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    Clinical Trial Results:
    Fulvestrant with or without AZD6244, a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor: a randomized placebo-controlled double-blind phase II trial.

    Summary
    EudraCT number
    		 2010-019965-27
    Trial protocol
    		 BE  
    Global end of trial date
    08 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SAKK21/08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01160718
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer Research, +41 31389 91 91, sakkcc@sakk.ch
    Scientific contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer Research, +41 31389 91 91, sakkcc@sakk.ch
    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
    12 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Sep 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to assess the efficacy of the combination AZD6244-fulvestrant in patients with endocrine sensitive breast cancer progressing after aromatase inhibitors.
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 All patients received Fulvestrant 500mg i.m. on day 1, day 15 and day 1 of cycle 2 then every 28 +/- 3 days.
    Evidence for comparator
    		 A placebo-controlled study design was chosen to test the effect of AZD6244 when provided in combination with Fulvestrant.
    Actual start date of recruitment
    10 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 32
    Country: Number of subjects enrolled
    Belgium: 14
    Worldwide total number of subjects
    46
    EEA total number of subjects
    14
    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)
    22
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 89 patients were planned to be enrolled. The trial was prematurely closed for accrual following the interim analysis as defined in the protocol after the inclusion of 46 patients. 14 patients had been enrolled in Belgium (1 center) and 32 patients in Switzerland (19 centres). First patient was enrolled on 18-Nov-2010.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was randomized.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A: Fulvestrat + AZD6244
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6244
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg (3 capsules of 25 mg) twice daily (150 mg per day), p.o.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Arm title
    		 B: Fulvestrat + Placebo
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Arm type
    		 Placebo

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally

    Number of subjects in period 1
    		A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Started
    23
    23
    Completed
    23
    22
    Not completed
    0
    1
         No treatment received
    -
    1
    Period 2
    Period 2 title
    Baseline (Safety)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A: Fulvestrat + AZD6244
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6244
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg (3 capsules of 25 mg) twice daily (150 mg per day), p.o.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Arm title
    		 B: Fulvestrat + Placebo
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Arm type
    		 Placebo

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally

    Number of subjects in period 2
    		A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Started
    23
    22
    Completed
    22
    20
    Not completed
    1
    2
         Major eligibility criteria not met (posteriori)
    1
    2
    Period 3
    Period 3 title
    Baseline (ITT)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A: Fulvestrat + AZD6244
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6244
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg (3 capsules of 25 mg) twice daily (150 mg per day), p.o.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Arm title
    		 B: Fulvestrat + Placebo
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Arm type
    		 Placebo

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: A randomization and baseline period had to be prepended, as one patient in the Placebo arm did not receive study medication (randomization period) and baseline data were assessed for the ITT analysis set which is different from the safety analysis set (baseline period).
    Number of subjects in period 3 [2]
    		A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Started
    22
    20
    Completed
    22
    20
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline data were assessed for the ITT population which is different from the total number on enrolled patients. The ITT population excluded one randomized patient that did not receive study medication and three patients that posteriori did not satisfy major eligibility criteria and were excluded from the analysis set.
    Period 4
    Period 4 title
    Treatment (ITT)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A: Fulvestrat + AZD6244
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6244
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg (3 capsules of 25 mg) twice daily (150 mg per day), p.o.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Arm title
    		 B: Fulvestrat + Placebo
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Arm type
    		 Placebo

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally

    Number of subjects in period 4
    		A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Started
    22
    20
    Completed
    22
    20
    Period 5
    Period 5 title
    Follow-up (ITT)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A: Fulvestrat + AZD6244
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD6244
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg (3 capsules of 25 mg) twice daily (150 mg per day), p.o.

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Arm title
    		 B: Fulvestrat + Placebo
    Arm description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Arm type
    		 Placebo

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally

    Number of subjects in period 5
    		A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Started
    22
    20
    Completed
    6
    5
    Not completed
    16
    15
         Death (non AE related)
    16
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    A: Fulvestrat + AZD6244
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.

    Reporting group title
    B: Fulvestrat + Placebo
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally

    Reporting group values
    		 A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo Total
    Number of subjects
    		 22 20 42
    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
    Baseline data were assessed for the ITT population.
    Units: years
        median (full range (min-max))
    		 65.5 (40.0 to 79.0) 69.0 (46.0 to 79.0) -
    Gender categorical
    Baseline data were assessed for the ITT population.
    Units: Subjects
        Female
    		 22 20 42
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    A: Fulvestrat + AZD6244
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.

    Reporting group title
    B: Fulvestrat + Placebo
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Reporting group title
    A: Fulvestrat + AZD6244
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.

    Reporting group title
    B: Fulvestrat + Placebo
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Reporting group title
    A: Fulvestrat + AZD6244
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.

    Reporting group title
    B: Fulvestrat + Placebo
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Reporting group title
    A: Fulvestrat + AZD6244
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.

    Reporting group title
    B: Fulvestrat + Placebo
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally
    Reporting group title
    A: Fulvestrat + AZD6244
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + AZD6244, 75 mg (3 capsules of 25 mg) twice daily (150 mg per day), taken orally.

    Reporting group title
    B: Fulvestrat + Placebo
    Reporting group description
    		 Fulvestrant, 500 mg as intrasmuscular injection on day 1, on day 15, on day 1 of cycle 2, and then every 28 +/- 3 days + Placebo (3 capsules, same appearance as AZD6244) twice daily, taken orally

    Subject analysis set title
    Duration of response
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients rreaching CR or PR

    Primary: Primary Endpoint - Disease control

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    End point title
    		 Primary Endpoint - Disease control [1]
    End point description
    Disease control defined as the sum of CR + PR + stable disease ≥ 24 weeks, according to RECIST 1.1
    End point type
    Primary
    End point timeframe
    24 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the study has been terminated prematurely and the number of enrolled patients was reduced, statistical hypothesis testing on the primary endpoint was waived.
    End point values
    		 A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Number of subjects analysed
    22
    20
    Units: Percentage (Pts with CR, PR or SD≥24 w.)
        number (confidence interval 95%)
    23 (8 to 45)
    50 (27 to 73)
    No statistical analyses for this end point

    Secondary: Secondary endpoint - Overall response

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    End point title
    		 Secondary endpoint - Overall response
    End point description
    The best overall response (i.e. CR or PR) is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). In the case of stable disease, measurements must have met the SD criteria at least once after trial entry at a minimum interval of [6 to 8 weeks].
    End point type
    Secondary
    End point timeframe
    From treatment initiation until disease progression/recurrence
    End point values
    		 A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Number of subjects analysed
    22
    20
    Units: Percentage (Pts with CR or PR)
        number (confidence interval 95%)
    5 (0 to 23)
    15 (3 to 38)
    No statistical analyses for this end point

    Secondary: Secondary endpoint - Time to treatment failure (TTF)

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    End point title
    		 Secondary endpoint - Time to treatment failure (TTF)
    End point description
    Time to treatment failure was calculated from randomization until discontinuation of all trial treatment due to any reason (e.g. progressive disease, toxicity, refusal, death).
    End point type
    Secondary
    End point timeframe
    From randomization until discontinuation of the trial treatment.
    End point values
    		 A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Number of subjects analysed
    22 [2]
    20 [3]
    Units: TTF (months)
        median (confidence interval 95%)
    5.1 (2.3 to 6.7)
    5.6 (3.4 to 10.2)
    Notes
    [2] - 22 patients with events | 0 patients censored
    [3] - 20 patients with events | 0 patients censored
    No statistical analyses for this end point

    Secondary: Secondary endpoint - Time to AZD6244 discontinuation

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    End point title
    		 Secondary endpoint - Time to AZD6244 discontinuation
    End point description
    Time to AZD6244 discontinuation will be calculated from randomization to discontinuation of AZD6244 treatment due to any reason (e.g. progressive disease, toxicity, refusal, death).
    End point type
    Secondary
    End point timeframe
    From randomization until discontinuation of AZD6244 treatment.
    End point values
    		 A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Number of subjects analysed
    22 [4]
    20 [5]
    Units: Months
        median (confidence interval 95%)
    2.7 (1.2 to 5.7)
    5.5 (3.4 to 8.4)
    Notes
    [4] - 22 patients with events | 0 patients censored
    [5] - 20 patients with events | 0 patients censored
    No statistical analyses for this end point

    Secondary: Secondary endpoint - Duration of response

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    End point title
    		 Secondary endpoint - Duration of response
    End point description
    Duration of overall response (CR+PR) was calculated from the time that measurement criteria were met for the first time until documented tumor progression. Second-line treatment started before documented progression was not allowed. If done nevertheless, the duration of overall response was censored at the time when the second-line treatment was initiated.
    End point type
    Secondary
    End point timeframe
    Duration of overall response (CR+PR) was calculated from the time that measurement criteria were met for the first time until documented tumor progression.
    End point values
    		 Duration of response
    Number of subjects analysed
    4
    Units: Days
    number (not applicable)
        Arm A: Patient 21 (censored, EoT)
    1222
        Arm B: Patient 19 (event)
    932
        Arm B: Patient 28 (censored, withdrawal of IC)
    51
        Arm B: Patient 30 (event)
    197
    No statistical analyses for this end point

    Secondary: Secondary Endpoint - Progression free survival (PFS)

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    End point title
    		 Secondary Endpoint - Progression free survival (PFS)
    End point description
    Progression-free survival was calculated from randomization until documented tumor progression or death, whichever occurred first. The start of a new line of anticancer treatment was not allowed before documented progression. If done nevertheless, progression-free survival for these patients was censored at the time when the new line of treatment was initiated.
    End point type
    Secondary
    End point timeframe
    Time from randomization until disease progression or death.
    End point values
    		 A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Number of subjects analysed
    22 [6]
    20 [7]
    Units: PFS (month)
        median (confidence interval 95%)
    3.7 (1.9 to 5.8)
    5.6 (3.4 to 13.6)
    Notes
    [6] - 20 patients with progression | 2 patients censored
    [7] - 17 patients with progression | 3 patients censored
    No statistical analyses for this end point

    Secondary: Secondary endpoint - Overall survival

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    End point title
    		 Secondary endpoint - Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Time from randomization until death.
    End point values
    		 A: Fulvestrat + AZD6244 B: Fulvestrat + Placebo
    Number of subjects analysed
    22 [8]
    20 [9]
    Units: OS (months)
        median (confidence interval 95%)
    30.6 (16.1 to 36.1)
    31.7 (15.2 to 45.8)
    Notes
    [8] - 16 patients with death | 6 patients censored
    [9] - 15 patients with death | 5 patients censored
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion until end-oftreatment visit (max. 5 weeks after end of treatment)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Arm A: Safety Set
    Reporting group description
    		 -

    Reporting group title
    Arm B: Safety Set
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A: Safety Set Arm B: Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 23 (21.74%)
    7 / 22 (31.82%)
         number of deaths (all causes)
    17
    15
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestinal obstruction
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A: Safety Set Arm B: Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    22 / 22 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Tumour pain
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 22 (13.64%)
         occurrences all number
    2
    3
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Hot flush
         subjects affected / exposed
    1 / 23 (4.35%)
    9 / 22 (40.91%)
         occurrences all number
    1
    10
    Hypertension
         subjects affected / exposed
    11 / 23 (47.83%)
    12 / 22 (54.55%)
         occurrences all number
    11
    17
    Lymphoedema
         subjects affected / exposed
    5 / 23 (21.74%)
    2 / 22 (9.09%)
         occurrences all number
    6
    4
    Peripheral ischaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Angiopathy
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Face oedema
         subjects affected / exposed
    5 / 23 (21.74%)
    0 / 22 (0.00%)
         occurrences all number
    6
    0
    Oedema peripheral
         subjects affected / exposed
    7 / 23 (30.43%)
    4 / 22 (18.18%)
         occurrences all number
    14
    6
    Fatigue
         subjects affected / exposed
    13 / 23 (56.52%)
    11 / 22 (50.00%)
         occurrences all number
    18
    15
    Pyrexia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Influenza like illness
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 22 (4.55%)
         occurrences all number
    2
    2
    Ill-defined disorder
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    Pain
         subjects affected / exposed
    4 / 23 (17.39%)
    6 / 22 (27.27%)
         occurrences all number
    4
    7
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 23 (30.43%)
    9 / 22 (40.91%)
         occurrences all number
    8
    11
    Dyspnoea
         subjects affected / exposed
    4 / 23 (17.39%)
    6 / 22 (27.27%)
         occurrences all number
    6
    6
    Epistaxis
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Nasal congestion
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Pneumothorax
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Respiratory failure
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Respiratory disorder
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 22 (9.09%)
         occurrences all number
    2
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Investigation
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    4
    Weight decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Hip fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Recall phenomenon
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Angina pectoris
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Palpitations
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 23 (4.35%)
    3 / 22 (13.64%)
         occurrences all number
    1
    4
    Dysaesthesia
         subjects affected / exposed
    1 / 23 (4.35%)
    4 / 22 (18.18%)
         occurrences all number
    1
    4
    Dysgeusia
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    3 / 23 (13.04%)
    6 / 22 (27.27%)
         occurrences all number
    3
    13
    Memory impairment
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    5 / 23 (21.74%)
    4 / 22 (18.18%)
         occurrences all number
    5
    5
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 22 (13.64%)
         occurrences all number
    4
    3
    Syncope
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Tremor
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Tinnitus
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Cataract
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
         occurrences all number
    1
    2
    Dry eye
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    6
    Eye disorder
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 22 (4.55%)
         occurrences all number
    4
    1
    Photophobia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Retinopathy
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Periorbital oedema
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 22 (9.09%)
         occurrences all number
    4
    2
    Ascites
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Colitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    6 / 23 (26.09%)
    7 / 22 (31.82%)
         occurrences all number
    7
    8
    Dental caries
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Diarrhoea
         subjects affected / exposed
    12 / 23 (52.17%)
    8 / 22 (36.36%)
         occurrences all number
    14
    8
    Dry mouth
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 22 (0.00%)
         occurrences all number
    5
    0
    Duodenal hemorrhage
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    Gingival pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 22 (4.55%)
         occurrences all number
    4
    1
    Nausea
         subjects affected / exposed
    9 / 23 (39.13%)
    10 / 22 (45.45%)
         occurrences all number
    10
    11
    Oral dysaesthesia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Periodontal disease
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Salivary duct inflammation
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Enteritis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Vomiting
         subjects affected / exposed
    8 / 23 (34.78%)
    5 / 22 (22.73%)
         occurrences all number
    9
    9
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    4 / 23 (17.39%)
    2 / 22 (9.09%)
         occurrences all number
    4
    2
    Dry skin
         subjects affected / exposed
    5 / 23 (21.74%)
    1 / 22 (4.55%)
         occurrences all number
    5
    1
    Erythema multiforme
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Onychomadesis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Nail ridging
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Pruritus
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    3
    Dermatitis acneiform
         subjects affected / exposed
    12 / 23 (52.17%)
    2 / 22 (9.09%)
         occurrences all number
    16
    2
    Rash maculo-papular
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 22 (0.00%)
         occurrences all number
    4
    0
    Skin disorder
         subjects affected / exposed
    7 / 23 (30.43%)
    1 / 22 (4.55%)
         occurrences all number
    8
    1
    Skin ulcer
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Urinary tract pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 23 (17.39%)
    5 / 22 (22.73%)
         occurrences all number
    5
    11
    Arthritis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 22 (18.18%)
         occurrences all number
    6
    9
    Bone pain
         subjects affected / exposed
    3 / 23 (13.04%)
    7 / 22 (31.82%)
         occurrences all number
    3
    11
    Flank pain
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Kyphosis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    3
    Musculoskeletal disorder
         subjects affected / exposed
    7 / 23 (30.43%)
    1 / 22 (4.55%)
         occurrences all number
    8
    1
    Myalgia
         subjects affected / exposed
    4 / 23 (17.39%)
    4 / 22 (18.18%)
         occurrences all number
    8
    7
    Myositis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Osteoporosis
         subjects affected / exposed
    1 / 23 (4.35%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2
    Pain in extremity
         subjects affected / exposed
    1 / 23 (4.35%)
    5 / 22 (22.73%)
         occurrences all number
    1
    6
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    3
    Bronchitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Infection
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 22 (4.55%)
         occurrences all number
    6
    1
    Lung infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1
    Lymph gland infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Nail infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    Paronychia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 22 (18.18%)
         occurrences all number
    0
    4
    Skin infection
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Vaginal infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 23 (26.09%)
    3 / 22 (13.64%)
         occurrences all number
    6
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    Obesity
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2010
    Adaptations were made regarding the collection of information about available tumor tissue and the safety section has been changed by listing only adverse events which were considered as related to AZD6244.
    02 Feb 2011
    Eligibility criteria were clarified and especially not only patients with measurable disease or bone-only disease were eligible but also patients with assessable unequivocal small liver or lung metastases.
    15 Sep 2011
    Following the interim safety analysis, Amendment 3 was issued in order to adapt the definition of dose modification of AZD6244/placebo: it was advised to proceed to a dose reduction as soon as AEs of grade 2 appear, instead of upon appearance of AEs of grade 3 or higher.

    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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