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    Clinical Trial Results:
    A Phase 1/2 Multicenter Study of the Combination of AZD2014 and Palbociclib on a background of Hormonal Therapy in Patients with Locally Advanced/Metastatic Estrogen Receptor Positive Breast Cancer Comprising a Safety, Pharmacokinetic and Preliminary Efficacy Evaluation (PASTOR)

    Summary
    EudraCT number
    		 2015-003320-30
    Trial protocol
    		 GB  
    Global end of trial date
    23 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2024
    First version publication date
    20 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D2270C00020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02599714
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sarah Cannon Development Innovations, LLC: BRE 253
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Melbourn Science Park, Cambridge Road, Melbourn, Royston, Hertfordshire, United Kingdom, SG8 6EE
    Public contact
    Jan Cosaert, MD, AstraZeneca, +44 7384 807033, jan.cosaert@astrazeneca.com
    Scientific contact
    Jan Cosaert, MD, AstraZeneca, +44 7384 807033, jan.cosaert@astrazeneca.com
    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
    23 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The amended primary objectives for parts A and B were to investigate the safety and tolerability of the combination of AZD2014 and palbociclib on a background of fulvestrant in patients with locally advanced/metastatic ER positive breast cancer and to define the combination dose(s)/schedule(s) for further clinical evaluation.
    Protection of trial subjects
    The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonisation (ICH) Good Clinical Practice guidance, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples. Precautions were taken to preserve confidentiality and prevent genetic data being linked to the identity of the subject. An Institutional Review Board (IRB) or Ethics Committee reviewed and approved the study protocol, as well as the Informed Consent Form document and other written information provided to the subjects.
    Background therapy
    		 All patients received Fulvestrant 500 mg by intramuscular injection on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles. Additionally all patients received Palbociclib administered orally with food orally, once daily on days 1-21 of a 28 day cycle (alternative frequencies were instigated in some cohorts - 7 days on, 7 days off on a 28 day cycle).
    Evidence for comparator
    		 Fulvestrant (Faslodex®) has been approved by regulatory agencies in both the US and the UK for treatment of: • Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy. • HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy. • HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with ribociclib, as initial endocrine based therapy or following disease progression on endocrine therapy. • HR-positive, HER2-negative advanced or metastatic breast cancer in combination with palbociclib or abemaciclib in women with disease progression after endocrine therapy. Palbociclib (Ibrance®) has been approved by regulatory agencies in both the US and the UK for treatment of adults with HR+, HER2- breast cancer that has spread to other parts of the body (metastatic) in combination with an aromatase inhibitor as the first hormonal based therapy in postmenopausal women or in men, or fulvestrant with disease progression following hormonal therapy.
    Actual start date of recruitment
    01 Dec 2015
    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 States: 29
    Country: Number of subjects enrolled
    United Kingdom: 25
    Worldwide total number of subjects
    54
    EEA total number of subjects
    0
    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)
    35
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Fifty-four (54) patients were enrolled in the study and received treatment at 7 sites in the US and the UK between 19 January 2016 and 26 September 2017. The last visit of the last patient for data collection occurred on 27 March 2018.

    Pre-assignment
    Screening details
    		 Fifty-four (54) patients pased the screening criteria and received treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (Part A)
    Arm description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    AZD2014
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Arm title
    		 Cohort 2 (Part A)
    Arm description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    AZD2014
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Arm title
    		 Cohort 3 (Part A)
    Arm description
    		 Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    AZD2014
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Arm title
    		 Cohort 4 (Part A)
    Arm description
    		 Vistusertib 50 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    AZD2014
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vistusertib 50 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Arm title
    		 Cohort 5 Low ANC (Part A)
    Arm description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-7, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    AZD2014
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (7 days on, 7 days off). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Arm title
    		 Cohort 6 High ANC (Part A)
    Arm description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    AZD2014
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Arm title
    		 Cohort 7 (Part B)
    Arm description
    		 Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    AZD2014
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Number of subjects in period 1
    		Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Started
    6
    6
    6
    6
    6
    7
    17
    Completed
    6
    6
    6
    6
    6
    7
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 2 (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 3 (Part A)
    Reporting group description
    		 Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 4 (Part A)
    Reporting group description
    		 Vistusertib 50 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 5 Low ANC (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-7, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 6 High ANC (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 7 (Part B)
    Reporting group description
    		 Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B) Total
    Number of subjects
    		 6 6 6 6 6 7 17 54
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 3 4 6 5 4 8 35
        From 65-84 years
    		 1 3 2 0 1 3 9 19
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 55.0 ± 5.73 64.8 ± 7.49 58.8 ± 7.63 47.7 ± 9.77 55.5 ± 12.26 57.7 ± 14.37 62.8 ± 9.49 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 6 6 6 6 6 7 17 54
        Male
    		 0 0 0 0 0 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 5 5 6 6 5 6 12 45
        Black or African American
    		 1 0 0 0 0 0 0 1
        Asian
    		 0 1 0 0 0 1 0 2
        Other
    		 0 0 0 0 1 0 4 5
        Missing
    		 0 0 0 0 0 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0 0 0 0
        Not Hispanic or Latino
    		 6 6 6 6 5 5 15 49
        Unknown or Not Reported
    		 0 0 0 0 1 2 2 5
    ECOG Performance Status at Baseline
    ECOG Performance Status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory, able to carry out light or sedentary work; 2 = Ambulatory and capable of all self care but unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, cannot carry on any self care. Totally confined to bed or chair; 5 = Dead.
    Units: Subjects
        ECOG Score = 0
    		 2 1 4 6 4 4 12 33
        ECOG Score = 1
    		 4 5 2 0 2 3 5 21
    Tumour Grade
    G1 = Well Differentiated G2 = Moderately Differentiated G3 = Poorly Differentiated G4 = Undifferentiated GX = Unassessable
    Units: Subjects
        Well Differentiated (G1)
    		 0 1 0 1 1 0 2 5
        Moderately Differentiated (G2)
    		 4 3 3 3 4 1 9 27
        Poorly Differentiated (G3)
    		 1 2 3 2 0 2 4 14
        Undifferentiated (G4)
    		 0 0 0 0 1 0 0 1
        Unassessable (GX)
    		 1 0 0 0 0 2 0 3
        Missing
    		 0 0 0 0 0 2 2 4
    Histology Type
    Units: Subjects
        Invasive Carcinoma (NOS)
    		 0 1 1 2 2 3 2 11
        Invasive Ductal
    		 2 3 2 4 4 1 8 24
        Invasive Ductal -Extensive Intraductal Component
    		 1 0 3 0 0 0 1 5
        Invasive Lobular
    		 3 1 0 0 0 1 5 10
        Other
    		 0 1 0 0 0 2 0 3
        Missing
    		 0 0 0 0 0 0 1 1
    Overall Disease Classification
    Metastatic or Locally Advanced
    Units: Subjects
        Metastatic
    		 6 6 6 6 6 7 17 54
        Locally Advanced
    		 0 0 0 0 0 0 0 0
    Visceral Disease
    Units: Subjects
        Visceral Disease
    		 3 5 5 4 6 3 10 36
        No Visceral Disease
    		 3 1 1 2 0 4 7 18
    Age Continuous |
    Units: Years
        median (full range (min-max))
    		 54.0 (50 to 65) 65.5 (53 to 75) 57.5 (48 to 69) 46.5 (36 to 60) 61.0 (36 to 68) 59.0 (36 to 75) 65.0 (47 to 77) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set includes all patients who received at least 1 dose of study medication.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set includes all patients who received at least 1 dose of AZD2014 or palbociclib.

    Subject analysis set title
    Pharmacokinetics Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Pharmacokinetics Analysis Set includes all dosed patients with reportable AZD2014 or palbociclib concentrations. However, the number of participants with reportable data varies between PK parameters. Single-dose PK parameters were only determined in Part A, Cohorts 1-4.

    Subject analysis set title
    Evaluable for Response
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Evaluable for Response analysis set includes all patients who received at least one dose of vistusertib, palbociclib, or fulvestrant with measurable disease at baseline as per RECIST 1.1.

    Subject analysis set title
    Evaluable for Efficacy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Evaluable for Efficacy Analysis Set includes all patients who received at least 1 dose of study medication and who had efficacy data.

    Subject analysis sets values
    		 Full Analysis Set Safety Analysis Set Pharmacokinetics Analysis Set Evaluable for Response Evaluable for Efficacy
    Number of subjects
    54
    54
    53
    47
    54
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    35
    35
    35
    33
    35
        From 65-84 years
    19
    19
    18
    14
    19
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    58.6 ± 10.68
    58.6 ± 10.68
    58.4 ± 10.71
    ±
    ±
    Sex: Female, Male
    Units: Subjects
        Female
    54
    54
    53
    47
    54
        Male
    0
    0
    0
    0
    0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    45
    45
    44
    38
    45
        Black or African American
    1
    1
    1
    1
    1
        Asian
    2
    2
    2
    2
    2
        Other
    5
    5
    5
    5
    5
        Missing
    1
    1
    1
    1
    1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0
    0
    0
    0
    0
        Not Hispanic or Latino
    49
    49
    49
    42
    49
        Unknown or Not Reported
    5
    5
    4
    5
    5
    ECOG Performance Status at Baseline
    ECOG Performance Status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory, able to carry out light or sedentary work; 2 = Ambulatory and capable of all self care but unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, cannot carry on any self care. Totally confined to bed or chair; 5 = Dead.
    Units: Subjects
        ECOG Score = 0
    33
    33
    33
    28
    33
        ECOG Score = 1
    21
    21
    20
    19
    21
    Tumour Grade
    G1 = Well Differentiated G2 = Moderately Differentiated G3 = Poorly Differentiated G4 = Undifferentiated GX = Unassessable
    Units: Subjects
        Well Differentiated (G1)
    5
    5
    5
    4
    5
        Moderately Differentiated (G2)
    27
    27
    27
    23
    27
        Poorly Differentiated (G3)
    14
    14
    14
    13
    14
        Undifferentiated (G4)
    1
    1
    1
    1
    1
        Unassessable (GX)
    3
    3
    2
    2
    2
        Missing
    4
    4
    4
    4
    4
    Histology Type
    Units: Subjects
        Invasive Carcinoma (NOS)
    11
    11
    10
    8
    10
        Invasive Ductal
    24
    24
    24
    21
    24
        Invasive Ductal -Extensive Intraductal Component
    5
    5
    5
    4
    5
        Invasive Lobular
    10
    10
    10
    10
    10
        Other
    3
    3
    3
    3
    3
        Missing
    1
    1
    1
    1
    1
    Overall Disease Classification
    Metastatic or Locally Advanced
    Units: Subjects
        Metastatic
    54
    54
    53
    47
    54
        Locally Advanced
    0
    0
    0
    0
    0
    Visceral Disease
    Units: Subjects
        Visceral Disease
    36
    36
    53
    47
    36
        No Visceral Disease
    18
    18
    0
    0
    18
    Age Continuous |
    Units: Years
        median (full range (min-max))
    59.0 (36 to 77)
    59.0 (36 to 77)
    59.0 (36 to 77)
    58.0 (36 to 77)
    59.0 (36 to 77)

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 2 (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 3 (Part A)
    Reporting group description
    		 Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 4 (Part A)
    Reporting group description
    		 Vistusertib 50 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 5 Low ANC (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-7, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 6 High ANC (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 7 (Part B)
    Reporting group description
    		 Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set includes all patients who received at least 1 dose of study medication.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set includes all patients who received at least 1 dose of AZD2014 or palbociclib.

    Subject analysis set title
    Pharmacokinetics Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Pharmacokinetics Analysis Set includes all dosed patients with reportable AZD2014 or palbociclib concentrations. However, the number of participants with reportable data varies between PK parameters. Single-dose PK parameters were only determined in Part A, Cohorts 1-4.

    Subject analysis set title
    Evaluable for Response
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Evaluable for Response analysis set includes all patients who received at least one dose of vistusertib, palbociclib, or fulvestrant with measurable disease at baseline as per RECIST 1.1.

    Subject analysis set title
    Evaluable for Efficacy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Evaluable for Efficacy Analysis Set includes all patients who received at least 1 dose of study medication and who had efficacy data.

    Primary: Number of participants who experienced an adverse event.

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    End point title
    		 Number of participants who experienced an adverse event. [1]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    6
    6
    6
    6
    6
    7
    17
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not causally related to palbociclib).

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    End point title
    		 Number of participants who experienced an adverse event causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not causally related to palbociclib). [2]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    3
    5
    3
    3
    3
    6
    8
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event causally related to palbociclib and vistusertib (irrespective of fulvestrant).

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    End point title
    		 Number of participants who experienced an adverse event causally related to palbociclib and vistusertib (irrespective of fulvestrant). [3]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [3] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    5
    6
    5
    5
    6
    7
    17
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not causally related to vistusertib).

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    End point title
    		 Number of participants who experienced an adverse event causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not causally related to vistusertib). [4]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [4] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    5
    4
    4
    0
    3
    2
    4
    No statistical analyses for this end point

    Primary: Number of participants who experienced any adverse event of CTCAE grade 3 or higher.

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    End point title
    		 Number of participants who experienced any adverse event of CTCAE grade 3 or higher. [5]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events. Severity grading was defined by the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03)
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [5] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    6
    5
    5
    4
    4
    6
    10
    No statistical analyses for this end point

    Primary: Number of participants who experienced any adverse event of CTCAE grade 3 or higher causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not causally related to palbociclib).

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    End point title
    		 Number of participants who experienced any adverse event of CTCAE grade 3 or higher causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not causally related to palbociclib). [6]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events. Severity grading was defined by the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03)
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [6] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    2
    1
    0
    1
    1
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced any adverse event of CTCAE grade 3 or higher causally related to palbociclib and vistusertib (irrespective of fulvestrant).

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    End point title
    		 Number of participants who experienced any adverse event of CTCAE grade 3 or higher causally related to palbociclib and vistusertib (irrespective of fulvestrant). [7]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events. Severity grading was defined by the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03)
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [7] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    2
    3
    2
    3
    3
    5
    10
    No statistical analyses for this end point

    Primary: Number of participants who experienced any adverse event of CTCAE grade 3 or higher causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not causally related to vistusertib).

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    End point title
    		 Number of participants who experienced any adverse event of CTCAE grade 3 or higher causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not causally related to vistusertib). [8]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events. Severity grading was defined by the Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03)
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [8] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    3
    1
    2
    0
    1
    0
    1
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event with outcome of death.

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    End point title
    		 Number of participants who experienced an adverse event with outcome of death. [9]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [9] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced a serious adverse event (SAE).

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    End point title
    		 Number of participants who experienced a serious adverse event (SAE). [10]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [10] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    3
    3
    3
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of participants who experienced a serious adverse event (SAE), causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not casually related to palbociclib).

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    End point title
    		 Number of participants who experienced a serious adverse event (SAE), causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not casually related to palbociclib). [11]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [11] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced a serious adverse event (SAE), causally related to palbociclib and vistusertib (irrespective of fulvestrant).

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    End point title
    		 Number of participants who experienced a serious adverse event (SAE), causally related to palbociclib and vistusertib (irrespective of fulvestrant). [12]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [12] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    1
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced a serious adverse event (SAE), causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not casually related to vistusertib).

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    End point title
    		 Number of participants who experienced a serious adverse event (SAE), causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not casually related to vistusertib). [13]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [13] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event leading to discontinuation of vistusertib

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    End point title
    		 Number of participants who experienced an adverse event leading to discontinuation of vistusertib [14]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [14] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    2
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event leading to discontinuation of vistusertib and causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not causally related to palbociclib)

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    End point title
    		 Number of participants who experienced an adverse event leading to discontinuation of vistusertib and causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not causally related to palbociclib) [15]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [15] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event leading to discontinuation of vistusertib, causally related to palbociclib and vistusertib (irrespective of fulvestrant)

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    End point title
    		 Number of participants who experienced an adverse event leading to discontinuation of vistusertib, causally related to palbociclib and vistusertib (irrespective of fulvestrant) [16]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [16] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event leading to discontinuation of vistusertib, causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not causally related to vistusertib).)

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    End point title
    		 Number of participants who experienced an adverse event leading to discontinuation of vistusertib, causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not causally related to vistusertib).) [17]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [17] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event leading to discontinuation of palbociclib

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    End point title
    		 Number of participants who experienced an adverse event leading to discontinuation of palbociclib [18]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [18] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    2
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event leading to discontinuation of palbociclib, causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not causally related to palbociclib)

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    End point title
    		 Number of participants who experienced an adverse event leading to discontinuation of palbociclib, causally related to vistusertib (regardless of whether also causally related to fulvestrant, but not causally related to palbociclib) [19]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [19] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event leading to discontinuation of palbociclib, causally related to palbociclib and vistusertib (irrespective of fulvestrant)

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    End point title
    		 Number of participants who experienced an adverse event leading to discontinuation of palbociclib, causally related to palbociclib and vistusertib (irrespective of fulvestrant) [20]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [20] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    1
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who experienced an adverse event leading to discontinuation of palbociclib, causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not causally related to vistusertib)

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    End point title
    		 Number of participants who experienced an adverse event leading to discontinuation of palbociclib, causally related to palbociclib (regardless of whether also causally related to fulvestrant, but not causally related to vistusertib) [21]
    End point description
    Safety and tolerability were assessed through the incidence of adverse events.
    End point type
    Primary
    End point timeframe
    Approximately 16 months
    Notes
    [21] - 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: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Participants
        Number of participants
    0
    1
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Progression Free Survival (Part B)

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    End point title
    		 Progression Free Survival (Part B) [22]
    End point description
    Progression (or Progressive Disease) is defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Progressive disease is declared when there is at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Progression Free Survival is the elapsed time from the start of treatment until progression as defined by RECIST v1.1 or death from any cause. This analysis was conducted on the Evaluable for Efficacy Analysis Set.
    End point type
    Secondary
    End point timeframe
    Assessed every 8 weeks for approximately 16 months
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 7 (Part B)
    Number of subjects analysed
    17
    Units: Months
        median (confidence interval 80%)
    5.7 (3.68 to 8.21)
    No statistical analyses for this end point

    Secondary: Overall Survival (Part B)

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    End point title
    		 Overall Survival (Part B) [23]
    End point description
    Overall Survival is the elapsed time from the start of treatment until death from any cause. The upper limit of the 80% Confidence Interval could not be calculated. This analysis was conducted on the Full Analysis set.
    End point type
    Secondary
    End point timeframe
    Assessed every 8 weeks for approximately 16 months
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 7 (Part B)
    Number of subjects analysed
    17
    Units: Months
        median (confidence interval 80%)
    11.93 (11.93 to 99999.9)
    No statistical analyses for this end point

    Secondary: Best Objective Response (Parts A and B)

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    End point title
    		 Best Objective Response (Parts A and B)
    End point description
    The best objective response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. This analysis was conducted on the Evaluable for Response analysis set.
    End point type
    Secondary
    End point timeframe
    Assessed every 8 weeks for approximately 16 months
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    5
    6
    6
    4
    5
    5
    16
    Units: Number of Participants
        Complete Response
    0
    0
    0
    0
    0
    0
    0
        Partial Response
    1
    1
    1
    1
    1
    1
    0
        Stable Disease ≥ 8 weeks
    2
    5
    5
    3
    3
    4
    11
        Progression
    2
    0
    0
    0
    1
    0
    4
        Not Evaluable
    0
    0
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Objective Response Rate (Parts A and B)

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    End point title
    		 Objective Response Rate (Parts A and B)
    End point description
    The objective response rate is calculated as the number of participants who respond to treatment recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). This analysis was conducted on the Evaluable for Response anlaysis set.
    End point type
    Secondary
    End point timeframe
    Assessed every 8 weeks for approximately 16 months
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    5
    6
    6
    4
    5
    5
    16
    Units: Percentage
    number (not applicable)
        Lower Bound of 80% C.I.for Objective Response Rate
    2.1
    1.7
    1.7
    2.6
    2.1
    2.1
    0
        Upper Bound of 80% C.I.for Objective Response Rate
    58.4
    51.0
    51.0
    68.0
    58.4
    58.4
    99999.9
    No statistical analyses for this end point

    Secondary: Number of Patients Experiencing Clinical Benefit at 24 Weeks (Parts A and B)

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    End point title
    		 Number of Patients Experiencing Clinical Benefit at 24 Weeks (Parts A and B)
    End point description
    Patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer treatment are defined to have Clinical Benefit. This analysis was conducted on the Evaluable for Efficacy analysis set.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    6
    6
    6
    6
    6
    7
    17
    Units: Percentage
        number (confidence interval 80%)
    33.3 (9.3 to 66.7)
    66.7 (33.3 to 90.7)
    83.3 (49.0 to 98.3)
    83.3 (49.0 to 98.3)
    16.7 (1.7 to 51.0)
    57.1 (27.9 to 83.0)
    47.1 (29.7 to 65.0)
    No statistical analyses for this end point

    Secondary: Peak Plasma Concentration (Cmax) of Vistusertib After Single Dose (ng/mL) when Administered in Combination with Palbociclib and Fulvestrant (Part A)

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    End point title
    		 Peak Plasma Concentration (Cmax) of Vistusertib After Single Dose (ng/mL) when Administered in Combination with Palbociclib and Fulvestrant (Part A) [24]
    End point description
    Peak Plasma Concentration (also called Cmax) is the maximum concentration of drug in plasma.
    End point type
    Secondary
    End point timeframe
    Up to 12 hours
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    6
    6
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1395 ± 43.67
    1983 ± 61.08
    1201 ± 30.18
    1016 ± 24.59
    No statistical analyses for this end point

    Secondary: Time to Peak Plasma Concentration (tmax) of Vistusertib After Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A)

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    End point title
    		 Time to Peak Plasma Concentration (tmax) of Vistusertib After Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A) [25]
    End point description
    The time to peak plasma concentration is the elapsed time from drug administration until the maximum concentration of drug in plasma is reached.
    End point type
    Secondary
    End point timeframe
    Up to 12 hours
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    6
    6
    6
    Units: hours
        median (full range (min-max))
    2.5 (1 to 6)
    1.0 (0.5 to 2.0)
    2.0 (0.98 to 3.17)
    1.3 (0.5 to 2.98)
    No statistical analyses for this end point

    Secondary: AUC (0-24) (ng·h/mL) of Vistusertib after Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A)

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    End point title
    		 AUC (0-24) (ng·h/mL) of Vistusertib after Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A) [26]
    End point description
    AUC (0-24) is the area under the plasma concentration - time curve from zero time to 24 hours.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    5
    6
    6
    6
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    10830 ± 52.31
    9695 ± 117.4
    8194 ± 31.37
    5712 ± 71.34
    No statistical analyses for this end point

    Secondary: AUC (0-12) (ng·h/mL) of Vistusertib After Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A)

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    End point title
    		 AUC (0-12) (ng·h/mL) of Vistusertib After Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A) [27]
    End point description
    AUC (0-12) is the area under the plasma concentration - time curve from zero time to 12 hours.
    End point type
    Secondary
    End point timeframe
    Up to 16 Days
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    6
    5
    5
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    9309 ± 49.26
    8417 ± 99.87
    6808 ± 23.01
    4641 ± 55.55
    No statistical analyses for this end point

    Secondary: AUC (0-t) (ng·h/mL) of Vistusertib after Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A)

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    End point title
    		 AUC (0-t) (ng·h/mL) of Vistusertib after Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A) [28]
    End point description
    AUC (0-t) is the area under the plasma concentration - time curve from zero time a defined time.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    6
    6
    6
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    9278 ± 48.97
    8282 ± 100.4
    6483 ± 29.01
    4590 ± 55.64
    No statistical analyses for this end point

    Secondary: AUC (0-∞) (ng·h/mL) of Vistusertib after Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A)

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    End point title
    		 AUC (0-∞) (ng·h/mL) of Vistusertib after Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A) [29]
    End point description
    AUC (0-∞) is the area under the plasma concentration - time curve from time zero extrapolated to ∞.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    4
    6
    6
    6
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    13380 ± 45.97
    10300 ± 129.2
    8617 ± 34.68
    6101 ± 78.42
    No statistical analyses for this end point

    Secondary: Elimination Half-Life (t½λz) of Vistusertib after Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A)

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    End point title
    		 Elimination Half-Life (t½λz) of Vistusertib after Single Dose when Administered in Combination with Palbociclib and Fulvestrant (Part A) [30]
    End point description
    Elimination half-life is the period of time required for the one-half of the amount of drug administered to be eliminated.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    5
    6
    6
    6
    Units: hours
        arithmetic mean (standard deviation)
    5.342 ± 1.448
    4.515 ± 4.010
    4.86 ± 2.021
    5.119 ± 2.465
    No statistical analyses for this end point

    Secondary: Peak Plasma Concentration (Cmax) of Palbociclib Single Dose (Cmax, ng/mL) when Administered in Combination with Vistusertib and Fulvestrant (Part A)

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    End point title
    		 Peak Plasma Concentration (Cmax) of Palbociclib Single Dose (Cmax, ng/mL) when Administered in Combination with Vistusertib and Fulvestrant (Part A) [31]
    End point description
    Peak Plasma Concentration (also called Cmax) is the maximum concentration of drug in plasma.
    End point type
    Secondary
    End point timeframe
    Up to 12 hours
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    6
    6
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    43.06 ± 54.56
    35.73 ± 30.71
    33.07 ± 39.08
    22.56 ± 62.46
    No statistical analyses for this end point

    Secondary: Time to Peak Plasma Concentration (tmax) of Palbociclib Single Dose when Administered in Combination with Vistusertib and Fulvestrant (Part A)

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    End point title
    		 Time to Peak Plasma Concentration (tmax) of Palbociclib Single Dose when Administered in Combination with Vistusertib and Fulvestrant (Part A) [32]
    End point description
    The time to peak plasma concentration is the elapsed time from drug administration until the maximum concentration of drug in plasma is reached.
    End point type
    Secondary
    End point timeframe
    Up to 12 hours
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    6
    6
    6
    Units: hours
        median (full range (min-max))
    5.7 (3.92 to 8.0)
    5.0 (2.0 to 8.0)
    6.0 (4.0 to 8.0)
    7.0 (4.0 to 12.0)
    No statistical analyses for this end point

    Secondary: AUC (0-24) (ng·h/mL) of Palbociclib After Single Dose when Administered in Combination with Vistusertib and Fulvestrant (Part A, Cohorts 1-4)

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    End point title
    		 AUC (0-24) (ng·h/mL) of Palbociclib After Single Dose when Administered in Combination with Vistusertib and Fulvestrant (Part A, Cohorts 1-4) [33]
    End point description
    AUC (0-24) is the area under the plasma concentration - time curve from zero time to 24 hours.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    5
    6
    5
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    684.0 ± 64.72
    539.4 ± 35.13
    473.3 ± 26.81
    359.7 ± 74.92
    No statistical analyses for this end point

    Secondary: AUC (0-∞) (ng·h/mL) of Palbociclib After Single Dose when Administered in Combination with Vistusertib and Fulvestrant (Part A, Cohorts 1-4)

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    End point title
    		 AUC (0-∞) (ng·h/mL) of Palbociclib After Single Dose when Administered in Combination with Vistusertib and Fulvestrant (Part A, Cohorts 1-4) [34]
    End point description
    AUC (0-∞) is the area under the plasma concentration - time curve from time zero extrapolated to ∞.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    5
    5
    4
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    1161 ± 73.13
    963.6 ± 27.62
    938 ± 32.28
    851.9 ± 82.27
    No statistical analyses for this end point

    Secondary: AUC (0-t) (ng·h/mL) of Palbociclib After Single Dose when Administered in Combination with Vistusertib and Fulvestrant (Part A, Cohorts 1-4)

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    End point title
    		 AUC (0-t) (ng·h/mL) of Palbociclib After Single Dose when Administered in Combination with Vistusertib and Fulvestrant (Part A, Cohorts 1-4) [35]
    End point description
    AUC (0-t) is the area under the plasma concentration - time curve from zero time a defined time.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A)
    Number of subjects analysed
    6
    6
    6
    6
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    684.9 ± 63.83
    548.4 ± 31.21
    484.0 ± 26.36
    378.5 ± 66.48
    No statistical analyses for this end point

    Secondary: Peak Plasma Concentration (Cmax, ng/mL) of Vistusertib on Cycle 1, Day 16 after Multiple Doses when Administered in Combination with Palbociclib and Fulvestrant (Parts A and B)

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    End point title
    		 Peak Plasma Concentration (Cmax, ng/mL) of Vistusertib on Cycle 1, Day 16 after Multiple Doses when Administered in Combination with Palbociclib and Fulvestrant (Parts A and B)
    End point description
    Peak Plasma Concentration (also called Cmax) is the maximum concentration of drug in plasma as multiple doses accumulate.
    End point type
    Secondary
    End point timeframe
    Up to 16 Days
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    4
    6
    5
    5
    5
    5
    15
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    2816 ± 43.65
    3153 ± 48.7
    2262 ± 29.89
    1906 ± 44.14
    2278 ± 44.01
    1862 ± 88.39
    1611 ± 49.02
    No statistical analyses for this end point

    Secondary: Time to Peak Plasma Concentration (tmax) of Vistusertib after Multiple Doses when Administered in Combination with Palbociclib and Fulvestrant (Parts A and B)

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    End point title
    		 Time to Peak Plasma Concentration (tmax) of Vistusertib after Multiple Doses when Administered in Combination with Palbociclib and Fulvestrant (Parts A and B)
    End point description
    The time to peak plasma concentration is the elapsed time from drug administration until the maximum concentration of drug in plasma is reached as multiple doses accumulate.
    End point type
    Secondary
    End point timeframe
    Up to 16 Days
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    4
    6
    5
    5
    5
    5
    15
    Units: hours
        median (full range (min-max))
    1.3 (0.5 to 3.0)
    1.5 (0.47 to 3.0)
    1.5 (1.0 to 2.0)
    1.5 (0.5 to 4.02)
    4.0 (1.08 to 8.0)
    1.1 (1.0 to 6.0)
    2.0 (0.97 to 4.0)
    No statistical analyses for this end point

    Secondary: AUC (0-12) (ng·h/mL) of Vistusertib on Cycle 1, Day 16 after Multiple Doses when Administered in Combination with Palbociclib and Fulvestrant (Parts A and B)

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    End point title
    		 AUC (0-12) (ng·h/mL) of Vistusertib on Cycle 1, Day 16 after Multiple Doses when Administered in Combination with Palbociclib and Fulvestrant (Parts A and B)
    End point description
    AUC (0-12) is the area under the plasma concentration - time curve from zero time to 12 hours.
    End point type
    Secondary
    End point timeframe
    Up to 16 Days
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    4
    6
    5
    5
    5
    5
    15
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    20920 ± 70.42
    20130 ± 111.4
    15000 ± 38.3
    12200 ± 58.5
    17900 ± 68.52
    12930 ± 108.6
    10640 ± 65.38
    No statistical analyses for this end point

    Secondary: Peak Plasma Concentration (Cmax, ng/mL) of Palbociclib on Cycle 1, Day 16 after Multiple Doses when Administered in Combination with Vistusertib and Fulvestrant (Parts A and B)

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    End point title
    		 Peak Plasma Concentration (Cmax, ng/mL) of Palbociclib on Cycle 1, Day 16 after Multiple Doses when Administered in Combination with Vistusertib and Fulvestrant (Parts A and B) [36]
    End point description
    Peak Plasma Concentration (also called Cmax) is the maximum concentration of drug in plasma as multiple doses accumulate.
    End point type
    Secondary
    End point timeframe
    Up to 16 Days
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    4
    5
    4
    5
    3
    14
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    119.7 ± 43.85
    73.40 ± 17.24
    81.00 ± 14.34
    73.68 ± 28.84
    80.06 ± 22.86
    66.55 ± 37.44
    No statistical analyses for this end point

    Secondary: Time to peak plasma concentration (tmax) of Palbociclib after Multiple Doses when Administered in Combination with Vistusertib and Fulvestrant (Parts A and B)

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    End point title
    		 Time to peak plasma concentration (tmax) of Palbociclib after Multiple Doses when Administered in Combination with Vistusertib and Fulvestrant (Parts A and B) [37]
    End point description
    The time to peak plasma concentration is the elapsed time from drug administration until the maximum concentration of drug in plasma is reached as multiple doses accumulate.
    End point type
    Secondary
    End point timeframe
    Up to 16 Days
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    4
    5
    4
    5
    3
    14
    Units: hours
        median (full range (min-max))
    5.2 (4.0 to 6.0)
    6.0 (4.0 to 8.0)
    4.0 (2.0 to 6.0)
    6.0 (4.0 to 12.0)
    6.0 (4.03 to 6.0)
    6.0 (0.0 to 10.0)
    No statistical analyses for this end point

    Secondary: AUC (0-12) (ng·h/mL) of Palbociclib on Cycle 1, Day 16 after Multiple Doses when Administered in Combination with Vistusertib and Fulvestrant (Parts A and B)

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    End point title
    		 AUC (0-12) (ng·h/mL) of Palbociclib on Cycle 1, Day 16 after Multiple Doses when Administered in Combination with Vistusertib and Fulvestrant (Parts A and B) [38]
    End point description
    AUC (0-12) is the area under the plasma concentration - time curve from zero time to 12 hours.
    End point type
    Secondary
    End point timeframe
    Up to 16 Days
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Progression Free Survival was only assessed in Part B.
    End point values
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 4 (Part A) Cohort 6 High ANC (Part A) Cohort 7 (Part B)
    Number of subjects analysed
    4
    5
    4
    5
    3
    13
    Units: ng·h/mL
        geometric mean (geometric coefficient of variation)
    1172 ± 43.19
    714.1 ± 13.47
    819.4 ± 16.73
    724.2 ± 27.79
    756.2 ± 13.69
    639.9 ± 37.03
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events data were collected throughout the life of the trial, until the data cut-off in March 2018.
    Adverse event reporting additional description
    All serious adverse events are reported, regardless of causality or frequency. All other AEs (excluding SAEs) that were reported in ≥ 5% of participants in any cohort are reported, regardless of causality or severity. Adverse events are reported for the Safety Analysis Set comprised of all participants who received at least one dose of treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Cohort 1 (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 2 (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 3 (Part A)
    Reporting group description
    		 Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 7 (Part B)
    Reporting group description
    		 Vistusertib 75 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 5 Low ANC (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-7, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 6 High ANC (Part A)
    Reporting group description
    		 Vistusertib 100 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 100 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Reporting group title
    Cohort 4 (Part A)
    Reporting group description
    		 Vistusertib 50 mg BD (Days 1 and 2, then off for 5 days each week). Palbociclib 75 mg QD (Days 1-21, then off 7 days). Fulvestrant 500 mg on Cycle 1, Days 1 and 15 and Day 1 only for subsequent cycles.

    Serious adverse events
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 7 (Part B) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 4 (Part A)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    4
    0
    1
    4
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Mitral Valve Disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 (Part A) Cohort 2 (Part A) Cohort 3 (Part A) Cohort 7 (Part B) Cohort 5 Low ANC (Part A) Cohort 6 High ANC (Part A) Cohort 4 (Part A)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    17 / 17 (100.00%)
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    2
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    1
    1
    2
    0
    Injection site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Influenza-like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    5 / 6 (83.33%)
    5 / 6 (83.33%)
    2 / 6 (33.33%)
    9 / 17 (52.94%)
    5 / 6 (83.33%)
    6 / 7 (85.71%)
    1 / 6 (16.67%)
         occurrences all number
    5
    6
    3
    10
    5
    6
    1
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    1
    2
    0
    1
    0
    Catheter site thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Injection site reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Injection site swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Nodule
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    2
    4
    3
    1
    3
    1
    1
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    0
    Localised oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Vessel puncture site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Temperature intolerance
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    2
    0
    4
    2
    0
    Pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    1
    Oedema, peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Vulvovaginal pruritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    2
    3
    5
    2
    0
    2
    1
    Dysphonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    2
    1
    0
    1
    0
    Dyspnoea, exertional
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    1
    Lung consolidation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Lung infiltration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    3
    1
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    0
    0
    Rhinitis, allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    1
    0
    Sinus congestion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    1
    Confusional State
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    1
    1
    2
    0
    Libido Decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Irritability
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Restlessness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Product issues
    Device Occlusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    2
    0
    0
    2
    Blood albumin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    2
    0
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Blood urine present
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    2
    Blood pressure increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Blood insulin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    1
    Red cell distribution width increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Protein urine present
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    4
    0
    0
    2
    Monocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Urine specific gravity increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Urine leukocyte esterase positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Urine bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Urinary sediment present
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Fall
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Foot Fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Humerus fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tooth fracture
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Dysarthria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    1
    2
    1
    0
    1
    Burning Sensation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    0
    0
    2
    1
    1
    Facial Paralysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 17 (11.76%)
    1 / 6 (16.67%)
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    2
    2
    1
    3
    0
    Memory Impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    4
    1
    0
    0
    Neuropathy, peripheral
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    Perineurial cyst
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Sensory disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    1
    0
    Anaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    3 / 17 (17.65%)
    4 / 6 (66.67%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    3
    2
    1
    5
    7
    3
    3
    Neutropenia
         subjects affected / exposed
    4 / 6 (66.67%)
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    10 / 17 (58.82%)
    5 / 6 (83.33%)
    5 / 7 (71.43%)
    3 / 6 (50.00%)
         occurrences all number
    7
    5
    21
    27
    11
    9
    7
    Thrombocytopenia
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    4
    2
    4
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Middle ear effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Ear pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    0
    Eye disorders
    Dry Eye
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    0
    Eye movement disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Eyelid edema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Conjunctival hemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Visual impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    3
    2
    0
    1
    1
    Photopsia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    4
    0
    0
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Abdominal pain, upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Abdominal tenderness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Colitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    1
    1
    3
    1
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 6 (66.67%)
    3 / 6 (50.00%)
    8 / 17 (47.06%)
    3 / 6 (50.00%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
         occurrences all number
    1
    5
    7
    9
    3
    4
    2
    Dry mouth
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    0
    Dyschezia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Glossodynia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gingival swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    2
    0
    Gastritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Odynophagia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    5 / 17 (29.41%)
    4 / 6 (66.67%)
    5 / 7 (71.43%)
    3 / 6 (50.00%)
         occurrences all number
    2
    5
    3
    6
    5
    6
    3
    Mouth ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    1
    Lip, dry
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hypoaesthesia, oral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Reflux gastritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Oral pain
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    0
    Sensitivity of teeth
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Tongue discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    3 / 17 (17.65%)
    1 / 6 (16.67%)
    4 / 7 (57.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    4
    3
    2
    5
    0
    Toothache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Tongue erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis, contact
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    1
    0
    0
    0
    1
    Dry Skin
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    1
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    3 / 17 (17.65%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    3 / 6 (50.00%)
         occurrences all number
    0
    5
    7
    5
    3
    2
    6
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    1
    1
    1
    1
    0
    Plantar erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    Onychomadesis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Nail disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Rash, papular
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Rash, maculo-papular
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    3
    0
    1
    0
    2
    Renal and urinary disorders
    Hematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Micturition urgency
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Pollakiura
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Urine odour abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Urine abnormality
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    5 / 17 (29.41%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    6
    1
    1
    1
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    3
    3
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    2
    0
    Masticatory pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ligamentum flavum hypertrophy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Coccydynia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    2
    0
    Bone pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    Vertebral foraminal stenosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    3 / 17 (17.65%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    3
    3
    0
    1
    Myalgia, intercostal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pain in neck
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    1
    1
    0
    1
    0
    Spinal column stenosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Infections and infestations
    Arthritis infective
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Bacterial infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Catheter site infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Device related infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Localised infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Osteolmyelitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Nail infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Purulent discharge
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Rash pustular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Sialoadenitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 17 (23.53%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    4
    1
    0
    1
    Skin Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    1
    Urinary Tract Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 17 (11.76%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    4
    4
    2
    4
    1
    Sinusitis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 17 (11.76%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    3
    2
    2
    0
    0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 17 (17.65%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    1
    Metabolism and nutrition disorders
    Hypoalbunimaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Fluid Retention
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hypokalemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Decreased Appetite
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    3
    1
    0
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 17 (5.88%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    5
    1
    0
    0
    5
    Hyperglycemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 17 (11.76%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    2
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 17 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2015
    Protocol Amendment 1: 1) The protocol was amended to include ophthalmological assessments and more intensive blood glucose monitoring in order to address the potential for overlapping toxicities associated with combination therapy with palbociclib and vistusertib and the potential for sustained hyperglycemia with accompanying visual toxicity. 2) The protocol was amended to add information regarding patients receiving a sensitive CYP3A substrate with a narrow therapeutic index may need to be have the dose of the agent reduced as palbociclib may increase their exposure to it. 3) The protocol was amended to specify that any case of elevated AST or ALT (≥3x ULN) and total bilirubin (≥2x ULN) (Hy’s Law) is defined to be a DLT since there was a liver safety concern. 4) To protect against the possibility of a study-wide type I error the protocol was amended to specify that if p-values were calculated at the time of the administrative interim analysis in Part C, the Haybittle-Peto boundary (p-value significance threshold of 0.001) to the endpoint of the planned Part C analysis was to be used.
    03 Dec 2015
    Protocol Amendment 2: 1) The protocol was amended to include fulvestrant as an Investigational Medicinal Product. Further, the duration of safety follow-up was increased to to 5 times the half-life of fulvestrant (250 days following last dose). 2) The protocol was amended to specify that patients under 50 years of age were required to have medically-confirmed irreversible premature ovarian failure, bilateral oophorectomy, bilateral salpingectomy, or complete or partial hysterectomy. 3) Virology for Hepatitis B, Hepatitis C and Human Immunodeficiency Virus (HIV) assessments were added to the screening tests and patients with these infections were excluded from the study. 4) The following criteria were added as a required parameter before retreatment after interruption for toxicity or at the start of each treatment cycle: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.0 times the upper limit of normal (ULN) (CTCAE Grade 1) or back to baseline values and total bilirubin <1.5 x ULN (CTCAE Grade 1) or back to baseline values.
    16 Dec 2015
    Amendment 3: Improve the feasibility of the study by permitting patients to be enrolled in Part A who have received prior fulvestrant, everolimus or agents with a MOA through inhibition of the PI3K-mTOR pathway. Further changes or clarifications include: 1) Amended Exclusion Criterion # 6 to make it specific to protocol Parts B and C. This now permits inclusion into Part A for patients who have received priortreatment with fulvestrant, or with everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway. 2) Clarification that patients from Part A who will be included in the Part B1 assessment of recommended phase 2 dose must meet the specific eligibility for Part B1, in addition to having measurable disease evaluable for response. 3) Amended Overall Benefit/Risk and Ethical Assessment Conclusion: Clarification that the starting dose for palbociclib is one dose level below the standard dose for palbociclib. 4) Modified Exclusion Criterion # 2 to permit patients to enter the study who have been exposed to potent or moderate inhibitors or inducers of CYP2C8 taken within the wash-out period before the first dose. 5) Updated protocol to remove restrictions around CYP2C8 inhibitors and inducers. 6) Amended protocol to remove 1 day window for visits with palbociclib or AZD2014 PK assessments during Part B2 and Part C. 7) The Schedule of assessments was updated to require ECG, Biochemistry and Haematology, Coagulation, Lipid Panel, Glucose and Insulin C-Peptide to be done at Cycle 0 Day 1 in Part B3. 8) Amended Table 34 to state that all dosed patients with reportable AZD2014, palbociclib or fulvestrant plasma concentrations will be included in the PK analysis set, regardless of whether they have available PK parameters. 9) Clarification that the rules are the same for handling PK parameters and plasma concentrations at a given timepoint, which for example, have non-quantifiable values.
    16 Dec 2016
    Note - There was no amendment 4 due to a change in the protocol template whereby updated protocols were referred to a "versions" rather than amendments. Version 5: 1) The protocol was amended to remove Parts B2 and B3. This was no longer considered required. 2) The protocol was amended to remove fulvestrant PK sampling. 3) The protocol was modified to allow flexibility to test alternative dosing schedules of AZD2014 and palbociclib in Part A, and to apply those schedules to Parts B and C. 4) The protocol was modified to remove the AZD2014 monotherapy period (Cycle 0) for the assessment of single dose PK from Part B (formerly Part B1) as this was no longer considered required because the data was already available for the program through PK/PD modelling and to avoid collection of unnecessary samples from patients. 5) The protocol was amended to prohibit PPI use in the drug interaction (DDI) and dose limiting toxicity (DLT) evaluation period since PPIs may reduce palbociclib Cmax and AUC by 41% and 13%, respectively and could affect the DDI evaluation and MTD determination of the combination. 6) The protocol was updated to conform to current guidance for investigators, as a clinically relevant PK drug interaction with sensitive substrates of P450 enzymes and transporters is unlikely. 7) The sample size of Part B was increased from 9-15 to 27 patients in order to allow internal decision making at the end of Part B based on Clinical Benefit Rate (CBR). 8) The protocol was amended to allow enrollment of a different patient population for Part B to understand tolerability in a population that is more in line with the proposed Part C population. 9) The protocol was amended to allow flexibility in Part A to enroll additional cohorts for patients with specific ranges of neutrophil (ANC). The rationale for this was the hypothesis that baseline ANC value may be a risk factor for a DLT.
    14 Jun 2017
    Protocol Version 6: 1) Consent to tumor biopsy was made a mandatory part of the study. The study design, exploratory objectives and end points, inclusion criteria, study plan, description of biopsy collection, and description of the analysis sets were updated. 2) The guidelines for dose modifications and interruptions, Appendix N, were revised so that dose modifications could be made in consultation with the AZ Medical Director as well as the Sarah Cannon Development Innovations medical monitor and that dose interruption decisions can be made by the Investigator on a case by case basis. In addition the recommendation for dose interruption in the case of uncomplicated Grade 3 neutropenia was removed and there was clarification that dose interruption in the case of QTc prolongation and hematological events should be assessed based on severity. 3) The safety portion of the protocol was updated to clarify the overdose reporting process by directing that overdoses should be reported on the Overdose Reporting Form. 4) The protocol was amended to allow patients to have extended vital signs monitoring done during long PK days or only up to the point that they leave the clinic. 5) Amended to allow patients to have last fasting glucose at the time of leaving the clinic if they are not staying overnight for assessment.'
    12 Dec 2017
    Protocol Version 7: 1) The protocol was amended to end enrollment in Part B after 17 patients and not to perform the Futility Interim analysis. This decision was made based on the result of a strategic portfolio review by the sponsor. Further, Part C of the protocol was removed. No patients were enrolled into Part C. 2) The protocol was amended to establish the primary data cut-off after the Cycle 7 Day 1 visit for the last patient enrolled in the study. Following the data cut-off patients continued to receive study treatment and attended for dispensing and SAE reporting. Assessments were no longer performed for the purposes of the study after the data cut-off, instead assessments were only as per standard of care in accordance with the palbociclib label or as clinically indicated. This decision was made based on the result of a strategic portfolio review.

    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.
    In cases where the upper limit of a Confidence Interval could not be calculated the value 99999.9 was entered because the software does not permit no numeric entries such as NC (not calculated) or NA (not available)
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