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    Clinical Trial Results:
    A Randomised three-arm, open label, Phase II study of continuous Selumetinib versus continuous or interrupted Selumetinib in combination with weekly Paclitaxel in metastatic Uveal Melanoma

    Summary
    EudraCT number
    		 2014-004437-22
    Trial protocol
    		 GB   DE  
    Global end of trial date
    04 Aug 2020

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UoL001077
    Additional study identifiers
    ISRCTN number
    		 ISRCTN29621851
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    Research Support Office, 2nd Floor Block D, Waterhouse Building, 3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
    Public contact
    Charlotte Rawcliffe, Liverpool Clinical Trials Centre - University of Liverpool, +44 151 794 8167, c.rawcliffe@liv.ac.uk
    Scientific contact
    Charlotte Rawcliffe, Liverpool Clinical Trials Centre - University of Liverpool, +44 151 794 8167, c.rawcliffe@liv.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
    11 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess progression-free survival time between selumetinib alone or combination selumetinib in either a continuous or intermittent schedule with weekly paclitaxel.
    Protection of trial subjects
    Consent was obtained prior to each patient participating in the trial, after a full explanation had been given of the treatment options, including the conventional and generally accepted methods of treatment. All risks and potential benefits were explained to the patients, and all patients were provided with Patient Information Sheets prior to consent. Patients were given the right to refuse their consent to participate in the trial, and to withdraw at any time. The study also had a Trial Steering Committee (TSC) and Data Monitoring Comittee (DMC) that provided overall supervision of the trial, particularly focusing on the progress of the trial, adherence to the protocol, patient safety and consideration of new information. The TSC included experienced diabetes and sleep respiratory experts and clinical trialists. Meetings were held annually, but additional meetings could have been held if required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2015
    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
    Germany: 5
    Country: Number of subjects enrolled
    United Kingdom: 72
    Worldwide total number of subjects
    77
    EEA total number of subjects
    5
    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)
    37
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place over 36 months from 14 recruiting centres, the first patient was randomised on and the last patient was screened on 24th November 2015 and the 25th October 2018.

    Pre-assignment
    Screening details
    		 112 patients were screened prior to randomisation. 35 patients did not enter the study, 25 of which were due to not meeting the inclusion/exclusion criteria and 10 were due to 'Other' reasons

    Period 1
    Period 1 title
    Intervention Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Selumetinib alone
    Arm description
    		 75gm twice daily - continuous
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Selumetinib
    Investigational medicinal product code
    AZD6244
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Given as 3 25mg tables

    Arm title
    		 Selumetinib (Continuous) plus Paclitaxel
    Arm description
    		 PO Selumetinib - 75mg twice daily - continuous IV Paclitaxel - 80mg/m2 administered on day 1, 8 and 15 (for 6 cycles)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selumetinib
    Investigational medicinal product code
    AZD6244
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Given as 3 25mg tables

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    L01CD01
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel will be supplied and prepared according to local policy. Paclitaxel must be handled and stored according to the instructions within the corresponding Summary of Products Characteristics (Please refer to current paclitaxel SmPCs supplied by the appropriate manufacturer). Dose banding may be performed as per local practice. Paclitaxel should be labelled as per standard hospital labelling procedures. For the purposes of this study an Annex 13 compliant label is required. 80mg/m2 paclitaxel should be administered through an in-line filter with a microporous membrane ≤0.22μm. All patients must be premedicated with corticosteroids, antihistamines, and H2 antagonists prior to paclitaxel therapy. Paclitaxel should be given under the supervision of a physician with experience in using cancer chemotherapeutic agents. Appropriate equipment for emergency treatment should be available.

    Arm title
    		 Selumetinib plus Paclitaxel
    Arm description
    		 PO Selumetinib - 75mg twice daily - 2 days off prior to (and morning of) each paclitaxel IV Paclitaxel - 80mg/m2 administered on day 1, 8 and 15 (for 6 cycles)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selumetinib
    Investigational medicinal product code
    AZD6244
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Given as 3 25mg tables - 2 days off prior to (and morning of) each Paclitaxel administration

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    L01CD01
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel will be supplied and prepared according to local policy. Paclitaxel must be handled and stored according to the instructions within the corresponding Summary of Products Characteristics (Please refer to current paclitaxel SmPCs supplied by the appropriate manufacturer). Dose banding may be performed as per local practice. Paclitaxel should be labelled as per standard hospital labelling procedures. For the purposes of this study an Annex 13 compliant label is required. 80mg/m2 paclitaxel should be administered through an in-line filter with a microporous membrane ≤0.22μm. All patients must be premedicated with corticosteroids, antihistamines, and H2 antagonists prior to paclitaxel therapy. Paclitaxel should be given under the supervision of a physician with experience in using cancer chemotherapeutic agents. Appropriate equipment for emergency treatment should be available.

    Number of subjects in period 1
    		Selumetinib alone Selumetinib (Continuous) plus Paclitaxel Selumetinib plus Paclitaxel
    Started
    26
    26
    25
    Completed
    21
    19
    19
    Not completed
    5
    7
    6
         Adverse event, serious fatal
    -
    1
    -
         Adverse event, non-fatal
    5
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selumetinib alone
    Reporting group description
    		 75gm twice daily - continuous

    Reporting group title
    Selumetinib (Continuous) plus Paclitaxel
    Reporting group description
    		 PO Selumetinib - 75mg twice daily - continuous IV Paclitaxel - 80mg/m2 administered on day 1, 8 and 15 (for 6 cycles)

    Reporting group title
    Selumetinib plus Paclitaxel
    Reporting group description
    		 PO Selumetinib - 75mg twice daily - 2 days off prior to (and morning of) each paclitaxel IV Paclitaxel - 80mg/m2 administered on day 1, 8 and 15 (for 6 cycles)

    Reporting group values
    		 Selumetinib alone Selumetinib (Continuous) plus Paclitaxel Selumetinib plus Paclitaxel Total
    Number of subjects
    		 26 26 25 77
    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))
    		 65.5 (56 to 72) 65 (61 to 70) 65 (58.5 to 71) -
    Gender categorical
    Units: Subjects
        Female
    		 14 11 12 37
        Male
    		 12 15 13 40
    ECOG
    Units: Subjects
        ECOG 0
    		 12 15 12 39
        ECOG 1
    		 13 10 11 34
        ECOG 2
    		 1 1 2 4
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Set on the Intention to treat principle retaining patients in their randomised groups irrespective of any protocol deviations

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    77
    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))
    65 (58 to 71)
    Gender categorical
    Units: Subjects
        Female
    37
        Male
    40
    ECOG
    Units: Subjects
        ECOG 0
    39
        ECOG 1
    34
        ECOG 2
    4

    End points

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    End points reporting groups
    Reporting group title
    Selumetinib alone
    Reporting group description
    		 75gm twice daily - continuous

    Reporting group title
    Selumetinib (Continuous) plus Paclitaxel
    Reporting group description
    		 PO Selumetinib - 75mg twice daily - continuous IV Paclitaxel - 80mg/m2 administered on day 1, 8 and 15 (for 6 cycles)

    Reporting group title
    Selumetinib plus Paclitaxel
    Reporting group description
    		 PO Selumetinib - 75mg twice daily - 2 days off prior to (and morning of) each paclitaxel IV Paclitaxel - 80mg/m2 administered on day 1, 8 and 15 (for 6 cycles)

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Set on the Intention to treat principle retaining patients in their randomised groups irrespective of any protocol deviations

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    End point type
    Primary
    End point timeframe
    Randomisation until disease progression
    End point values
    		 Selumetinib alone Selumetinib (Continuous) plus Paclitaxel Selumetinib plus Paclitaxel
    Number of subjects analysed
    26
    26
    25
    Units: Months
        median (confidence interval 95%)
    3.45 (2.04 to 4.96)
    4.80 (3.45 to 8.25)
    4.96 (4.01 to 6.27)
    Statistical analysis title
    		 PFS
    Comparison groups
    Selumetinib alone v Selumetinib (Continuous) plus Paclitaxel v Selumetinib plus Paclitaxel
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0447 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6074
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2483
    Notes
    [1] - Dispersion value about log hazard ratio (-0.4986)

    Secondary: Time To Treatment Failure

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    End point title
    		 Time To Treatment Failure
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation until time to treatment failure
    End point values
    		 Selumetinib alone Selumetinib (Continuous) plus Paclitaxel Selumetinib plus Paclitaxel
    Number of subjects analysed
    26
    26
    25
    Units: Months
        median (confidence interval 95%)
    3.45 (2.04 to 5.42)
    5.32 (3.45 to 8.67)
    5.58 (4.96 to 11.33)
    Statistical analysis title
    		 TTF
    Comparison groups
    Selumetinib alone v Selumetinib (Continuous) plus Paclitaxel v Selumetinib plus Paclitaxel
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.541
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.347
         upper limit
    		 0.842
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.269
    Notes
    [2] - Standard error about log hazard ratio presented (-0.615)

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    From Randomisation until Death by any cause
    End point values
    		 Selumetinib alone Selumetinib (Continuous) plus Paclitaxel Selumetinib plus Paclitaxel
    Number of subjects analysed
    26
    26
    25
    Units: Months
        median (confidence interval 95%)
    11.17 (6.73 to 16.5)
    8.94 (6.93 to 12.6)
    9.10 (5.49 to 15.0)
    Statistical analysis title
    		 OS
    Comparison groups
    Selumetinib alone v Selumetinib (Continuous) plus Paclitaxel v Selumetinib plus Paclitaxel
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.354 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.276
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.828
         upper limit
    		 1.967
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.263
    Notes
    [3] - Dispersion parameter presented about log hazard ratio (0.2439)

    Secondary: Response Rate

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    End point title
    		 Response Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Full study period
    End point values
    		 Selumetinib alone Selumetinib (Continuous) plus Paclitaxel Selumetinib plus Paclitaxel
    Number of subjects analysed
    26
    26
    25
    Units: Patients
    0
    4
    2
    Statistical analysis title
    		 ORR
    Statistical analysis description
    Analysis performed on overall response rate
    Comparison groups
    Selumetinib alone v Selumetinib (Continuous) plus Paclitaxel v Selumetinib plus Paclitaxel
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0866
    Method
    		 Fisher exact
    Parameter type
    		 NA due to zero value
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.642
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Full study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Selumetinib
    Reporting group description
    		 -

    Reporting group title
    Selumetinib (cont) plus Paclitaxel
    Reporting group description
    		 -

    Reporting group title
    Selumetinib plus Paclitaxel
    Reporting group description
    		 -

    Serious adverse events
    		 Selumetinib Selumetinib (cont) plus Paclitaxel Selumetinib plus Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 26 (42.31%)
    15 / 26 (57.69%)
    9 / 25 (36.00%)
         number of deaths (all causes)
    24
    22
    20
         number of deaths resulting from adverse events
    0
    1
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
    Investigations - Other, specify
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Vasovagal reaction
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (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
    Thromboembolic Event
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Muscle Weakness left-sided
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Facial Muscle Weakness
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Paresthesia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    3 / 26 (11.54%)
    6 / 26 (23.08%)
    4 / 25 (16.00%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 26 (3.85%)
    3 / 26 (11.54%)
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (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
    Odema
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (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
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (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
    Abdominal distension
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Mucositis oral
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    3 / 26 (11.54%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Productive Cough
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (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
    Epistaxis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (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
    Lung Infection
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sore Throat
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (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
    Renal and urinary disorders
    Akute Kidney Injury
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         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 - other, specify
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (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
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (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
    Bone Pain
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (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
    muscle weakness lower limb
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (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
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (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
    Dehydration
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 25 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Selumetinib Selumetinib (cont) plus Paclitaxel Selumetinib plus Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 26 (96.15%)
    24 / 26 (92.31%)
    23 / 25 (92.00%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 26 (23.08%)
    4 / 26 (15.38%)
    1 / 25 (4.00%)
         occurrences all number
    16
    5
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 26 (26.92%)
    7 / 26 (26.92%)
    2 / 25 (8.00%)
         occurrences all number
    22
    7
    2
    GGT Increased
         subjects affected / exposed
    3 / 26 (11.54%)
    3 / 26 (11.54%)
    0 / 25 (0.00%)
         occurrences all number
    3
    5
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 26 (0.00%)
    6 / 26 (23.08%)
    3 / 25 (12.00%)
         occurrences all number
    0
    15
    6
    Creatinine increased
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    1 / 25 (4.00%)
         occurrences all number
    0
    5
    1
    Blood bilirubin increased
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    0
    6
    Alkaline phosphatase increased
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    2
    White Blood Cell Decreased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    0
    5
    Lymphoblast count decreased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    0
    4
    Vascular disorders
    Thromboembolic Event
         subjects affected / exposed
    0 / 26 (0.00%)
    4 / 26 (15.38%)
    1 / 25 (4.00%)
         occurrences all number
    0
    4
    2
    Epistaxis
         subjects affected / exposed
    2 / 26 (7.69%)
    5 / 26 (19.23%)
    4 / 25 (16.00%)
         occurrences all number
    2
    7
    6
    Hypertenstion
         subjects affected / exposed
    7 / 26 (26.92%)
    9 / 26 (34.62%)
    5 / 25 (20.00%)
         occurrences all number
    15
    18
    6
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 26 (3.85%)
    9 / 26 (34.62%)
    9 / 25 (36.00%)
         occurrences all number
    1
    11
    9
    Headache
         subjects affected / exposed
    4 / 26 (15.38%)
    4 / 26 (15.38%)
    1 / 25 (4.00%)
         occurrences all number
    4
    9
    1
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 26 (3.85%)
    8 / 26 (30.77%)
    8 / 25 (32.00%)
         occurrences all number
    1
    11
    14
    Paresthesia
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
         occurrences all number
    2
    2
    1
    Dizzyness
         subjects affected / exposed
    2 / 26 (7.69%)
    4 / 26 (15.38%)
    1 / 25 (4.00%)
         occurrences all number
    3
    4
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 26 (46.15%)
    15 / 26 (57.69%)
    11 / 25 (44.00%)
         occurrences all number
    13
    29
    20
    Oedema
         subjects affected / exposed
    6 / 26 (23.08%)
    8 / 26 (30.77%)
    7 / 25 (28.00%)
         occurrences all number
    12
    10
    8
    Pain
         subjects affected / exposed
    9 / 26 (34.62%)
    10 / 26 (38.46%)
    9 / 25 (36.00%)
         occurrences all number
    14
    18
    14
    Infusion related reaction
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    1 / 25 (4.00%)
         occurrences all number
    0
    3
    1
    Fever
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    6 / 25 (24.00%)
         occurrences all number
    1
    2
    9
    Flu like sypmtoms
         subjects affected / exposed
    0 / 26 (0.00%)
    4 / 26 (15.38%)
    2 / 25 (8.00%)
         occurrences all number
    0
    5
    2
    Lethargy
         subjects affected / exposed
    2 / 26 (7.69%)
    7 / 26 (26.92%)
    2 / 25 (8.00%)
         occurrences all number
    2
    8
    2
    Edema Limbs
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    0
    1
    Eye disorders
    Blurred Vision
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 26 (11.54%)
    3 / 25 (12.00%)
         occurrences all number
    4
    3
    3
    Eye disorders - other, specify
         subjects affected / exposed
    1 / 26 (3.85%)
    4 / 26 (15.38%)
    1 / 25 (4.00%)
         occurrences all number
    1
    4
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 26 (34.62%)
    17 / 26 (65.38%)
    15 / 25 (60.00%)
         occurrences all number
    13
    32
    30
    Constipation
         subjects affected / exposed
    2 / 26 (7.69%)
    8 / 26 (30.77%)
    10 / 25 (40.00%)
         occurrences all number
    3
    12
    12
    Vomiting
         subjects affected / exposed
    3 / 26 (11.54%)
    7 / 26 (26.92%)
    10 / 25 (40.00%)
         occurrences all number
    4
    13
    15
    Abdominal pain
         subjects affected / exposed
    2 / 26 (7.69%)
    4 / 26 (15.38%)
    3 / 25 (12.00%)
         occurrences all number
    4
    5
    3
    Nausea
         subjects affected / exposed
    4 / 26 (15.38%)
    14 / 26 (53.85%)
    16 / 25 (64.00%)
         occurrences all number
    5
    17
    23
    Mucositosis oral
         subjects affected / exposed
    3 / 26 (11.54%)
    10 / 26 (38.46%)
    13 / 25 (52.00%)
         occurrences all number
    4
    18
    21
    Gastroesophageal reflux disease
         subjects affected / exposed
    2 / 26 (7.69%)
    4 / 26 (15.38%)
    2 / 25 (8.00%)
         occurrences all number
    2
    4
    3
    Dry Mouth
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 26 (3.85%)
    4 / 25 (16.00%)
         occurrences all number
    3
    1
    4
    Dyspepsia
         subjects affected / exposed
    1 / 26 (3.85%)
    5 / 26 (19.23%)
    3 / 25 (12.00%)
         occurrences all number
    2
    7
    4
    Abdominal distension
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
         occurrences all number
    2
    1
    1
    Sore throat
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 26 (11.54%)
    0 / 25 (0.00%)
         occurrences all number
    2
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    2 / 26 (7.69%)
    6 / 26 (23.08%)
    7 / 25 (28.00%)
         occurrences all number
    3
    8
    10
    Cough
         subjects affected / exposed
    3 / 26 (11.54%)
    5 / 26 (19.23%)
    4 / 25 (16.00%)
         occurrences all number
    3
    5
    5
    Hepatobiliary disorders
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences all number
    1
    3
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    14 / 26 (53.85%)
    16 / 26 (61.54%)
    10 / 25 (40.00%)
         occurrences all number
    44
    41
    20
    Alopecia
         subjects affected / exposed
    1 / 26 (3.85%)
    8 / 26 (30.77%)
    10 / 25 (40.00%)
         occurrences all number
    1
    12
    12
    Rash Aceniform
         subjects affected / exposed
    6 / 26 (23.08%)
    10 / 26 (38.46%)
    6 / 25 (24.00%)
         occurrences all number
    13
    27
    13
    Rash Generalized
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    1
    0
    4
    Dry Skin
         subjects affected / exposed
    3 / 26 (11.54%)
    2 / 26 (7.69%)
    2 / 25 (8.00%)
         occurrences all number
    3
    3
    2
    Nail discolouration
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    3
    Papulopustular rash
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
         occurrences all number
    0
    10
    0
    Rash pustular
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
         occurrences all number
    3
    1
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 26 (3.85%)
    5 / 26 (19.23%)
    1 / 25 (4.00%)
         occurrences all number
    1
    7
    2
    Rash Macular
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
         occurrences all number
    0
    6
    1
    Pruritus
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
         occurrences all number
    2
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
         occurrences all number
    0
    3
    3
    Infections and infestations
    Infections and Infestations - Other
         subjects affected / exposed
    1 / 26 (3.85%)
    4 / 26 (15.38%)
    3 / 25 (12.00%)
         occurrences all number
    1
    7
    5
    Upper respiratory infection
         subjects affected / exposed
    0 / 26 (0.00%)
    4 / 26 (15.38%)
    1 / 25 (4.00%)
         occurrences all number
    0
    4
    1
    Eye Infection
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
         occurrences all number
    3
    2
    1
    Paronychia
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
         occurrences all number
    0
    4
    1
    Mucosal Infection
         subjects affected / exposed
    4 / 26 (15.38%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    4
    0
    0
    Lung Infection
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    2
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    2 / 26 (7.69%)
    7 / 26 (26.92%)
    9 / 25 (36.00%)
         occurrences all number
    4
    10
    12
    Hypokalemia
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    6
    0
    2
    Hypophosphatemia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
         occurrences all number
    2
    3
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Mar 2015
    Original approved version, with updates as requested by the competent authority.
    20 Jul 2016
    a. Addition of ISRCTN and EudraCT number and update to trial contact details. b. Update to UK Registration statement to document the HRA Approval process. c. Update to trial background to include SUMIT study findings. d. Inclusion criteria: change in reporting units for haemoglobin and creatinine. e. Exclusion criteria: point 2 and point 6 consolidated to avoid repetition i.e. leptomeningeal metastases added to list in point 2 - exclusion for patients who have a known or suspected brain or leptomeningeal metastases, or spinal cord compression, unless asymptomatic. f. Exclusion criteria: point 11, update to wording, effective methods of contraception rather than method. g. Clarification for arm C dosing schedule, selumetinib is to be omitted 2 days prior to (and the morning of) each paclitaxel infusion. h. Addition of information for the preparation of paclitaxel. i. Addition of information for the continued provision of selumetinib. j. Addition of liver MRI as a technique for radiological disease assessment. k. Scan and LVEF assessment times to be performed from the treatment start date. l. Update to the schedule of procedures for clarification only; to clarify screening assessment timeframes, visits for arm A patients, visits and procedures for cycle 7 onwards (continuous selumetinib) and the allowed window for 8 weekly (±3 days) scans and 12 weekly (±14 days) LVEF assessments. m. Medical history review to be carried out at screening & baseline only. n. If a patient has progressed clinic visits will be as per standard of care until death. o. Biopsy procedures to be performed under ultrasound or CT-guidance. p. Update to contraception advice; two reliable methods of contraception required. q. Addition of the use of participant identification centres for the SelPac study. r. Updates to statistical considerations with more detail about planned analyses. s. Update to the statement of indemnity, UoL holds appropriate insurance for the design
    24 Jan 2018
    a. Addition of sponsor protocol reference number and update to trial contact details, including named trial statistician. b. Further detail on the rationale for IMP doses provided. c. Retinal vein occlusion added to the list of identified risks with selumetinib use. d. Inclusion criteria: point 7, updated to consider endocrinopathies treated with hormone replacement. e. Inclusion criteria: point 10, requirement for written informed consent added for clarification. f. Exclusion criteria: point 5 updated, statement concerning toxicities from previous treatments removed as this is defined in the inclusion criteria. g. Exclusion criteria: point 7 updated, caveat added for hypertension criteria concerning German-patients only. h. Exclusion criteria: point 12 added, German-patients who are placed on administrative order in an institution or are dependant from the sponsor or study doctor are excluded from the study. i. Further clarification on follow up visit schedule provided. j. Pregnancy test information updated, urine or serum testing is permitted. k. Biochemistry information updated, GGT test is not required on day 8 and 15 of each cycle. Phosphate test added. l. Clarification provided on arm B and C selumetinib dosing following paclitaxel discontinuation. m. Update to selumetinib specific restrictions advice for consistency with the main trial PIS. Patients should avoid consuming grapefruits, Seville oranges, or any other products that may contain these fruits. n. Update to the schedule of procedures for clarification only; to clarify end of treatment, follow-up and end of study visit timeframes. o. Pregnancy testing (for women of child bearing potential only) should be performed at screening and as clinically indicated. p. SAE reporting instructions for site, wording updated for clarity. q. Miscellaneous administrative and formatting changes.
    04 Jul 2018
    a. Update to the statistical design, planned sample size and overall study duration. b. Update to the primary analysis method (removal of post stratification factors). c. Removal of the futility analysis. d. Wording for translational sample chain of custody added for clarification purposes. e. Miscellaneous administrative and formatting changes.
    22 Mar 2019
    Update to the statistical analysis section for clarification purposes; wording updated to allow analyses to be undertaken with statistical software other than Stata, exploratory translational outcomes paragraph separated into a subsection and wording corrected for final analysis trigger.
    13 May 2020
    a. Contact details updated. b. Paragraph added to provide information on trials unit merger. c. Update to translational sample storage location. d. Update to the wording for LPLV and trial closure. e. Update to statistical section 10.4 for consistency with LPLV statement.

    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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    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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