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    Clinical Trial Results:
    A Phase II study to assess the safety and efficacy of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER positive locally advanced or metastatic breast cancer patients.

    Summary
    EudraCT number
    		 2011-005680-25
    Trial protocol
    		 GB  
    Global end of trial date
    17 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2016
    First version publication date
    08 Apr 2016
    Other versions
    Summary report(s)
    		 IRIS Clinical Study Report Summary 230316

    Trial information

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    Trial identification
    Sponsor protocol code
    C/22/2011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01785992
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Funder Reference (Cancer Research UK): C20208/A13392, IPSEN Study Protocol Number: X-52-58064-010
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    Room 215 Level 2, Medical School Building Norfolk Place, London, United Kingdom, W2 1PG
    Public contact
    Professor Carlo Palmieri, University of Liverpool, 0044 151 706 3616, C.Palmieri@liverpool.ac.uk
    Scientific contact
    Professor Carlo Palmieri, University of Liverpool, 0044 151 706 3616, C.Palmieri@liverpool.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
    04 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess if adding Irosustat to existing aromatase inhibitor (AI) treatment in patients who have progressed on an AI can control cancer growth by either stopping its growth or reducing its size for a period of 6 months.
    Protection of trial subjects
    At study conception three known drug-related adverse events were identified as requiring specific inclusion/exclusion criteria and/or monitoring throughout the study: 1. Muscoskeletal Side Effects: Regular assessments of Calcium, Phosphate and Magnesium levels were included in the standard clinical chemistry bloods and were monitored regularly. 2. Renal Toxicity: Patients with serum creatinine ≥1.5 x ULN were excluded from the study. Serum urea and creatinine were included in the standard clinical chemistry bloods and were monitored regularly. 3. Cardio Toxicity: Patients with a history of prolonged QT or a prolonged QT at baseline were excluded from the study. ECG activity and blood pressure were routinely monitored. Expected adverse events relating to study treatment were summarised in the patient information sheet. As per protocol, an interim analysis was conducted after 13 patients had completed study treatment, the protocol specified that if none of these patients had responded to treatment (complete response, partial response, stable disease) the study would stop. After review of the efficacy and safety data the IDMC recommended that the study continue without change.
    Background therapy
    		 This trial recruited postmenopausal women with ER positive locally advanced or metastatic breast cancer who have progressed during 1st line treatment with an Aromatase Inhibtior (AI). Eligible patients who were enrolled on the study continued to take the class of AI on which they progressed (either Anastrazole (1mg o.d), Letrozole (2.5mg o.d) or Exemestane (25mg o.d)) in addition to the study drug (Irusostat). AIs were considered to be a non-Investigational Medicinal Product (NIMP). Concomitant medications could be prescribed at the treating physicians discretion, with the exception of prohibited medications described in the study protocol. Concomitant medications (and the reason for the medication) were recorded in the study database for the period 4-weeks prior to starting study treatment until the patient's last study visit.
    Evidence for comparator
    		 Not Applicable
    Actual start date of recruitment
    06 Feb 2013
    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: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    15
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Nine UK sites were opened to recruitment, six of these enrolled patients to the study. The first site opened to recruitment on 22/10/2012 and the first patient consent was on 06/02/2013 with the patient confirmed as eligible to enroll into the study on 09/02/2015; the last patient consent was on 26/02/2014 with study enrollment on 05/03/2014.

    Pre-assignment
    Screening details
    		 28 patients were consented to the study. 1 patient was found to be ineligible, due to not meeting the cardiac criteria. The remaining 27 patients were all enrolled on the trial.

    Pre-assignment period milestones
    Number of subjects started
    		 28
    Number of subjects completed
    		 27

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Ineligible: 1
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not Applicable

    Arms
    Arm title
    		 Intervention
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Irosustat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    40mg once daily (O.D) until disease progression, unacceptable toxicity or withdrawal.

    Number of subjects in period 1 [1]
    		Intervention
    Started
    27
    Completed
    23
    Not completed
    4
         Consent withdrawn by subject
    3
         Physician decision
    1
    Notes
    [1] - 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: One patient was found to be ineligible so did not start study treatment. She has not been included int he baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 All patients enrolled on the trial

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 27 27
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.7 ( 10.5 ) -
    Gender categorical
    Only female patients were eligible
    Units: Subjects
        Female
    		 27 27
        Male
    		 0 0
    Ethnicity
    Units: Subjects
        White
    		 24 24
        Mixed
    		 0 0
        Asian
    		 1 1
        Black
    		 1 1
        Chinese
    		 1 1
        Other
    		 0 0
    Treatment History: Prior Chemotherapy
    Patients may have had multiple lines of chemotherapy (i.e. in neoadjuvant, adjuvant and/or advanced 1st line).
    Units: Subjects
        No prior chemotherapy
    		 10 10
        Prior chemotherapy
    		 17 17
    Treatment History: Prior Radiotherapy
    Patients may have had radiotherapy in the adjuvant and/or palliative setting
    Units: Subjects
        No Prior Radiotherapy
    		 13 13
        Prior Radiotherapy
    		 14 14
    Treatment History: Prior Endocrine Therapy
    Patients may have had endocrine therapy in any setting (i.e. neoadjuvant, adjuvant and/or advanced 1st line).
    Units: Subjects
        No prior endocrine therapy
    		 0 0
        Prior endocrine therapy
    		 27 27
    Treatment History: Breast Cancer Surgery
    Units: Subjects
        None
    		 7 7
        Yes
    		 20 20
    Tumour Type
    Units: Subjects
        Invasive Ductal Carcinoma
    		 20 20
        Invasive Lobular Carcinoma
    		 4 4
        Invasive Mixed Carcinoma
    		 1 1
        Other Specified Invasive Histology
    		 1 1
        Unable to Classify
    		 1 1
    Nodal Status
    Units: Subjects
        N0
    		 2 2
        N1
    		 12 12
        N2
    		 1 1
        N3
    		 1 1
        NX
    		 4 4
        Not Appliable
    		 6 6
        Not Known
    		 1 1
    Primary Cancer Stage
    Units: Subjects
        Stage I
    		 4 4
        Stage II
    		 10 10
        Stage III
    		 3 3
        Stage IV
    		 2 2
        Not Applicable
    		 6 6
        Not Known
    		 1 1
        Not Done
    		 1 1
    Primary Tumour Grade
    Units: Subjects
        Grade 1
    		 3 3
        Grade 2
    		 12 12
        Grade 3/4
    		 5 5
        Not Applicable
    		 4 4
        Not Known
    		 3 3
    Progesterone receptor (PgR) Status
    Units: Subjects
        Positive
    		 12 12
        Negative
    		 5 5
        Not Applicable
    		 5 5
        Not Known
    		 5 5
    HER2 Status
    Units: Subjects
        Zero
    		 6 6
        1+
    		 8 8
        2+
    		 2 2
        Not Done
    		 6 6
        Not Applicable
    		 5 5
    Type of 1st Breast Cancer Relapse
    Units: Subjects
        Local Recurrence
    		 0 0
        Distant Recurrence / Metastatic
    		 26 26
        Not Done
    		 1 1
    Body Mass Index
    Units: kg/m2
        median (standard deviation)
    		 28.1 ( 6.3 ) -
    Primary Tumour Size
    Longest Diameter Data provided for N=17 in overall trial and N=15 in per protocol analysis
    Units: mm
        median (full range (min-max))
    		 28 (15 to 120) -
    Duration of AI treatment at enrolment
    Duration of treatment with aromatase inhibitor at study enrolment
    Units: Months
        median (inter-quartile range (Q1-Q3))
    		 21.1 (13.3 to 37.6) -
    Time from primary diagnosis to metastatic diagnosis
    Based on diagnositc biopsy result. N=23 in overall trial; N=19 in per-protocol analysis
    Units: Months
        median (inter-quartile range (Q1-Q3))
    		 60.7 (2 to 116.1) -
    Subject analysis sets

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients evaulable for efficacy endpoints (i.e. had at least one tumour assessment on study drug; or death (due to breast cancer) prior to tumour assessment)

    Subject analysis sets values
    		 Per Protocol
    Number of subjects
    23
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.3 ( 9.9 )
    Gender categorical
    Only female patients were eligible
    Units: Subjects
        Female
    23
        Male
    0
    Ethnicity
    Units: Subjects
        White
    21
        Mixed
    0
        Asian
    1
        Black
    0
        Chinese
    1
        Other
    0
    Treatment History: Prior Chemotherapy
    Patients may have had multiple lines of chemotherapy (i.e. in neoadjuvant, adjuvant and/or advanced 1st line).
    Units: Subjects
        No prior chemotherapy
    9
        Prior chemotherapy
    14
    Treatment History: Prior Radiotherapy
    Patients may have had radiotherapy in the adjuvant and/or palliative setting
    Units: Subjects
        No Prior Radiotherapy
    11
        Prior Radiotherapy
    12
    Treatment History: Prior Endocrine Therapy
    Patients may have had endocrine therapy in any setting (i.e. neoadjuvant, adjuvant and/or advanced 1st line).
    Units: Subjects
        No prior endocrine therapy
    0
        Prior endocrine therapy
    23
    Treatment History: Breast Cancer Surgery
    Units: Subjects
        None
    6
        Yes
    17
    Tumour Type
    Units: Subjects
        Invasive Ductal Carcinoma
    16
        Invasive Lobular Carcinoma
    4
        Invasive Mixed Carcinoma
    1
        Other Specified Invasive Histology
    1
        Unable to Classify
    1
    Nodal Status
    Units: Subjects
        N0
    2
        N1
    10
        N2
    1
        N3
    1
        NX
    2
        Not Appliable
    6
        Not Known
    1
    Primary Cancer Stage
    Units: Subjects
        Stage I
    4
        Stage II
    10
        Stage III
    1
        Stage IV
    1
        Not Applicable
    6
        Not Known
    0
        Not Done
    1
    Primary Tumour Grade
    Units: Subjects
        Grade 1
    3
        Grade 2
    8
        Grade 3/4
    5
        Not Applicable
    4
        Not Known
    3
    Progesterone receptor (PgR) Status
    Units: Subjects
        Positive
    9
        Negative
    4
        Not Applicable
    5
        Not Known
    5
    HER2 Status
    Units: Subjects
        Zero
    6
        1+
    5
        2+
    1
        Not Done
    6
        Not Applicable
    5
    Type of 1st Breast Cancer Relapse
    Units: Subjects
        Local Recurrence
    0
        Distant Recurrence / Metastatic
    22
        Not Done
    1
    Body Mass Index
    Units: kg/m2
        median (standard deviation)
    28.2 ( 6.6 )
    Primary Tumour Size
    Longest Diameter Data provided for N=17 in overall trial and N=15 in per protocol analysis
    Units: mm
        median (full range (min-max))
    25 (15 to 46)
    Duration of AI treatment at enrolment
    Duration of treatment with aromatase inhibitor at study enrolment
    Units: Months
        median (inter-quartile range (Q1-Q3))
    21.1 (10.3 to 35.7)
    Time from primary diagnosis to metastatic diagnosis
    Based on diagnositc biopsy result. N=23 in overall trial; N=19 in per-protocol analysis
    Units: Months
        median (inter-quartile range (Q1-Q3))
    60.7 (2 to 105.4)

    End points

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

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients evaulable for efficacy endpoints (i.e. had at least one tumour assessment on study drug; or death (due to breast cancer) prior to tumour assessment)

    Primary: Clinical Benefit Rate - Local RECIST Review

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    End point title
    		 Clinical Benefit Rate - Local RECIST Review [1]
    End point description
    Clinical Benefit Rate is defined as Complete Response (CR), Partial Response (PR) or Stable Disease (SD) by Response Evaluation Criteria In Solid Tumors (RECIST; version 1.1). The primary endpoint has been reported based on local site RECIST review.
    End point type
    Primary
    End point timeframe
    6 months
    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: This study is a one arm design. Therefore the statistical analysis does not have more than one comparison arm. The EudraCT system would not allow statistical analysis details to be completed without defining a second comparison arm, however, this does not exist for this data set. Therefore we are unable to add statistical analysis details due to operational errors with the database.
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    27
    23
    Units: percent
        median (confidence interval 95%)
    18.5 (6.3 to 38.1)
    21.7 (7.4 to 43.7)
    No statistical analyses for this end point

    Primary: Clinical Benefit Rate - Central RECIST Review

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    End point title
    		 Clinical Benefit Rate - Central RECIST Review [2]
    End point description
    Clinical Benefit Rate is defined as Complete Response (CR), Partial Response (PR), or Stable Disease (SD) by Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1). This has been reported by central RECIST review.
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [2] - 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: This study is a one arm design. Therefore the statistical analysis does not have more than one comparison arm. The EudraCT system would not allow statistical analysis details to be completed without defining a second comparison arm, however, this does not exist for this data set. Therefore we are unable to add statistical analysis details due to operational errors with the database.
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    27
    23
    Units: percent
        median (confidence interval 95%)
    14.8 (4.2 to 33.7)
    17.4 (5 to 38.8)
    No statistical analyses for this end point

    Secondary: Duration of Clinical Benefit

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    End point title
    		 Duration of Clinical Benefit
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    26 [3]
    23
    Units: No Days
        median (inter-quartile range (Q1-Q3))
    77.5 (66 to 139)
    80 (75 to 160)
    Notes
    [3] - For one patient start date of study drug is not known
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective Response Rate is defined as Complete Response (CR) or Partial Response (PR), as per Response Evaluation Criteria In Solid Tumors (RECIST; version 1.1)
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    27
    23
    Units: Number of Patients
        Complete Response
    0
    0
        Partial Response
    0
    0
    No statistical analyses for this end point

    Secondary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    End point type
    Secondary
    End point timeframe
    First evidence of progression or death due to any cause
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    27
    23
    Units: Months
        median (confidence interval 95%)
    2.7 (2.5 to 4.6)
    2.7 (2.5 to 4.6)
    Attachments
    		 PFS Graph
    No statistical analyses for this end point

    Secondary: Circulating Steroid Hormones - Andrstenedione

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    End point title
    		 Circulating Steroid Hormones - Andrstenedione
    End point description
    End point type
    Secondary
    End point timeframe
    Samples were collected monthly for the duration of a patients participation on study up to 6 months
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    24 [4]
    21 [5]
    Units: ng/dl
    median (inter-quartile range (Q1-Q3))
        Baseline
    59.5 (46.8 to 78.2)
    57 (46 to 77)
        Month 1
    35 (28.5 to 55)
    36 (28 to 56)
        Month 2
    44 (41 to 63)
    44 (41 to 63)
        Month 3
    46 (30.5 to 55.5)
    46 (30.5 to 55.5)
        Month 4
    36 (30.5 to 52)
    36 (30.5 to 52)
        Month 5
    23 (21 to 29)
    23 (21 to 29)
        Month 6
    36 (31.5 to 42)
    36 (31.5 to 42)
    Attachments
    		 SH Graphs
    Notes
    [4] - Baseline N=24; Month 1 N=23; Month 2 N = 21; Month 3 N=19; Month 4 N=7; Month 5 N=7; Month 6 N=4.
    [5] - Baseline N=21; Month 1 N=21; Month 2 N = 21; Month 3 N=19; Month 4 N=7; Month 5 N=7; Month 6 N=4.
    No statistical analyses for this end point

    Secondary: Circulating Steroid Hormones - Oestrone Sulphate

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    End point title
    		 Circulating Steroid Hormones - Oestrone Sulphate
    End point description
    End point type
    Secondary
    End point timeframe
    Samples were collected monthly for the duration of a patients participation on study
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    26 [6]
    23 [7]
    Units: ng/dl
    median (inter-quartile range (Q1-Q3))
        Basline
    40 (40 to 70.8)
    40 (40 to 64.5)
        Month 1
    40 (40 to 70)
    40 (40 to 70)
        Month 2
    40 (40 to 81)
    40 (40 to 81)
        Month 3
    40 (40 to 53.5)
    40 (40 to 53.5)
        Month 4
    40 (40 to 158)
    40 (40 to 158)
        Month 5
    65 (40 to 152.5)
    65 (40 to 152.5)
        Month 6
    61 (57 to 113.8)
    61 (57 to 113.8)
    Attachments
    		 SH Graphs
    Notes
    [6] - Baseline N=26; Month 1 N=26; Month 2 N = 21; Month 3 N=20; Month 4 N=7; Month 5 N=7; Month 6 N=6.
    [7] - Baseline N=23; Month 1 N=23; Month 2 N = 21; Month 3 N=20; Month 4 N=7; Month 5 N=7; Month 6 N=6.
    No statistical analyses for this end point

    Secondary: Circulating Steroid Hormones - Dehydroepiandrosterone (DHEA)

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    End point title
    		 Circulating Steroid Hormones - Dehydroepiandrosterone (DHEA)
    End point description
    End point type
    Secondary
    End point timeframe
    Samples were collected monthly for the duration of a patients participation on study
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    24 [8]
    21 [9]
    Units: ng/dl
    median (inter-quartile range (Q1-Q3))
        Basline
    118.5 (77.5 to 194)
    114 (80 to 172)
        Month 1
    84.5 (56 to 137.2)
    84.5 (59 to 134.5)
        Month 2
    83 (43 to 155)
    83 (43 to 155)
        Month 3
    62.5 (47.8 to 105.8)
    62.5 (47.8 to 105.8)
        Month 4
    56 (40.5 to 73)
    56 (40.5 to 73)
        Month 5
    69 (48 to 75)
    69 (48 to 75)
        Month 6
    53 (26.8 to 77.8)
    53 (26.8 to 77.8)
    Attachments
    		 SH Graphs
    Notes
    [8] - Baseline N=24; Month 1 N=24; Month 2 N = 21; Month 3 N=20; Month 4 N=7; Month 5 N=7; Month 6 N=6.
    [9] - Baseline N=21; Month 1 N=22; Month 2 N = 21; Month 3 N=20; Month 4 N=7; Month 5 N=7; Month 6 N=6.
    No statistical analyses for this end point

    Secondary: Circulating Steroid Hormones - Dehydroepiandrosterone Sulphate (DHEAS)

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    End point title
    		 Circulating Steroid Hormones - Dehydroepiandrosterone Sulphate (DHEAS)
    End point description
    End point type
    Secondary
    End point timeframe
    Samples were collected monthly for the duration of a patients participation on study
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    23 [10]
    21 [11]
    Units: ng/dl
    median (inter-quartile range (Q1-Q3))
        Baseline
    64 (51 to 98.5)
    64 (50 to 92)
        Month 1
    149.5 (104 to 196.8)
    151 (10.3 to 199)
        Month 2
    135 (73.5 to 175)
    135 (73.5 to 175)
        Month 3
    146 (46 to 188)
    146 (46 to 188)
        Month 4
    84 (76 to 126.5)
    84 (76 to 126.5)
        Month 5
    103 (81.2 to 151.8)
    103 (81.2 to 151.8)
        Month 6
    124 (74 to 187)
    124 (74 to 187)
    Attachments
    		 SH Graphs
    Notes
    [10] - Baseline N=22; Month 1 N=223; Month 2 N = 19; Month 3 N=17; Month 4 N=7; Month 5 N=4; Month 6 N=5.
    [11] - Baseline N=21; Month 1 N=21; Month 2 N = 19; Month 3 N=17; Month 4 N=7; Month 5 N=4; Month 6 N=5.
    No statistical analyses for this end point

    Secondary: Circulating Steroid Hormones - DHEA to DHEAS ratio

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    End point title
    		 Circulating Steroid Hormones - DHEA to DHEAS ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Samples were collected monthly for the duration of a patients participation on study
    End point values
    		 Per Protocol
    Number of subjects analysed
    21 [12]
    Units: Ratio
    median (inter-quartile range (Q1-Q3))
        Baseline
    2 (1.2 to 2.5)
        Month 1
    0.7 (0.4 to 1.3)
        Month 2
    0.9 (0.5 to 1)
        Month 3
    0.7 (0.5 to 1)
        Month 4
    0.6 (0.3 to 1)
        Month 5
    0.7 (0.3 to 0.9)
        Month 6
    0.4 (0.3 to 0.9)
    Attachments
    		 SH Graphs
    Notes
    [12] - Baseline N=21; Month 1 N=20; Month 2 N = 19; Month 3 N=17; Month 4 N=7; Month 5 N=4; Month 6 N=5.
    No statistical analyses for this end point

    Secondary: Circulating Steroid Hormones - Testosterone

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    End point title
    		 Circulating Steroid Hormones - Testosterone
    End point description
    End point type
    Secondary
    End point timeframe
    Samples were collected monthly for the duration of a patients participation on study
    End point values
    		 Intervention Per Protocol
    Number of subjects analysed
    21 [13]
    20 [14]
    Units: ng/dl
    median (inter-quartile range (Q1-Q3))
        Basline
    12 (8 to 21)
    12.5 (8 to 21.2)
        Month 1
    10.5 (8.8 to 15.2)
    10.5 (8.8 to 15.2)
        Month 2
    11 (6 to 15)
    11 (6 to 15)
        Month 3
    11.5 (6.2 to 17.2)
    11.5 (6.2 to 17.2)
        Month 4
    8.5 (6 to 12.5)
    8.5 (6 to 12.5)
        Month 5
    8 (3.5 to 12.2)
    8 (3.5 to 12.2)
        Month 6
    5 (4 to 10)
    5 (4 to 10)
    Attachments
    		 SH Graphs
    Notes
    [13] - Baseline N=21; Month 1 N=16; Month 2 N = 17; Month 3 N=14; Month 4 N=6; Month 5 N=4; Month 6 N=5.
    [14] - Baseline N=20; Month 1 N=16; Month 2 N = 17; Month 3 N=14; Month 4 N=6; Month 5 N=4; Month 6 N=5.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from the time a patient signed informed consent until the end of follow-up. AEs were followed-up according to local practice until the event has stabilised or resolved, or until the last follow-up visit, whichever was sooner
    Adverse event reporting additional description
    AEs were reviewed at every patient visit. Disease progression was not classed as an AE. AEs we assessed for severity (NCI CTCAE v4.03) and causality by the local PI; the CI provided an assessment for SAEs. All AEs were recorded in the study EDC system.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Full Analysis Set
    Reporting group description
    		 All patients who received at least one dose of study medication

    Serious adverse events
    		 Full Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 27 (22.22%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Nervous system disorders
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea, Vomiting, Fever
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Full Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 27 (100.00%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    2
    Phlebitis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Surgical and medical procedures
    Pleurodesis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Death
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    12 / 27 (44.44%)
         occurrences all number
    15
    Gravitational oedema
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Lethargy
         subjects affected / exposed
    5 / 27 (18.52%)
         occurrences all number
    7
    Oedema
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Breast ulceration
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Hot flush
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Aphonia
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Blood glucose
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    2
    Haemoglobin
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Weight decreased
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Cardiac disorders
    Dizziness
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Bundle branch block
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Nervous system disorders
    Circadian rhythm sleep disorder
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    5 / 27 (18.52%)
         occurrences all number
    7
    Insomnia
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Neuropathy peripheral
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    8 / 27 (29.63%)
         occurrences all number
    8
    Dry mouth
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    12 / 27 (44.44%)
         occurrences all number
    13
    Vomiting
         subjects affected / exposed
    4 / 27 (14.81%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    20 / 27 (74.07%)
         occurrences all number
    28
    Rash
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    6
    Rash erythematous
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Rash generalised
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Stress urinary incontinence
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 27 (11.11%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Bone pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    3
    Bursitis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Fracture
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Joint stiffness
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    3
    Pain in jaw
         subjects affected / exposed
    2 / 27 (7.41%)
         occurrences all number
    2
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    2
    Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Sepsis
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 27 (18.52%)
         occurrences all number
    7
    Hypokalaemia
         subjects affected / exposed
    1 / 27 (3.70%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2012
    Substantial Amendments: 1. Safety visit timeline. 2. End of trial definition. 3. Updated Investigator’s Brochure. 4. Addition of ALP and Creatinine Clearance assessments to every study visit (study protocol).
    30 Oct 2013
    Substantial Amendments: 1. The removal of the collection of blood for the steroid sulfatase (STS) activity analysis from the IRIS protocol and PIS. 2. Change in Contact details for the Chief Investigator. 3. Confirmation of the definition of progression free survival. 4. Clarification of the inclusion criteria defining the previous response to the aromatase inhibitor (AI) required for entry into the trial. 5. Change in the inclusion criteria stating the definition of postmenopausal. 6. Change in the exclusion criterion stating that the AI must not be discontinued prior to study entry. 7. Confirmation of the timing of the post treatment visit within the definition of the early discontinuation of the study. 8. Update of additional expected adverse events defined by the investigator brochure for Irosustat v6.0.

    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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