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    Clinical Trial Results:
    A randomised phase 2 study of paclitaxel with or without GSK1120212 in advanced wt BRAF melanoma

    Summary
    EudraCT number
    2011-002545-35
    Trial protocol
    GB   DE  
    Global end of trial date
    31 Dec 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Mar 2018
    First version publication date
    11 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OCTO_026
    Additional study identifiers
    ISRCTN number
    ISRCTN43327231
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    Joint Research Office, Block 60, Churchill Hospital, Oxford, United Kingdom, OX3 7LE, Oxford, United Kingdom, OX3 7LE
    Public contact
    Ms Heather House , Clinical Trials & Research Governance Joint Research Office Block 60, Churchill Hospital, 44 186557224, ctrg@admin.ox.ac.uk
    Scientific contact
    PACMEL Trial Office Oncology Clinical Trials Office (OCTO) Department of Oncology, University of Oxford Old Road Campus Research Building Oxford OX3 7DQ, UK, 44 1865617003, octo-enquires@oncology.ox.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
    19 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 1 - To establish the maximum tolerated dose of GSK1120212 in combination with paclitaxel in the treatment of patients with advanced melanoma. Phase 2 - To compare the efficacy of GSK1120212 in combination with paclitaxel, compared with paclitaxel alone in the treatment of patients with advanced or metastatic melanoma.
    Protection of trial subjects
    This protocol was conducted in compliance with the UK Clinical Trials Regulations3, the principles of Good Clinical Practice (GCP) and the applicable policies of the Sponsoring Organisation. Together, these implement the ethical principles of the Declaration of Helsinki (1996) and the regulatory requirements for clinical trials of an investigational medicinal product under the European Union Clinical Trials Directive. In Germany, country-specific legal requirements were taken into account (the current version of German Drug Law [Arzneimittel Gesetzt]).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Dec 2011
    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: 86
    Country: Number of subjects enrolled
    Germany: 25
    Worldwide total number of subjects
    111
    EEA total number of subjects
    111
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    62
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial started with two arms (Paclitaxel and paclitaxel+GSK GSK1120212) aiming for three arms. Therefore, between March 2013 and April 2016, 111 eligible participants were recruited to the randomised phase. These were 86 in UK centres and 25 in the German.

    Pre-assignment
    Screening details
    382 patients assessed for eligibility and consent. out of the total patients screened 271 (185 ineligible and 86 refused to participate) patients excluded from the trial. As a result, 111 eligible patients randomised to the three arms on the ratio of 1:1:1

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Paclitaxel
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Paclitaxel
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    paclitaxel 80 mg/m2 by weekly intravenous infusion 3 weeks out of every 4. Treatment will be given on day 1, 8 and 15 of each cycle for up to 6 cycles

    Arm title
    GSK1120212 + Paclitaxel
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    GSK1120212
    Investigational medicinal product code
    trametinib
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients will receive the recommended dose of GSK1120212 once a day by mouth – as a result of the dose escalation component of the PACMEL trial the maximum tolerated dose was confirmed to be 2.0mg OD.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Paclitaxel
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will receive paclitaxel 80 mg/m2 by weekly intravenous infusion 3 weeks out of every 4. Treatment will be given on day 1, 8 and 15 of each cycle for up to 6 cycles.

    Arm title
    Pazopanib + Paclitaxel
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Pazopanib
    Investigational medicinal product code
    Pazopanib
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The recommended dose for the trial is pazopanib 800mg once a day by mouth.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Paclitaxel
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will receive paclitaxel 65 mg/m2 by weekly intravenous infusion 3 weeks out of every 4. Treatment will be given on day 1, 8 and 15 of each cycle for up to 6 cycles.

    Number of subjects in period 1
    Paclitaxel GSK1120212 + Paclitaxel Pazopanib + Paclitaxel
    Started
    38
    36
    37
    Completed
    38
    36
    37

    Baseline characteristics

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

    Reporting group title
    GSK1120212 + Paclitaxel
    Reporting group description
    -

    Reporting group title
    Pazopanib + Paclitaxel
    Reporting group description
    -

    Reporting group values
    Paclitaxel GSK1120212 + Paclitaxel Pazopanib + Paclitaxel Total
    Number of subjects
    38 36 37 111
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    20 24 18 62
        From 65-84 years
    18 12 19 49
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    64 (35 to 80) 60 (27 to 80) 66 (41 to 80) -
    Gender categorical
    Units: Subjects
        Female
    11 13 12 36
        Male
    27 23 25 75
    NRAS status
    Units: Subjects
        Yes
    15 15 17 47
        No
    23 21 20 64
    Prior therapy
    Units: Subjects
        Yes
    13 12 14 39
        No
    25 24 23 72
    LDH
    Units: Subjects
        Elevated
    19 18 19 56
        Within normal limits
    19 18 18 55
    Subject analysis sets

    Subject analysis set title
    Primary Analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The primary analysis was intention-to-treat and involved all 111 patients who were randomly assigned, irrespective of the treatment they received.

    Subject analysis sets values
    Primary Analysis
    Number of subjects
    111
    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)
    62
        From 65-84 years
    49
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    63 (27 to 84)
    Gender categorical
    Units: Subjects
        Female
    36
        Male
    75
    NRAS status
    Units: Subjects
        Yes
    47
        No
    64
    Prior therapy
    Units: Subjects
        Yes
    39
        No
    72
    LDH
    Units: Subjects
        Elevated
    56
        Within normal limits
    55

    End points

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

    Reporting group title
    GSK1120212 + Paclitaxel
    Reporting group description
    -

    Reporting group title
    Pazopanib + Paclitaxel
    Reporting group description
    -

    Subject analysis set title
    Primary Analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The primary analysis was intention-to-treat and involved all 111 patients who were randomly assigned, irrespective of the treatment they received.

    Primary: Progression free survival (PFS)

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    End point title
    Progression free survival (PFS)
    End point description
    End point type
    Primary
    End point timeframe
    The time from date of randomisation to the first date of progression (using CT scans and RECIST criteria) or date of death from any cause (events).
    End point values
    Paclitaxel GSK1120212 + Paclitaxel Pazopanib + Paclitaxel
    Number of subjects analysed
    38
    36
    37
    Units: Months
        median (confidence interval 90%)
    3.43 (2.00 to 3.77)
    5.20 (3.73 to 7.00)
    5.33 (3.37 to 6.43)
    Statistical analysis title
    PFS Paclitaxel + GSK1120212 Versus Paclitaxel
    Statistical analysis description
    In the SAP, it was stated that Cox regression model will be used to analyse the PFS, if the proportional hazard assumption was met but if this was not the case an AFT model will be used. Since the proportional hazard assumption did not meet, a log-logistic AFT model adjusted for NRAS mutations, prior treatment and LDH levels was applied.
    Comparison groups
    Paclitaxel v GSK1120212 + Paclitaxel
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Accelerated failure time (AFT) model
    Parameter type
    Time ratio
    Point estimate
    1.47
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    2.01
    Statistical analysis title
    PFS Paclitaxel + Pazopanib Versus Paclitaxel
    Comparison groups
    Paclitaxel v Pazopanib + Paclitaxel
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    AFT model
    Parameter type
    Time ratio
    Point estimate
    1.36
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.96
         upper limit
    1.93

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    End point type
    Secondary
    End point timeframe
    This is defined as the best response recorded from date of randomisation to disease progression or date of last follow-up. ORR = (CR + PR)/all patients randomised
    End point values
    Paclitaxel GSK1120212 + Paclitaxel Pazopanib + Paclitaxel
    Number of subjects analysed
    38
    36
    37
    Units: subjects
        Complete response
    2
    0
    0
        Partial response
    3
    15
    8
        Stable disease
    13
    11
    16
        Progressive disease
    13
    6
    9
        Not evaluable
    7
    4
    4
    Statistical analysis title
    ORR (GSK + Paclitaxel Vs Paclitaxel)
    Statistical analysis description
    Objective response rate calculated as the number of patients with CR or PR overall patients randomised. This was analysed using a Chi-Squared test.
    Comparison groups
    Paclitaxel v GSK1120212 + Paclitaxel
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.01
    Method
    Chi-squared
    Confidence interval
    Statistical analysis title
    ORR (Pazopanib + Paclitaxel Vs Paclitaxel)
    Statistical analysis description
    Objective response rate calculated as the number of patients with CR or PR overall patients randomised. This was analysed using a Chi-Squared test.
    Comparison groups
    Paclitaxel v Pazopanib + Paclitaxel
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.33
    Method
    Chi-squared
    Confidence interval

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    The time from date of randomisation to date of death for any cause (event). For patients without event, the time is censored at the date of the last follow-up.
    End point values
    Paclitaxel GSK1120212 + Paclitaxel Pazopanib + Paclitaxel
    Number of subjects analysed
    38
    36
    37
    Units: Months
        median (confidence interval 90%)
    10.8 (8.77 to 9999)
    9.37 (8.3 to 13.47)
    10.57 (8.93 to 13.47)
    Statistical analysis title
    OS Analysis (GSK + Pacli Vs Pacli)
    Comparison groups
    Paclitaxel v GSK1120212 + Paclitaxel
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.25
    Method
    Logrank
    Confidence interval
    Statistical analysis title
    OS Analysis ( Pazo + Pacli Vs Pacli)
    Comparison groups
    Paclitaxel v Pazopanib + Paclitaxel
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.22
    Method
    Logrank
    Confidence interval

    Secondary: PFS at 6 months

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    End point title
    PFS at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    PFS at 6 months is the six month PFS estimate from the primary PFS KM plot with a 90%CI
    End point values
    Paclitaxel GSK1120212 + Paclitaxel Pazopanib + Paclitaxel
    Number of subjects analysed
    38
    36
    37
    Units: Percentage
    number (confidence interval 90%)
        6 Months PFS rate
    27 (16 to 40)
    39 (26 to 52)
    41 (28 to 55)
    Statistical analysis title
    PFS rate at 6 months (GSK+Paclitaxel Vs Paclitaxe)
    Statistical analysis description
    The estimated difference in PFS at 6 months were calculated using the formula for the 90% confidence interval for the difference in survival proportions (P_1-P_2 )±1.645xSE(P_1-P_2)* Where SE(P_1-P_2)=√(〖SE(P_1 )〗^2+〖SE(P_2 )〗^2 ) P= the proportion of survival at 6 months in each arm SE= Standard error *Practical statistics for medical research. Douglas G. Altman, Chapman and Hall, London, 1991. Page no. 384
    Comparison groups
    GSK1120212 + Paclitaxel v Paclitaxel
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Kaplan Meier method
    Parameter type
    PFS rate
    Point estimate
    12
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -6
         upper limit
    30
    Statistical analysis title
    PFS rate at 6 months (Pazo + Pacli Vs Pacli)
    Statistical analysis description
    PFS at 6 months is the six month PFS estimate from the primary PFS KM plot with a 90%CI. The estimated difference in PFS at 6 months were calculated using the formula for the 90% confidence interval for the difference in survival proportions (P_1-P_2 )±1.645xSE(P_1-P_2)* Where SE(P_1-P_2)=√(〖SE(P_1 )〗^2+〖SE(P_2 )〗^2 ) P= the proportion of survival at 6 months in each arm SE= Standard error *Practical statistics for medical research. Douglas G. Altman, Chapman and Hall, London, 1991
    Comparison groups
    Pazopanib + Paclitaxel v Paclitaxel
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Kaplan Meier method
    Parameter type
    PFS rate
    Point estimate
    15
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -3
         upper limit
    32

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Event Monitoring starts from the time the patient receives any of the research procedures until they complete the trial (30 days post end of treatment) or beyond this time if the AE is an adverse reaction.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Paclitaxel
    Reporting group description
    -

    Reporting group title
    GSK1120212 + Paclitaxel
    Reporting group description
    -

    Reporting group title
    Pazopanib + Paclitaxel
    Reporting group description
    -

    Serious adverse events
    Paclitaxel GSK1120212 + Paclitaxel Pazopanib + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 38 (13.16%)
    17 / 36 (47.22%)
    25 / 37 (67.57%)
         number of deaths (all causes)
    20
    23
    23
         number of deaths resulting from adverse events
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 37 (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
    Immune system disorders
    Allergic reation
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 37 (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
    General disorders and administration site conditions
    Infusion site extravasation
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 37 (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
    Pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 37 (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
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 37 (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
    Infusion related reaction
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    other-source unknown
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 37 (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
    Nervous system disorders
    intracranial haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasovagal reaction
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 37 (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
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic perforation
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Gastric haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral hemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    bowel obstruction
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 37 (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
    Hematuria
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 37 (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
    Soft tissue infection
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Other - source unknown
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 36 (8.33%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Paclitaxel GSK1120212 + Paclitaxel Pazopanib + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 38 (94.74%)
    36 / 36 (100.00%)
    37 / 37 (100.00%)
    Vascular disorders
    Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 36 (8.33%)
    6 / 37 (16.22%)
         occurrences all number
    2
    4
    8
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
    12 / 37 (32.43%)
         occurrences all number
    1
    2
    21
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
    9 / 37 (24.32%)
         occurrences all number
    1
    3
    14
    Blood alkaline phosphatase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 36 (8.33%)
    8 / 37 (21.62%)
         occurrences all number
    2
    3
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 38 (15.79%)
    4 / 36 (11.11%)
    5 / 37 (13.51%)
         occurrences all number
    6
    4
    5
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 38 (21.05%)
    8 / 36 (22.22%)
    8 / 37 (21.62%)
         occurrences all number
    9
    9
    10
    Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 38 (10.53%)
    9 / 36 (25.00%)
    6 / 37 (16.22%)
         occurrences all number
    4
    9
    6
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 38 (10.53%)
    11 / 36 (30.56%)
    9 / 37 (24.32%)
         occurrences all number
    6
    14
    10
    Lymphopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 36 (8.33%)
    7 / 37 (18.92%)
         occurrences all number
    0
    3
    12
    Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 36 (13.89%)
    9 / 37 (24.32%)
         occurrences all number
    1
    5
    9
    Nervous system disorders
    Dysgeusia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 36 (11.11%)
    12 / 37 (32.43%)
         occurrences all number
    3
    4
    12
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 38 (5.26%)
    6 / 36 (16.67%)
    7 / 37 (18.92%)
         occurrences all number
    2
    7
    7
    General disorders and administration site conditions
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 38 (44.74%)
    23 / 36 (63.89%)
    18 / 37 (48.65%)
         occurrences all number
    27
    52
    50
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 38 (7.89%)
    8 / 36 (22.22%)
    3 / 37 (8.11%)
         occurrences all number
    3
    8
    3
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 38 (21.05%)
    14 / 36 (38.89%)
    21 / 37 (56.76%)
         occurrences all number
    9
    15
    24
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 38 (31.58%)
    16 / 36 (44.44%)
    2 / 37 (5.41%)
         occurrences all number
    12
    16
    2
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 38 (52.63%)
    35 / 36 (97.22%)
    29 / 37 (78.38%)
         occurrences all number
    20
    42
    41
    Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 38 (18.42%)
    4 / 36 (11.11%)
    4 / 37 (10.81%)
         occurrences all number
    7
    4
    4
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 38 (26.32%)
    10 / 36 (27.78%)
    16 / 37 (43.24%)
         occurrences all number
    11
    12
    17
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 38 (15.79%)
    5 / 36 (13.89%)
    9 / 37 (24.32%)
         occurrences all number
    6
    5
    9
    Skin and subcutaneous tissue disorders
    Alopecia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 38 (44.74%)
    13 / 36 (36.11%)
    13 / 37 (35.14%)
         occurrences all number
    21
    15
    15
    Dry skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 38 (2.63%)
    6 / 36 (16.67%)
    6 / 37 (16.22%)
         occurrences all number
    2
    7
    6
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 38 (15.79%)
    34 / 36 (94.44%)
    9 / 37 (24.32%)
         occurrences all number
    7
    103
    9
    Musculoskeletal and connective tissue disorders
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 38 (18.42%)
    2 / 36 (5.56%)
    4 / 37 (10.81%)
         occurrences all number
    9
    2
    4
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 36 (5.56%)
    4 / 37 (10.81%)
         occurrences all number
    4
    3
    4
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 38 (15.79%)
    13 / 36 (36.11%)
    11 / 37 (29.73%)
         occurrences all number
    7
    13
    12
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 38 (10.53%)
    3 / 36 (8.33%)
    3 / 37 (8.11%)
         occurrences all number
    4
    3
    3
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 36 (13.89%)
    5 / 37 (13.51%)
         occurrences all number
    2
    6
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2012
    N/A
    21 Jun 2013
    Protocol changes to reflect the addition of a third treatment (pazopanib in combination with paclitaxel) arm to the PACMEL trial and other additional changes are provided separately with the notification. Pazopanib is an antiangiogenic agent. Evidence suggests that antiangiogenic therapies can enhance the impact of chemotherapy by inducing vascular normalization, alleviating hypoxia and increasing the delivery of cytotoxic chemotherapies to cancer cells. Clinical trials using pazopanib in combination with paclitaxel in the treatment of melanoma have also shown promising results. However, these results could be explained by patient selection. Therefore there is a need to compare the combination against paclitaxel alone. The PACMEL study offers a means to do this very efficiently, as the required control arm is already included in the trial and the entry criteria and safety monitoring of the current study are consistent with what is required for the safety profile of pazopanib.
    06 Dec 2013
    Removal of the inclusion criterion "Maximum 2 prior lines of treatment for advanced disease" in the Protocol, to allow patients at any point in the treatment pathway to be considered. Patients are now considering cytotoxic chemotherapy later in the treatment pathway as more agents become available. Prior therapy will not impact upon the primary endpoint and removing this inclusion criterion will make the trial available to more patients. Change to exclusion point 1 (Any systemic anticancer therapy within 28 days prior to starting treatment) to permit eligibility 42 days after prior ipilimumab treatment – in the protocol synopsis this is given as 63 days prior to starting trial treatment, however, no statement has been made previously in the main exclusion criteria with regards ipilimumab. 28 days washout period is too short for ipilimumab, however, 63 is excessive and 42 is sufficient. The Main eligibility criteria have been updated to reflect the Synopsis for consistency. Additional blood sample for genetic testing which could previously be taken at screening is changed to being taken at cycle 1 day 1. Only blood samples donated by randomised patients will be analysed, therefore patients should not be asked to donate blood prior to randomisation as this blood will not be analysed if they are not subsequently randomised. Additions to the list of adverse events which do not require to be reported: medical/surgical procedures, day-to-day fluctuations in preexisting disease or conditions, expected progression or signs of the patients’ melanoma. This is done to improve protocol clarity and avoid unnecessary reporting of events which have no impact on patient safety in the trial.
    22 Sep 2014
    Addition of details for German sites. None sub-amendment for the UK.
    17 Jun 2015
    We were not on target to recruit according to the milestones stated. Recruitment had been lower than expected but has picked up in Q1 2015 due to competing studies/treatments no longer causing an issue, thus we have secured an extension until January 2016. Updates and clarifications to the safety sections of protocol due to amended working practices and amendments to bring the protocol in line with the German version.
    01 Jun 2016
    Change to recruitment end date from January 2016 to April 2016 due to slower recruitment rate than expected. Change of wording to MAX of 120 patients as fewer patients now needed according to statistical assessment. Change to definition of the end of the trial due to longer recruitment period. Updates to OCTO contact details throughout the protocol due to changes in staff and new email addresses for the trials unit.

    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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