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    Clinical Trial Results:
    Randomised phase II window study of short-term preoperative treatment with the PI3K inhibitor GDC-0941 plus Anastrozole versus Anastrozole alone in patients with ER-positive primary breast cancer

    Summary
    EudraCT number
    		 2011-003530-13
    Trial protocol
    		 GB  
    Global end of trial date
    09 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2020
    First version publication date
    03 Jan 2020
    Other versions
    Summary report(s)
    		 Clinical Study Report 2011-003530-13

    Trial information

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    Trial identification
    Sponsor protocol code
    18072011
    Additional study identifiers
    ISRCTN number
    		 ISRCTN26131497
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Brighton & Sussex University Hospitals NHS Trust
    Sponsor organisation address
    Eastern Road, Brighton, United Kingdom, BN2 5BE
    Public contact
    Head of Research & Development, Brighton & Sussex University Hospitals NHS Trust, +44 01273696955, bsuh.sponsorship.approvals@nhs.net
    Scientific contact
    Head of Research & Development, Brighton & Sussex University Hospitals NHS Trust, +44 01273696955, bsuh.sponsorship.approvals@nhs.net
    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 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In women with ER-positive breast cancer about to undergo surgery, does two week's pretreatment with a new drug (the PI3K inhibitor GDC-0941, given in combination with the estrogen-blocker anastrozole) increase the benefits of anastrozole in slowing down tumour cell growth, as measured by laboratory measurements on tumour cells?
    Protection of trial subjects
    The current experience with single agent GDC-0941 in cancer patients confirms that GDC-0941 can be given safely and is associated with an acceptable toxicity profile. However, GDC-0941 remains an experimental agent and additional side effects might be described at later stages. Most studies to date included heavily pre-treated patients with advanced or metastatic cancers. The majority of adverse effects in these studies were grade 1 or 2 and were generally rapidly reversible. The incidence of moderate or severe toxicities was low, especially during the first 2 weeks of treatment. Consequently, the risks associated with 15 days of preoperative treatment with GDC-0941 as part of this trial are expected to be low. All enrolled patients were evaluated clinically and with standard laboratory tests before and at regular intervals during their participation in this study. Safety evaluations consisted of medical interviews, recording of adverse events, physical examinations, ECG recordings, and laboratory measurements. Patients were evaluated for adverse events (all grades), serious adverse events, and any adverse events requiring drug interruption or discontinuation throughout the course of the study. Two committees were convened to evaluate the safety of this trial. The first committee was the Trial Management Group (TMG), which was composed of the chief investigator, principal investigators from each site, the study statistician, the study co-ordinator and the trial pharmacist. The second committee was a scientific Trial Steering Committee, composed of external advisors who advised the Sponsor and the TMG on data interpretation and appropriate modifications to the study, if appropriate. Safety assessments consisted of monitoring and recording protocol-defined adverse events (AEs) and serious adverse events (SAEs); measurement of protocol-specified haematology, clinical chemistry, coagulation variables; measurement of protocol-specified vital signs; and other protocol
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 167
    Worldwide total number of subjects
    167
    EEA total number of subjects
    167
    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)
    85
    From 65 to 84 years
    80
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between January 2012 and September 2015 180 patients were screened across 11 sites in the UK. 167 were randomized.

    Pre-assignment
    Screening details
    		 Confined to postmenopausal women with newly diagnosed, ER-positive, HER2- negative, invasive primary breast cancer. 13 screening failures based on protocol defined inclusion and exclusion criteria. 2 further patients excluded post randomization but prior to treatment due to consequent violations of key eligibility criteria and 2 withdrew consent.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Anastrazole only
    Arm description
    		 Comparitor
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anastrazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1mg OD

    Arm title
    		 Anastrazole + Pictilisib
    Arm description
    		 Treatment arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Anastrazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1mg OD

    Investigational medicinal product name
    Pictilisib
    Investigational medicinal product code
    Other name
    GDC-0941
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    340mg OD (5 evaluable patients) reduced to 260mg OD

    Number of subjects in period 1 [1]
    		Anastrazole only Anastrazole + Pictilisib
    Started
    46
    90
    Completed
    46
    90
    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: 2 patients withdrew consent and 29 patients were not evaluable due to protocol deviations
    Period 2
    Period 2 title
    End of Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Anastrozole
    Arm description
    		 Anastrozole treatment until surgery on day 15
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Arimidex
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozole 1 mg OD orally

    Arm title
    		 Anastrazole + Pictilisib
    Arm description
    		 Anastrozole combined with PI3K inhibitor pictilisib until surgery on day 15
    Arm type
    		 Experimental

    Investigational medicinal product name
    GDC-0941
    Investigational medicinal product code
    RO5314482
    Other name
    Pictilisib
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GDC-0941 260 mg OD orally

    Number of subjects in period 2
    		Anastrozole Anastrazole + Pictilisib
    Started
    46
    90
    Completed
    46
    90

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Anastrazole only
    Reporting group description
    		 Comparitor

    Reporting group title
    Anastrazole + Pictilisib
    Reporting group description
    		 Treatment arm

    Reporting group values
    		 Anastrazole only Anastrazole + Pictilisib Total
    Number of subjects
    		 46 90 136
    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
    Median (range)
    Units: years
        median (full range (min-max))
    		 66.9 (47.7 to 85.4) 64.1 (48.5 to 81.1) -
    Gender categorical
    Units: Subjects
        Female
    		 46 90 136
        Male
    		 0 0 0
    Tumour status
    Units: Subjects
        Grade 1
    		 5 14 19
        Grade 2
    		 34 62 96
        Grade 3
    		 7 14 21
    PR status
    Tumor is progesterone receptor (PR) positive or negative
    Units: Subjects
        Positive
    		 34 83 117
        Negative
    		 12 7 19
    PI3KCA mutation status
    phosphoinositide 3-kinase (PI3K) pathway catalytic subunit type
    Units: Subjects
        Wildtype
    		 27 58 85
        Kinase-domain mutation
    		 14 18 32
        Helical-domain mutation
    		 5 14 19
    Ki67
    Ki67 % positive tumour cells
    Units: 0-100
        median (full range (min-max))
    		 -
    Subject analysis sets

    Subject analysis set title
    Anastrazole
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients randomized to anastrazole only treatment

    Subject analysis set title
    Anastrazole + Pictilisib
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients randomized to anastrazole + pictilisib

    Subject analysis sets values
    		 Anastrazole Anastrazole + Pictilisib
    Number of subjects
    46
    90
    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
    Median (range)
    Units: years
        median (full range (min-max))
    66.9 (47.7 to 85.4)
    64.1 (48.5 to 81.1)
    Gender categorical
    Units: Subjects
        Female
    46
    90
        Male
    0
    0
    Tumour status
    Units: Subjects
        Grade 1
    5
    13
        Grade 2
    34
    62
        Grade 3
    7
    14
    PR status
    Tumor is progesterone receptor (PR) positive or negative
    Units: Subjects
        Positive
    33
    82
        Negative
    11
    6
    PI3KCA mutation status
    phosphoinositide 3-kinase (PI3K) pathway catalytic subunit type
    Units: Subjects
        Wildtype
    27
    53
        Kinase-domain mutation
    14
    15
        Helical-domain mutation
    5
    14
    Ki67
    Ki67 % positive tumour cells
    Units: 0-100
        median (full range (min-max))
    23.0 (1.9 to 84.1)
    22.7 (0.9 to 89.9)

    End points

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    End points reporting groups
    Reporting group title
    Anastrazole only
    Reporting group description
    		 Comparitor

    Reporting group title
    Anastrazole + Pictilisib
    Reporting group description
    		 Treatment arm
    Reporting group title
    Anastrozole
    Reporting group description
    		 Anastrozole treatment until surgery on day 15

    Reporting group title
    Anastrazole + Pictilisib
    Reporting group description
    		 Anastrozole combined with PI3K inhibitor pictilisib until surgery on day 15

    Subject analysis set title
    Anastrazole
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients randomized to anastrazole only treatment

    Subject analysis set title
    Anastrazole + Pictilisib
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients randomized to anastrazole + pictilisib

    Primary: Effect of study treatment on cell proliferation

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    End point title
    		 Effect of study treatment on cell proliferation [1]
    End point description
    Quantification of tumour Ki67 expression at day 15 as a biomarker of cell proliferation
    End point type
    Primary
    End point timeframe
    Baseline to End of Treatment (Day 15)
    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: Please see attached document and charts for results
    End point values
    		 Anastrozole Anastrazole + Pictilisib
    Number of subjects analysed
    46
    90
    Units: Ki67 supression
        geometric mean (confidence interval 95%)
    70.7 (61.0 to 78.0)
    82.5 (78.3 to 85.8)
    Attachments
    		 Opportune stats
    Primary endpoint results
    No statistical analyses for this end point

    Secondary: Effect of Study Treatment on Tumour Cell Apoptosis (killing cancer cells)

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    End point title
    		 Effect of Study Treatment on Tumour Cell Apoptosis (killing cancer cells)
    End point description
    Quantification of caspase-3 expression as a biomarker for apoptosis
    End point type
    Secondary
    End point timeframe
    Baseline to day 15 - end of treatment
    End point values
    		 Anastrozole Anastrazole + Pictilisib
    Number of subjects analysed
    33
    56
    Units: Casp-3 expression
        geometric mean (confidence interval 95%)
    0.14 (0.10 to 0.18)
    0.15 (0.11 to 0.19)
    Attachments
    		 Apoptosis charts
    No statistical analyses for this end point

    Other pre-specified: Link between treatment and biomarker status of patient

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    End point title
    		 Link between treatment and biomarker status of patient
    End point description
    Comparison of interaction between PIK3CA mutation subtypes [helical domain mutations (HD), kinase domain mutations (KD), wildtype (WT)] and mean Ki67 suppression
    End point type
    Other pre-specified
    End point timeframe
    Baseline to day 15 - end of treatment
    End point values
    		 Anastrozole Anastrazole + Pictilisib
    Number of subjects analysed
    46
    90
    Units: PIK3CA mutation status
    geometric mean (confidence interval 95%)
        PI3CA Wild Type
    69.9 (45.7 to 80.2)
    81.1 (75.2 to 85.6)
        helical domain mutations
    59.3 (42.8 to 75.7)
    84.6 (66.1 to 103.3)
        kinase domain mutations
    81.8 (59.7 to 103.9)
    78.6 (58.4 to 98.7)
    Attachments
    		 Treatment effect vs biomarker status
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After informed consent until 30 days following the last administration of study treatment or study discontinuation/termination, whichever is later.
    Adverse event reporting additional description
    monitoring and recording protocol-defined adverse events (AEs) and serious adverse events (SAEs); measurement of protocol-specified haematology, clinical chemistry, coagulation variables; measurement of protocol-specified vital signs; and other protocol-specified tests that are deemed critical to the safety evaluation of the study drugs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Anastrazole
    Reporting group description
    		 -

    Reporting group title
    Anastrazole + Pictilisib
    Reporting group description
    		 -

    Serious adverse events
    		 Anastrazole Anastrazole + Pictilisib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 109 (2.75%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Haematoma
    Additional description: Bleeding post wide local excision and sentinel node biopsy - haematoma in left axilla.
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia supraventricular
    Additional description: Supraventricular and nodal arrhythmia, sinus bradycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
    Additional description: Admitted to Accident and Emergency with oedema of the tongue and treated for anaphylaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Ulcer
    Additional description: Ulceration - wound breakdown and necrosis around excision area
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 109 (0.92%)
         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: 5%
    Non-serious adverse events
    		 Anastrazole Anastrazole + Pictilisib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 54 (48.15%)
    47 / 109 (43.12%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 54 (7.41%)
    4 / 109 (3.67%)
         occurrences all number
    4
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 54 (12.96%)
    13 / 109 (11.93%)
         occurrences all number
    7
    13
    Dysgeusia
         subjects affected / exposed
    1 / 54 (1.85%)
    6 / 109 (5.50%)
         occurrences all number
    1
    6
    Anorexia nervosa
    Additional description: anorexia
         subjects affected / exposed
    1 / 54 (1.85%)
    7 / 109 (6.42%)
         occurrences all number
    1
    7
    Nausea
         subjects affected / exposed
    3 / 54 (5.56%)
    27 / 109 (24.77%)
         occurrences all number
    3
    27
    Hyperglycaemia
         subjects affected / exposed
    0 / 54 (0.00%)
    4 / 109 (3.67%)
         occurrences all number
    0
    4
    Hot flush
         subjects affected / exposed
    6 / 54 (11.11%)
    2 / 109 (1.83%)
         occurrences all number
    6
    2
    Immune system disorders
    Rash generalised
         subjects affected / exposed
    0 / 54 (0.00%)
    9 / 109 (8.26%)
         occurrences all number
    0
    9
    Stomatitis
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 109 (2.75%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 54 (1.85%)
    24 / 109 (22.02%)
         occurrences all number
    1
    24
    Dyspepsia
         subjects affected / exposed
    0 / 54 (0.00%)
    8 / 109 (7.34%)
         occurrences all number
    0
    8
    Vomiting
         subjects affected / exposed
    0 / 54 (0.00%)
    7 / 109 (6.42%)
         occurrences all number
    0
    7
    Renal and urinary disorders
    Creatinine urine abnormal
         subjects affected / exposed
    0 / 54 (0.00%)
    6 / 109 (5.50%)
         occurrences all number
    0
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 54 (9.26%)
    2 / 109 (1.83%)
         occurrences all number
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2011
    addition of patient diary cards to help with recording participant compliance to the trial medication and drug accountability
    03 Apr 2012
    changes to the inclusion/exclusion criteria, changes to the definition of pathway A with regards to collecting baseline biopsies before trial entry, updating the screening process so that HER 2 status can be determined after the patient has been offered the trial, amending the safety reporting section in line with the sponsor SOP along with other minor amendments
    13 Jun 2012
    amendments to the protocol, the informed consent form (pathway A and B), the patient information sheet (pathway A and B), the GP letter, the quick summary and the patient diary card and addition of 2 new sites and change of PI at one site
    06 Sep 2012
    This amendment relates to the protocol and patient information sheets being updated in line with the annual investigator brochure update. Both the protocol and the patient information sheets have been updated with additional side effects for GDC-0941. The protocol has also been updated so that the Assessment during Treatment section is consistent with the Study Flow Chart section
    07 Feb 2013
    This amendment relates to the addition of two new research sites
    15 May 2013
    This amendment relates to a change in PI at one site
    30 May 2013
    This amendment relates to the addition of a new research site
    26 Jun 2013
    This amendment relates to the addition of two new research sites
    24 Jul 2013
    This amendment relates to the addition of two new research sites
    23 Aug 2013
    This amendment relates to the addition of a new research site
    23 Aug 2013
    This amendment relates to the Patient Information Sheets (pathway A and B) being updated to make the document more patient friendly and relevant to this two week window study
    18 Sep 2013
    This amendment relates to the addition of a new research site
    18 Sep 2013
    This amendment relates to the change of PI
    27 Dec 2013
    This amendment relates to the change of PI
    10 Jun 2014
    This amendment relates to the change of PI
    08 Jul 2014
    This amendment relates to the change of PI
    02 Oct 2014
    This amendment relates to the protocol and the patient information sheets in relation to obtaining verbal informed consent so that the patient can arrive at their first visit in a fasted state to avoid an additional clinic visit.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26976426
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