, he or she omitted the dose and took the next scheduled dose as planned. The missed dose was not made up.

    Arm title
    		 Safety of Vandetanib
    Arm description
    		 16 patients (including those 6 patients in the safety run-in phase and 10 patients in the randomised phase) were allocated to receive vandetanib followed by WBRT.
    Arm type
    		 Safety

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    L01XE12
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in the safety run-in phase received vandetanib 100 mg once daily (OD), starting 4 days (+/- 1 day) before Whole Brain Radiotherapy (WBRT) and continuing for 21 days in total, in oral tablet form. No study treatment was to be given beyond day 21, even if any doses were missed during this period. The exposure to vandetanib is unchanged whether given in the fasted state or with food and thus a restriction on dosing with food was not required. The dose of study drug was repeated if emesis occurred within 30 minutes of taking the tablet. If the patient inadvertently did not take the dose in the morning, he or she may have taken that day’s dose any time up to 10pm that same day. The study drug could therefore be taken before or after radiotherapy treatment. However, if a patient missed taking the scheduled dose and was unable to take the missed dose on the same day, he or she omitted the dose and took the next scheduled dose as planned. The missed dose was not made up.

    Arm title
    		 Placebo plus WBRT
    Arm description
    		 Placebo followed by WBRT
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients in the randomisation phase received vandetanib/placebo 100 mg once daily (OD), starting 4 days (+/- 1 day) before Whole Brain Radiotherapy (WBRT) and continuing for 21 days in total, in oral tablet form. No study treatment was to be given beyond day 21, even if any doses were missed during this period.

    Number of subjects in period 1
    		Vandetanib plus WBRT Safety of Vandetanib Placebo plus WBRT
    Started
    10
    16
    8
    Completed
    7
    12
    2
    Not completed
    3
    4
    6
         Physician decision
    2
    2
    1
         Disease progression
    -
    -
    1
         Adverse event, non-fatal
    1
    2
    1
         Patient died
    -
    -
    1
         Protocol deviation
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vandetanib plus WBRT
    Reporting group description
    		 Experimental treatment arm of Vandetanib followed by WBRT

    Reporting group title
    Safety of Vandetanib
    Reporting group description
    		 16 patients (including those 6 patients in the safety run-in phase and 10 patients in the randomised phase) were allocated to receive vandetanib followed by WBRT.

    Reporting group title
    Placebo plus WBRT
    Reporting group description
    		 Placebo followed by WBRT

    Reporting group values
    		 Vandetanib plus WBRT Safety of Vandetanib Placebo plus WBRT Total
    Number of subjects
    		 10 16 8
    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
        arithmetic mean (standard deviation)
    		 57.3 ± 11.1 61.7 ± 11.5 63.7 ± 14.8 -
    Gender categorical
    Units: Subjects
        Female
    		 5 7 5 12
        Male
    		 5 9 3 12
    Karnofsky Performance Status
    Units: Subjects
        100 - Normal; no evidence of disease
    		 2 3 1 4
        90 - Able to carry on normal activity; minor signs
    		 5 7 5 12
        80 - Normal activity with effort; some signs
    		 2 5 2 7
        70 - Cares for self; unable to carry on normal act
    		 1 1 0 1
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 81 ± 13.6 82.7 ± 14.3 75.2 ± 17.2 -
    Temperature
    Units: celsius temperature
        arithmetic mean (standard deviation)
    		 36.4 ± 0.6 36.3 ± 0.5 36.5 ± 0.5 -
    Pulse rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 77.2 ± 17.8 73.8 ± 16 73.3 ± 14.6 -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 131.7 ± 13.8 136.8 ± 15.1 135.3 ± 76.1 -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 74.3 ± 7.8 75.6 ± 11.9 76.1 ± 8.7 -

    End points

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    End points reporting groups
    Reporting group title
    Vandetanib plus WBRT
    Reporting group description
    		 Experimental treatment arm of Vandetanib followed by WBRT

    Reporting group title
    Safety of Vandetanib
    Reporting group description
    		 16 patients (including those 6 patients in the safety run-in phase and 10 patients in the randomised phase) were allocated to receive vandetanib followed by WBRT.

    Reporting group title
    Placebo plus WBRT
    Reporting group description
    		 Placebo followed by WBRT

    Subject analysis set title
    Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The primary analysis was intention-to-treat and involved all 18 patients who were randomly assigned, irrespective of the treatment they received.

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    9 patients were included in the per-protocol analysis and 9 patients were excluded as they did not did not receive 21 days of treatment drug (vandetanib/Placebo) and 10 fractions of radiotherapy.

    Subject analysis set title
    Safety and tolerability
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    16 patients were randomised and received at least one dose of treatment drug (vandetanib/Placebo).

    Subject analysis set title
    Safety of Vandetanib
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    16 patients (including those 6 patients in the safety sample) were allocated to receive vandetanib.

    Primary: Progression Free Survival in brain

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    End point title
    		 Progression Free Survival in brain
    End point description
    End point type
    Primary
    End point timeframe
    The time from date of randomisation to date of disease progression in the brain or date of death in the absence of RECIST progression. For patients without an event, the time from randomisation to date last known alive would be the censored PFS time.
    End point values
    		 Vandetanib plus WBRT Safety of Vandetanib Placebo plus WBRT
    Number of subjects analysed
    10
    16
    8
    Units: Months
        median (confidence interval 90%)
    3.25 (1.55 to 5.56)
    3.25 (1.81 to 5.56)
    2.5 (0.2 to 4.83)
    Statistical analysis title
    		 Difference in PFS between treatment groups
    Comparison groups
    Vandetanib plus WBRT v Placebo plus WBRT
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.45

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    The time from randomisation to death (event), or the time from randomisation to date last known alive for censored patients
    End point values
    		 Vandetanib plus WBRT Safety of Vandetanib Placebo plus WBRT
    Number of subjects analysed
    10
    16
    8
    Units: Months
        median (confidence interval 90%)
    4.6 (1.55 to 6.28)
    4.6 (1.55 to 6.28)
    2.5 (0.2 to 7.2)
    Statistical analysis title
    		 Difference in OS between treatment groups
    Comparison groups
    Vandetanib plus WBRT v Placebo plus WBRT
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.96

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to 30 days after the end of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Vandetanib
    Reporting group description
    		 Experimental treatment arm

    Reporting group title
    Safety run-in
    Reporting group description
    		 6 safety patients who received Vandetanib before randomised part of the trial.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Vandetanib Safety run-in Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    3 / 6 (50.00%)
    2 / 8 (25.00%)
         number of deaths (all causes)
    9
    6
    8
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemorrhage of brain metastases
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral edema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive disturbances
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic perforation
    Additional description: Diverticular Abscess/perforation (Colonic Perforation)
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial pneumonitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Vandetanib Safety run-in Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    6 / 6 (100.00%)
    7 / 8 (87.50%)
    Investigations
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Leg coldness
    Additional description: Leg coldness - possible ischaemic limb
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Pericardial effusion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    1
    Edema cerebral
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Encephalopathy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    1
    Intracranial hemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Transient headaches
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Transient visual disturbance
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Leg twitching
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Leg numbness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Leg weakness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Seizure
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Tremor
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 6 (66.67%)
    4 / 8 (50.00%)
         occurrences all number
    5
    4
    4
    Gait disturbance
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    2
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    2
    2
    0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
         occurrences all number
    1
    1
    2
    Dysphonia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Sore throat
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Excoriated skin
    Additional description: Excoriated Skin Peri-anal area
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    3
    2
    0
    Dry skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Pain of skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Scalp pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Skin rash
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Rash forehead
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Skin reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
         occurrences all number
    2
    3
    0
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Migraines with shapes in eyes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    2
    Infections and infestations
    Infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Mucosal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 6 (50.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    3
    0
    Upper respiratory infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Feb 2013
    Protocol amendment to remove the exclusion criterion of no more than 3 extra-cranial organ sites involved with melanoma and removal of the neuro-cognitive tests. Both changes were made to maximise recruitment.
    11 Aug 2014
    Protocol amendment to describe the early closing of recruitment to the trial due to the inability of the trial to achieve its sample size in a timely manner and to reduce the follow-up period.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Apr 2014
    Recruitment to the trial closed on 30 April 2014 with 24 patients recruited (6 to the safety cohort and 18 to the randomised trial) following significant difficulties encountered in recruiting from this patient population. This decision was made by the Trial Management Group (TMG) and agreed by the Independent Early Phase Trial Oversight Committee (IEPTOC) following concerns that slow recruitment would lead to an inability to answer the research question in a timely manner.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination of the trial due to failure to recruit patients has led to a small number of patients analysed. This meant there was a lack of statistical power to detect differences between treatment arms.
    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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