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    Clinical Trial Results:
    ARomatase Inhibition plus minus SaracaTinib as Advanced breast CAncer Therapy: a randomised phase II study of aromatase inhibition plus/minus the src-inhibitor AZD0530 in post-menopausal women with advanced breast cancer.

    Summary
    EudraCT number
    		 2011-002157-64
    Trial protocol
    		 GB  
    Global end of trial date
    30 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Mar 2020
    First version publication date
    14 Mar 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    v1.2 (14/04/2016)
    Additional study identifiers
    ISRCTN number
    		 ISRCTN23804370
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Common Services Agency
    Sponsor organisation address
    CSA at NHS NSS, Gyle Square, 1 South Gyle Cresent, Edinburgh, United Kingdom, EH12 9EB
    Public contact
    Eve Macdonald Chisholm, Scottish Clinical Trials Research Unit National Services Scotland, +44 01312757058, eve.macdonald.chisholm@nhs.net
    Scientific contact
    Professor David Cameron, Cancer Research UK Edinburgh Centre, +44 0131 651 8510, David.Cameron@igmm.ed.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
    20 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary research objective is to see whether patients taking an aromatase inhibitor in combination with saracatinib have a longer progression free survival (surving without their cancer growing or spreading) than the patients who are taking aromatase inhibitor with placebo.
    Protection of trial subjects
    No specific additional measures were implemented for this trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 140
    Worldwide total number of subjects
    140
    EEA total number of subjects
    140
    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)
    70
    From 65 to 84 years
    69
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 51% patients failed screening (conmeds, out of range labs [LFTs, EGFR, blood counts], HER2 status, performance status, comorbidities, not menopausal, disease not confirmed). 27% patients refused (did not want extra tests/travel/procedures; anxious about side effects; external influences.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    A centralised registration system will be used to assign patients to treatment groups. The packaging and tablets will appear identical for both active and matching placebo treatments. The label attached to each package of blinded study material will have a unique treatment kit number that is linked to the randomisation scheme.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AI plus Saracatinib
    Arm description
    		 Patients will receive an aromatase inhibitor and saracatinib (AZD0530). Patients will be enrolled into one of two strata: an “AI-sensitive/naïve” group of patients with potentially AI-sensitive tumours, and a second “prior-AI” group of women whose cancers have already progressed on an AI, but for whom there is likely to still be some endocrine sensitivity. For women in the “AI-sensitive/naïve” group, treatment would be with anastrazole 1mg daily plus saracatinib 175 mg daily. For women in the “prior AI” group, treatment would be exemestane 25mg daily plus saracatinib 175 mg daily. Saracatinib (AZD0530) is an oral Src inhibitor and can be administered with or without food.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Saracatinib
    Investigational medicinal product code
    Other name
    AZD0530
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    175 mg daily, with or without food. If a patient forgets to take a tablet, and it is within 6 hours of the scheduled time then the patient should be advised to take them as soon as possible. If it is more than 6 hours after the scheduled time, then study medication should not be taken for that day. Study medication should continue as scheduled previously on the subsequent day. A patient should not take more than a single day’s dose of tablets, within a day. In the event that the patient cannot hold the tablet(s) down (if the patient vomits) within 30 minutes from taking the tablet(s) or if can identify the tablet (s) in the vomit content, the patient can re-take new tablet(s) from the bottle(s).

    Investigational medicinal product name
    Anastrazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1mg daily

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25mg daily

    Arm title
    		 AI plus placebo
    Arm description
    		 Patients will receive an aromatase inhibitor and a placebo. Patients will be enrolled into one of two strata: an “AI-sensitive/naïve” group of patients with potentially AI-sensitive tumours, and a second “prior-AI” group of women whose cancers have already progressed on an AI, but for whom there is likely to still be some endocrine sensitivity. For women in the “AI-sensitive/naïve” group, treatment would be with anastrazole 1mg daily plus placebo. For women in the “prior AI” group, treatment would be exemestane 25mg daily plus placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    N/A

    Number of subjects in period 1
    		AI plus Saracatinib AI plus placebo
    Started
    69
    71
    Completed
    37
    58
    Not completed
    32
    13
         Adverse event, serious fatal
    4
    2
         Physician decision
    12
    3
         Consent withdrawn by subject
    6
    2
         Adverse event, non-fatal
    5
    4
         Drug discontinued
    1
    -
         Lost to follow-up
    1
    -
         Missing data
    -
    1
         Protocol deviation
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AI plus Saracatinib
    Reporting group description
    		 Patients will receive an aromatase inhibitor and saracatinib (AZD0530). Patients will be enrolled into one of two strata: an “AI-sensitive/naïve” group of patients with potentially AI-sensitive tumours, and a second “prior-AI” group of women whose cancers have already progressed on an AI, but for whom there is likely to still be some endocrine sensitivity. For women in the “AI-sensitive/naïve” group, treatment would be with anastrazole 1mg daily plus saracatinib 175 mg daily. For women in the “prior AI” group, treatment would be exemestane 25mg daily plus saracatinib 175 mg daily. Saracatinib (AZD0530) is an oral Src inhibitor and can be administered with or without food.

    Reporting group title
    AI plus placebo
    Reporting group description
    		 Patients will receive an aromatase inhibitor and a placebo. Patients will be enrolled into one of two strata: an “AI-sensitive/naïve” group of patients with potentially AI-sensitive tumours, and a second “prior-AI” group of women whose cancers have already progressed on an AI, but for whom there is likely to still be some endocrine sensitivity. For women in the “AI-sensitive/naïve” group, treatment would be with anastrazole 1mg daily plus placebo. For women in the “prior AI” group, treatment would be exemestane 25mg daily plus placebo.

    Reporting group values
    		 AI plus Saracatinib AI plus placebo Total
    Number of subjects
    		 69 71 140
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 36 34 70
        From 65-84 years
    		 32 37 69
        85 years and over
    		 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 69 71 140
        Male
    		 0 0 0
    AI sensitivity
    Patient sensitivity to AI: “AI-sensitive/naive”: either never previously treated with AI; or if treated with tamoxifen must not have rapid progression on tamoxifen (i.e. treated for >=24 mo adjuvant or >=6 mo in metastatic setting); or, if previously treated with an AI, only in the adjuvant or neo-adjuvant setting AND remained progression free for >=12mo whilst not being treated with an AI. “prior AI”: patients NOT meeting criteria above, but previously treated with non-steroidal AI without progression for >=24mo in (neo-) adjuvant setting or for >=6mo for advanced disease.
    Units: Subjects
        AI-sensitive/naive
    		 36 33 69
        prior AI
    		 33 38 71

    End points

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    End points reporting groups
    Reporting group title
    AI plus Saracatinib
    Reporting group description
    		 Patients will receive an aromatase inhibitor and saracatinib (AZD0530). Patients will be enrolled into one of two strata: an “AI-sensitive/naïve” group of patients with potentially AI-sensitive tumours, and a second “prior-AI” group of women whose cancers have already progressed on an AI, but for whom there is likely to still be some endocrine sensitivity. For women in the “AI-sensitive/naïve” group, treatment would be with anastrazole 1mg daily plus saracatinib 175 mg daily. For women in the “prior AI” group, treatment would be exemestane 25mg daily plus saracatinib 175 mg daily. Saracatinib (AZD0530) is an oral Src inhibitor and can be administered with or without food.

    Reporting group title
    AI plus placebo
    Reporting group description
    		 Patients will receive an aromatase inhibitor and a placebo. Patients will be enrolled into one of two strata: an “AI-sensitive/naïve” group of patients with potentially AI-sensitive tumours, and a second “prior-AI” group of women whose cancers have already progressed on an AI, but for whom there is likely to still be some endocrine sensitivity. For women in the “AI-sensitive/naïve” group, treatment would be with anastrazole 1mg daily plus placebo. For women in the “prior AI” group, treatment would be exemestane 25mg daily plus placebo.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population includes any patient who had at least one dose of study medication. There 136 patient in total, with 67 in Arm A (+study drug) and 69 in Arm B (placebo).

    Subject analysis set title
    Eligible patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This population excludes patients with gross eligibility deviations. Patients with gross deviations will be determined in consultation with the Chief Investigator. Arm A (study drug) has 66 patients, Arm B (placebo) has 68 patients; 134 patients in total.

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This includes all patients randomised into the study regardless of whether they received treatment or not. Arm A (study drug) has 69 patients; Arm B (placebo) has 71 patients.

    Primary: Efficacy (progression free survival)

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    End point title
    		 Efficacy (progression free survival)
    End point description
    Comparison of progression free survival between cohort receiving aromatase inhibition plus saracatinib, versus those receiving aromatase inhibition plus placebo. The duration of progression-free survival (PFS) is measured as the time from randomisation to the time that confirmed progression or death from any cause is documented (whichever comes first). Patients who neither progress nor die are censored at the date they were last known to be alive and progression free.
    End point type
    Primary
    End point timeframe
    48 months
    End point values
    		 AI plus Saracatinib AI plus placebo Intention to treat
    Number of subjects analysed
    61
    67
    140
    Units: Patients
    69
    71
    140
    Statistical analysis title
    		 Progression-free survival (Cox regression)
    Statistical analysis description
    Cox regression to assess whether there is a difference between the treatment and control arm with regards to progression-free survival .
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.955 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.369
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 1.735
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.185
    Notes
    [1] - One sided p-value, assessing whether there is reduced risk in the treatment arm.

    Secondary: Safety (toxicity)

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    End point title
    		 Safety (toxicity)
    End point description
    Toxicity assessment (e.g. vomiting, cough) based on criteria (CTCAE V4.0) for analysed patients for each assessment.
    End point type
    Secondary
    End point timeframe
    48 months
    End point values
    		 AI plus Saracatinib AI plus placebo Safety population
    Number of subjects analysed
    67
    69
    136
    Units: Patients
    67
    69
    136
    Statistical analysis title
    		 Fatigue (Mann Whitney U)
    Statistical analysis description
    Analysis of whether fatigue is more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 = 0.092
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Data was not assessed for the following numbers of patients: Arm A (study drug): 6 Arm B (placebo): 10
    Statistical analysis title
    		 Nausea (Mann Whitney U)
    Statistical analysis description
    Analysis of whether nausea is more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.817
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - Data was not assessed for the following numbers of patients: Arm A (study drug): 6 Arm B (placebo): 9
    Statistical analysis title
    		 Vomiting (Mann Whitney U)
    Statistical analysis description
    Analysis of whether vomiting is more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 = 0.016
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - Data was not assessed for the following numbers of patients: Arm A (study drug): 5 Arm B (placebo): 10
    Statistical analysis title
    		 Alopecia (Mann Whitney U)
    Statistical analysis description
    Analysis of whether alopecia is more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 = 0.002
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Data was not assessed for the following numbers of patients: Arm A (study drug): 6 Arm B (placebo): 10
    Statistical analysis title
    		 Neuropathy (Mann Whitney U)
    Statistical analysis description
    Analysis of whether neuropathy is more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 = 0.807
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - Data was not assessed for the following numbers of patients: Arm A (study drug): 6 Arm B (placebo): 10
    Statistical analysis title
    		 Mucositis/stomatitis (Mann Whitney U)
    Statistical analysis description
    Analysis of whether mucositis/stomatitisis more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    P-value
    		 = 0.559
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - Data was not assessed for the following numbers of patients: Arm A (study drug): 5 Arm B (placebo): 10
    Statistical analysis title
    		 Rash/desquamation (Mann Whitney U)
    Statistical analysis description
    Analysis of whether rash/desquamation more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    P-value
    		 = 0.004
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - Data was not assessed for the following numbers of patients: Arm A (study drug): 3 Arm B (placebo): 10
    Statistical analysis title
    		 Hypersensitivity (Mann Whitney U)
    Statistical analysis description
    Analysis of whether hypersensitivity more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    P-value
    		 = 0.327
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [9] - Data was not assessed for the following numbers of patients: Arm A (study drug): 6 Arm B (placebo): 10
    Statistical analysis title
    		 Anorexia (Mann Whitney U)
    Statistical analysis description
    Analysis of whether anorexia more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [10]
    P-value
    		 = 0.004
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [10] - Data was not assessed for the following numbers of patients: Arm A (study drug): 5 Arm B (placebo): 10
    Statistical analysis title
    		 Diarrhoea (Mann Whitney U)
    Statistical analysis description
    Analysis of whether diarrhoea more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [11]
    P-value
    		 = 0.048
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [11] - Data was not assessed for the following numbers of patients: Arm A (study drug): 4 Arm B (placebo): 10
    Statistical analysis title
    		 Constipation (Mann Whitney U)
    Statistical analysis description
    Analysis of whether constipation more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [12]
    P-value
    		 = 0.87
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [12] - Data was not assessed for the following numbers of patients: Arm A (study drug): 5 Arm B (placebo): 10
    Statistical analysis title
    		 Febrile neuropenia (Mann Whitney U)
    Statistical analysis description
    Analysis of whether febrile neuropenia more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [13]
    P-value
    		 = 0.59
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [13] - Data was not assessed for the following numbers of patients: Arm A (study drug): 5 Arm B (placebo): 10
    Statistical analysis title
    		 Infection (Mann Whitney U)
    Statistical analysis description
    Analysis of whether infection more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [14]
    P-value
    		 = 0.275
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [14] - Data was not assessed for the following numbers of patients: Arm A (study drug): 1 Arm B (placebo): 2
    Statistical analysis title
    		 Anaemia (Mann Whitney U)
    Statistical analysis description
    Analysis of whether anaemia (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [15]
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - All patients assessed.
    Statistical analysis title
    		 ALT (Mann Whitney U)
    Statistical analysis description
    Analysis of whether ALT (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [16]
    P-value
    		 = 0.729
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - All patients assessed.
    Statistical analysis title
    		 Alkaline phosphatase (Mann Whitney U)
    Statistical analysis description
    Analysis of whether alkaline phosphatase (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [17]
    P-value
    		 = 0.955
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [17] - All patients assessed.
    Statistical analysis title
    		 Phosphate (Mann Whitney U)
    Statistical analysis description
    Analysis of whether phosphate (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [18]
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [18] - All patients assessed.
    Statistical analysis title
    		 Low sodium (Mann Whitney U)
    Statistical analysis description
    Analysis of whether low sodium (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [19]
    P-value
    		 = 0.626
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [19] - All patients assessed.
    Statistical analysis title
    		 High sodium (Mann Whitney U)
    Statistical analysis description
    Analysis of whether high sodium (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [20]
    P-value
    		 = 0.535
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [20] - All patients assessed.
    Statistical analysis title
    		 Low potassium (Mann Whitney U)
    Statistical analysis description
    Analysis of whether low potassium (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [21]
    P-value
    		 = 0.073
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [21] - All patients assessed.
    Statistical analysis title
    		 High potassium (Mann Whitney U)
    Statistical analysis description
    Analysis of whether high potassium (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [22]
    P-value
    		 = 0.306
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [22] - All patients assessed.
    Statistical analysis title
    		 Neutropenia (Mann Whitney U)
    Statistical analysis description
    Analysis of whether neutropenia (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [23]
    P-value
    		 = 0.571
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [23] - All patients assessed.
    Statistical analysis title
    		 Thrombocytopenia (Mann Whitney U)
    Statistical analysis description
    Analysis of whether thrombocytopenia (as assessed by laboratory testing) more commonly associated with either arm.
    Comparison groups
    AI plus placebo v AI plus Saracatinib
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [24]
    P-value
    		 = 0.438
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [24] - All patients assessed.

    Secondary: Efficacy (change in tumour size)

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    End point title
    		 Efficacy (change in tumour size)
    End point description
    Change in tumour size (as captured by the sum of diameters measurement that informs the RECIST v1.1 response).
    End point type
    Secondary
    End point timeframe
    48 months
    End point values
    		 AI plus Saracatinib AI plus placebo Eligible patients
    Number of subjects analysed
    39 [25]
    57 [26]
    96 [27]
    Units: Number of reductions
    39
    57
    96
    Notes
    [25] - 30 patients had missing measurement data, so % reduction in tumour size could not be calculated.
    [26] - 14 patients had missing measurement data, so % reduction in tumour size could not be calculated.
    [27] - 44 patients had missing measurement data, so % reduction in tumour size could not be calculated.
    Statistical analysis title
    		 Change in sum of tumour diameters (Mann Whitney U)
    Statistical analysis description
    Assessing whether there is a significant difference in the percentage reduction in tumour size across arms.
    Comparison groups
    AI plus Saracatinib v AI plus placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.484
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Efficacy (overall survival)

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    End point title
    		 Efficacy (overall survival)
    End point description
    Comparison of overall survival between cohort receiving aromatase inhibition plus saracatinib, versus those receiving aromatase inhibition plus placebo. Overall Survival is defined as the time from the date of randomisation to the date of death from any cause. Patients who do not die are censored at the date they were last known to be alive.
    End point type
    Secondary
    End point timeframe
    48 months
    End point values
    		 AI plus Saracatinib AI plus placebo
    Number of subjects analysed
    69
    71
    Units: Patients
    69
    71
    Statistical analysis title
    		 Overall survival (Cox regression)
    Statistical analysis description
    Cox regression to assess whether there is a difference between the treatment and control arm with regards to overall survival .
    Comparison groups
    AI plus Saracatinib v AI plus placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.881 [28]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.322
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.976
         upper limit
    		 1.791
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.237
    Notes
    [28] - One sided p-value, assessing whether there is reduced risk in the treatment arm.

    Secondary: Efficacy (response)

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    End point title
    		 Efficacy (response)
    End point description
    Change in tumour response (as captured by the number of patients exhibiting a complete or partial responss using the RECIST v1.1 criteria).
    End point type
    Secondary
    End point timeframe
    48 months
    End point values
    		 AI plus Saracatinib AI plus placebo Intention to treat
    Number of subjects analysed
    44 [29]
    59 [30]
    103 [31]
    Units: Patients
    44
    59
    103
    Notes
    [29] - 25 patients had missing RECIST response.
    [30] - 20 patients had missing RECIST response.
    [31] - 37 patients had missing RECIST response.
    Statistical analysis title
    		 Difference in RECIST response
    Statistical analysis description
    Calculating the difference in % complete/partial response in each arm.
    Comparison groups
    AI plus Saracatinib v AI plus placebo
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    19.1
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 7.5
         upper limit
    		 30.7
    Notes
    [32] - Not an analysis as such - just a calculation of the difference in the means. Note that the mean difference is calculated as Arm B-Arm A (i.e., Placebo - study drug).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AE reported from consent signing to 30 days after final study treatment (exception: events considered unrelated before starting study drug). AEs occuring >30 days after final study treatment considred related to study drug will be reported to CSA.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    AI plus Saracatinib
    Reporting group description
    		 Patients will receive an aromatase inhibitor and saracatinib (AZD0530). Patients will be enrolled into one of two strata: an “AI-sensitive/naïve” group of patients with potentially AI-sensitive tumours, and a second “prior-AI” group of women whose cancers have already progressed on an AI, but for whom there is likely to still be some endocrine sensitivity. For women in the “AI-sensitive/naïve” group, treatment would be with anastrazole 1mg daily plus saracatinib 175 mg daily. For women in the “prior AI” group, treatment would be exemestane 25mg daily plus saracatinib 175 mg daily. Saracatinib (AZD0530) is an oral Src inhibitor and can be administered with or without food.

    Reporting group title
    AI plus placebo
    Reporting group description
    		 Patients will receive an aromatase inhibitor and a placebo. Patients will be enrolled into one of two strata: an “AI-sensitive/naïve” group of patients with potentially AI-sensitive tumours, and a second “prior-AI” group of women whose cancers have already progressed on an AI, but for whom there is likely to still be some endocrine sensitivity. For women in the “AI-sensitive/naïve” group, treatment would be with anastrazole 1mg daily plus placebo. For women in the “prior AI” group, treatment would be exemestane 25mg daily plus placebo.

    Serious adverse events
    		 AI plus Saracatinib AI plus placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 67 (44.78%)
    14 / 69 (20.29%)
         number of deaths (all causes)
    39
    41
         number of deaths resulting from adverse events
    Vascular disorders
    Bilateral Pulmonary Emboli
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver portal vein thrombosis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 67 (5.97%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu like symptoms
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi organ failure
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 67 (5.97%)
    4 / 69 (5.80%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Ejection fraction decreased
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Back pain (radiating)
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Low haemoglobin
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood in diarrhoea
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 67 (4.48%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Ascites
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma glutamyl transferase
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    High bilirubin
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin lesions/rash
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Derranged renal U+E
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Ankle fracture
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain (musculoskeletal)
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 67 (2.99%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Joint pain
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus aureus infection
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 69 (1.45%)
         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
    		 AI plus Saracatinib AI plus placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 67 (83.58%)
    46 / 69 (66.67%)
    Investigations
    ALT
    Additional description: Abnormal results of laboratory values. Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    Alkaline phosphatase
    Additional description: Abnormal results of laboratory values. Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    3 / 67 (4.48%)
    11 / 69 (15.94%)
         occurrences all number
    3
    11
    Phosphate
    Additional description: Abnormal results of laboratory values. Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    27 / 67 (40.30%)
    4 / 69 (5.80%)
         occurrences all number
    27
    4
    Low sodium
    Additional description: Abnormal results of laboratory values. Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    0 / 67 (0.00%)
    4 / 69 (5.80%)
         occurrences all number
    0
    4
    Low potassium
    Additional description: Abnormal results of laboratory values. Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    7 / 67 (10.45%)
    2 / 69 (2.90%)
         occurrences all number
    7
    2
    High potassium
    Additional description: Abnormal results of laboratory values. Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 69 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
    Additional description: Abnormal results of laboratory values. Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    3 / 67 (4.48%)
    3 / 69 (4.35%)
         occurrences all number
    3
    3
    Thrombocytopenia
    Additional description: Abnormal results of laboratory values. Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 69 (2.90%)
         occurrences all number
    0
    2
    Nervous system disorders
    Neuropathy
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Fatigue
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    30 / 67 (44.78%)
    20 / 69 (28.99%)
         occurrences all number
    30
    20
    Gastrointestinal disorders
    Nausea
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    17 / 67 (25.37%)
    8 / 69 (11.59%)
         occurrences all number
    17
    8
    Vomiting
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    6 / 67 (8.96%)
    1 / 69 (1.45%)
         occurrences all number
    6
    1
    Mucositis/Stomatitis
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 69 (1.45%)
         occurrences all number
    1
    1
    Diarrhoea
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    10 / 67 (14.93%)
    3 / 69 (4.35%)
         occurrences all number
    10
    3
    Constipation
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    6 / 67 (8.96%)
    4 / 69 (5.80%)
         occurrences all number
    6
    4
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    2 / 67 (2.99%)
    0 / 69 (0.00%)
         occurrences all number
    2
    0
    Rash/desquamation
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    6 / 67 (8.96%)
    1 / 69 (1.45%)
         occurrences all number
    6
    1
    Infections and infestations
    Infection
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    18 / 67 (26.87%)
    20 / 69 (28.99%)
         occurrences all number
    18
    20
    Metabolism and nutrition disorders
    Anorexia
    Additional description: Defining "affected" as CTCAE Grade 2 or above.
         subjects affected / exposed
    8 / 67 (11.94%)
    3 / 69 (4.35%)
         occurrences all number
    8
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2011
    • Patient Flyer V1.0 • Sponsor letter 5th May 2011 • GP Letter V1.0 • CI CV • Investigator Brochure Ed9 • Patient Invite Letter V1.0 • PIS Main trial V1.0 • ICF Main trial V1.0 • PIS Sub-study V1.0 • ICF Sub-study V1.0 • Protocol V1.0 • REC Application
    10 Feb 2012
    • CPAS comments • PIS Main trial V1.1 • ICF Main trial V1.1 • PIS Sub-study V1.1 • ICF Sub-study V1.1 • GP Letter & attachment V1.1 • Patient Flyer V1.1 • Summary PIS V1.0 • Patient Invite Letter V1.1 • Protocol V1.1
    15 Mar 2012
    • Summary PIS V1.1
    09 May 2012
    • Addition of site 005, 018, 008 & 011. • Removal of Addenbrooke’s Hospital & Queen Elizabeth Hospital, Woolich, Southend Hospital & Queen Elizabeth Hospital, Birmingham.
    24 Jul 2012
    • Addition of site 019. • Change of PI at site 011.
    06 Nov 2012
    • Addition of site 020.
    10 Dec 2012
    • Emergency ID Cards
    21 Mar 2013
    • Eligibility Flowchart
    30 Apr 2013
    • Screening Feedback Form v1.0
    17 Oct 2014
    • Updated CMC and Manufacturing Authorisation
    06 Nov 2014
    • Temporary halt of recruitment at St.Barts London
    24 Nov 2014
    • Change of site name and Trust for 007. • Change of PI, site name and Trust for 020. • Removal of site 017.
    19 Feb 2015
    • Dosing Instruction Card
    28 Apr 2016
    • Change of PI at sites 16, 21 & 22
    25 Oct 2016
    • Change of PI at site 008

    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
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