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    Clinical Trial Results:
    A Randomized, Double-Blind, Phase 2 Trial of Fulvestrant Plus Enzastaurin versus Fulvestrant Plus Placebo in Aromatase Inhibitor-Resistant Metastatic Breast Cancer

    Summary
    EudraCT number
    		 2006-005305-58
    Trial protocol
    		 NL   FR   DE   IT   ES  
    Global end of trial date
    18 Oct 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    26 Jan 2020
    First version publication date
    13 Oct 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    H6Q-MC-S023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00451555
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 10736
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    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
    18 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary purpose of this study is to help answer the following research question: whether enzastaurin given together with fulvestrant can help participants who have breast cancer and make the tumor smaller or disappear and for how long.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Apr 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    France: 60
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Netherlands: 20
    Worldwide total number of subjects
    152
    EEA total number of subjects
    152
    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)
    84
    From 65 to 84 years
    62
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 No Text Available

    Pre-assignment
    Screening details
    		 Completers include participants who had died from any cause, who discontinued due to progressive disease or were alive and on study but off treatment at end of the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Enzastaurin + Fulvestrant
    Arm description
    		 (Initial Therapy) Participants received Enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 500 mg orally (QD) once daily in a 28-day cycle. (Amended Therapy) Participants received enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 250 mg orally (BID) twice daily in a 28-day cycle. Enzastaurin Once Daily Dosing: Participants received Enzastaurin 500 mg QD. Enzastaurin Twice Daily Dosing: Participants received Enzastaurin 500 mg BID. Fulvestrant was given intramuscularly at a loading dose of 500 mg on Day 1 and 250 mg on Day 15 in Cycle 1. Subsequent doses of Fulvestrant 250 mg were given on Day 1 of Cycle 2 and every 28 days thereafter.
    Arm type
    		 Experimental

    Investigational medicinal product name
    enzastaurin
    Investigational medicinal product code
    Other name
    LY317615
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 500 mg orally (QD) once daily in a 28-day cycle. Participants received enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 250 mg orally (BID) twice daily in a 28-day cycle.

    Investigational medicinal product name
    fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg, intramuscular (IM), day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo, oral, daily.

    Arm title
    		 Fulvestrant + Placebo
    Arm description
    		 Participants received fulvestrant: 500 mg, intramuscular (IM), day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo, oral, daily.

    Investigational medicinal product name
    fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg, intramuscular (IM), day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression

    Number of subjects in period 1
    		Enzastaurin + Fulvestrant Fulvestrant + Placebo
    Started
    96
    60
    Enzastaurin Twice Daily Dosing (BID)
    39 [1]
    0 [2]
    Enzastaurin Once Daily Dosing (QD)
    55 [3]
    0 [4]
    Progressive Disease
    75 [5]
    54 [6]
    Death
    2 [7]
    0 [8]
    Received at least one dose of study drug
    94
    58
    Completed
    83
    56
    Not completed
    13
    4
         Consent withdrawn by subject
    6
    -
         Physician decision
    2
    1
         Adverse event, non-fatal
    3
    1
         Protocol deviation
    2
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this milestone is a subpopulation to the overall number of participants enrolled in the study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this milestone is a subpopulation to the overall number of participants enrolled in the study.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this milestone is a subpopulation to the overall number of participants enrolled in the study.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this milestone is a subpopulation to the overall number of participants enrolled in the study.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this milestone is a subpopulation to the overall number of participants enrolled in the study.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this milestone is a subpopulation to the overall number of participants enrolled in the study.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this milestone is a subpopulation to the overall number of participants enrolled in the study.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this milestone is a subpopulation to the overall number of participants enrolled in the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 152 152
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.9 ( 10.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 152 152
        Male
    		 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 57 57
        Not Hispanic or Latino
    		 95 95
        Unknown or Not Reported
    		 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 1 1
        White
    		 151 151
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Region of Enrollment
    Units: Subjects
        Netherlands
    		 20 20
        Italy
    		 18 18
        France
    		 60 60
        Germany
    		 19 19
        Spain
    		 35 35

    End points

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    End points reporting groups
    Reporting group title
    Enzastaurin + Fulvestrant
    Reporting group description
    		 (Initial Therapy) Participants received Enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 500 mg orally (QD) once daily in a 28-day cycle. (Amended Therapy) Participants received enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 250 mg orally (BID) twice daily in a 28-day cycle. Enzastaurin Once Daily Dosing: Participants received Enzastaurin 500 mg QD. Enzastaurin Twice Daily Dosing: Participants received Enzastaurin 500 mg BID. Fulvestrant was given intramuscularly at a loading dose of 500 mg on Day 1 and 250 mg on Day 15 in Cycle 1. Subsequent doses of Fulvestrant 250 mg were given on Day 1 of Cycle 2 and every 28 days thereafter.

    Reporting group title
    Fulvestrant + Placebo
    Reporting group description
    		 Participants received fulvestrant: 500 mg, intramuscular (IM), day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression.

    Subject analysis set title
    Enzastaurin + Fulvestrant BID
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Enzastaurin 1125 mg loading dose then 250 mg, oral, twice daily (BID) (for a total of 500 mg), until disease progression Fulvestrant was given intramuscularly at a loading dose of 500 mg on Day 1 and 250 mg on Day 15 in Cycle 1. Subsequent doses of Fulvestrant 250 mg were given on Day 1 of Cycle 2 and every 28 days thereafter.

    Subject analysis set title
    Enzastaurin + Fulvestrant QD
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Enzastaurin 1125 mg loading dose then received Enzastaurin once daily (QD) regimen of enzastaurin 500 mg orally QD in a 28-day cycle until disease progression. Fulvestrant was given intramuscularly at a loading dose of 500 mg on Day 1 and 250 mg on Day 15 in Cycle 1. Subsequent doses of Fulvestrant 250 mg were given on Day 1 of Cycle 2 and every 28 days thereafter.

    Subject analysis set title
    Placebo + Fulvestrant BID
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received fulvestrant: 500 mg, IM, day 1, 1250 mg, IM, day 15 cycle 1 then 250 mg, IM, every 28 days, until disease progression. Then, participants received placebo, oral, daily.

    Subject analysis set title
    Enzastaurin + Fulvestrant QD + BID
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 500 mg orally (QD) once daily in a 28-day cycle. Participants received enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 250 mg orally (BID) twice daily in a 28-day cycle. Fulvestrant was given intramuscularly at a loading dose of 500 mg on Day 1 and 250 mg on Day 15 in Cycle 1. Subsequent doses of Fulvestrant 250 mg were given on Day 1 of Cycle 2 and every 28 days thereafter. .

    Subject analysis set title
    Enzastaurin + Fulvestrant BID + QD Duration Clinical Benefit
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received Enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 500 mg orally (QD) once daily in a 28-day cycle. Participants received enzastaurin loading dose of 1125 mg, on Day 1 of Cycle 1 only then received Enzastaurin 250 mg orally (BID) twice daily in a 28-day cycle. Fulvestrant was given intramuscularly at a loading dose of 500 mg on Day 1 and 250 mg on Day 15 in Cycle 1. Subsequent doses of Fulvestrant 250 mg were given on Day 1 of Cycle 2 and every 28 days thereafter. .

    Primary: Percentage of Participants Who Achieved a Best Response of Complete Response, Partial Response, and Stable Disease (CR+PR+SD) (Clinical Benefit Rate)

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    End point title
    		 Percentage of Participants Who Achieved a Best Response of Complete Response, Partial Response, and Stable Disease (CR+PR+SD) (Clinical Benefit Rate)
    End point description
    Clinical benefit rate is defined as the rate of confirmed CR, confirmed PR, and SD for 24 weeks duration and is the best response CR, PR, or SD as classified by the investigators according to the RECIST v1.1. CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of not-target lesions or appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameter since treatment started. Kaplan-Meier (KM) techniques were used to assess the time-to-event endpoints. Progressive Disease (PD) was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir.
    End point type
    Primary
    End point timeframe
    Baseline to Measured Progressive Disease or Study Discontinuation (Up to 24 Weeks)
    End point values
    		 Enzastaurin + Fulvestrant BID Enzastaurin + Fulvestrant QD Placebo + Fulvestrant BID Enzastaurin + Fulvestrant QD + BID
    Number of subjects analysed
    39 [1]
    55 [2]
    58 [3]
    94 [4]
    Units: percentage of participants
        number (confidence interval 95%)
    43.6 (27.8 to 60.4)
    43.6 (30.3 to 57.7)
    44.8 (31.7 to 58.5)
    43.6 (33.4 to 54.2)
    Notes
    [1] - All randomized participants who received at least one dose of study drug.
    [2] - All randomized participants who received at least one dose of study drug.
    [3] - All randomized participants who received at least one dose of study drug.
    [4] - All randomized participants who received at least one dose of study drug.
    Statistical analysis title
    		 Achieved a Best Response of CR+PR+SD (CBR)
    Comparison groups
    Placebo + Fulvestrant BID v Enzastaurin + Fulvestrant BID
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6282
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Achieved a Best Response of CR+PR+SD (CBR)
    Comparison groups
    Enzastaurin + Fulvestrant QD v Placebo + Fulvestrant BID
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6242
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Achieved a Best Response CR+PR+SD (CBR)
    Comparison groups
    Placebo + Fulvestrant BID v Enzastaurin + Fulvestrant QD + BID
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6238
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percentage of Participants Achieving Overall Tumor Response Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR])

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    End point title
    		 Percentage of Participants Achieving Overall Tumor Response Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR])
    End point description
    The ORR is equal to the percentage of participants achieving a best overall response of partial response or complete response (PR + CR), according to RECIST version 1.1 criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes must have reduction in short axis to <10 millimeter (mm) and normalization of tumor marker level of non-target lesions; PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions; PD was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir; SD was defined as small changes that did not meet above criteria. Participants who had no post baseline tumor assessments were considered non-responders and included in the denominator when calculating response rate. The 95% confidence interval (CI) was calculated by exact method. Kaplan-Meier (KM) techniques were used to assess the time-to-event endpoints.
    End point type
    Secondary
    End point timeframe
    Baseline to Measured Progressive Disease or Study Discontinuation (Up to 24 Weeks)
    End point values
    		 Enzastaurin + Fulvestrant BID Enzastaurin + Fulvestrant QD Placebo + Fulvestrant BID Enzastaurin + Fulvestrant QD + BID
    Number of subjects analysed
    39 [5]
    55 [6]
    58 [7]
    94 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    5.1 (0.6 to 17.3)
    5.5 (1.1 to 15.1)
    5.2 (1.1 to 14.4)
    5.3 (1.7 to 12.0)
    Notes
    [5] - All randomized participants who received at least one dose of study drug.
    [6] - All randomized participants who received at least one dose of study drug.
    [7] - All randomized participants who received at least one dose of study drug.
    [8] - All randomized participants who received at least one dose of study drug.
    Statistical analysis title
    		 Percentage of Participants Achieving Overall Tumo
    Comparison groups
    Enzastaurin + Fulvestrant BID v Placebo + Fulvestrant BID
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6721
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Percentage of Participants Achieving Overall Tumo
    Comparison groups
    Enzastaurin + Fulvestrant QD v Placebo + Fulvestrant BID
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6349
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Percentage of Participants Achieving Overall Tumo
    Comparison groups
    Placebo + Fulvestrant BID v Enzastaurin + Fulvestrant QD + BID
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.639
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Duration of Clinical Benefit

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    End point title
    		 Duration of Clinical Benefit
    End point description
    The duration of clinical benefit was measured from the time of clinical benefit of CR, PR or SD to the time of progressive disease or death from any cause. PD was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir. Kaplan-Meier (KM) techniques were used to assess the time-to-event endpoints.
    End point type
    Secondary
    End point timeframe
    Time of Clinical Benefit to Progressive Disease or Death (Up to 3 Years)
    End point values
    		 Enzastaurin + Fulvestrant BID Enzastaurin + Fulvestrant QD Placebo + Fulvestrant BID Enzastaurin + Fulvestrant BID + QD Duration Clinical Benefit
    Number of subjects analysed
    17 [9]
    24 [10]
    26 [11]
    41 [12]
    Units: months
        median (confidence interval 95%)
    9.4 (7.4 to 12.2)
    9.6 (7.9 to 11.1)
    9.7 (7.4 to 12.6)
    9.6 (8.2 to 11.0)
    Notes
    [9] - All randomized participants who received at least one dose of study drug and had evaluable data.
    [10] - All randomized participants who received at least one dose of study drug and had evaluable data.
    [11] - All randomized participants who received at least one dose of study drug and had evaluable data.
    [12] - All randomized participants who received at least one dose of study drug and had evaluable data.
    Statistical analysis title
    		 Duration of Clinical Benefit
    Comparison groups
    Placebo + Fulvestrant BID v Enzastaurin + Fulvestrant BID + QD Duration Clinical Benefit
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8582
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Duration of Clinical Benefit
    Comparison groups
    Enzastaurin + Fulvestrant BID v Placebo + Fulvestrant BID
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7307
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Duration of Clinical Benefit
    Comparison groups
    Placebo + Fulvestrant BID v Enzastaurin + Fulvestrant QD
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9798
    Method
    		 Logrank
    Confidence interval

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression-free survival (PFS) time was defined as the time from baseline to the first date of progressive disease (symptomatic or objective) or death due to any cause, whichever occurred first. PD was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir.For participants who were not known to have died or progressed as of the data-inclusion cutoff date, PFS time was censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systematic anticancer therapy. PFS was summarized using Kaplan-Meier estimates. Participants were censored in Fulvestrant + Enzastaurin (QD) arm = 4, the Fulvestrant + Enzastaurin (BID) arm = 6, and the Fulvestrant + Placebo arm = 6.
    End point type
    Secondary
    End point timeframe
    Baseline to Measured Progressive Disease or Death Due to Any Cause (Up to 3 Years)
    End point values
    		 Enzastaurin + Fulvestrant BID Enzastaurin + Fulvestrant QD Placebo + Fulvestrant BID Enzastaurin + Fulvestrant QD + BID
    Number of subjects analysed
    39 [13]
    55 [14]
    58 [15]
    94 [16]
    Units: months
        median (confidence interval 95%)
    3.7 (2.8 to 7.4)
    6.0 (2.8 to 7.9)
    5.5 (3.8 to 7.4)
    5.2 (3.5 to 7.4)
    Notes
    [13] - All randomized participants who received at least one dose of study drug.
    [14] - All randomized participants who received at least one dose of study drug.
    [15] - All randomized participants who received at least one dose of study drug.
    [16] - All randomized participants who received at least one dose of study drug.
    Statistical analysis title
    		 Progression Free Survival (PFS)
    Comparison groups
    Placebo + Fulvestrant BID v Enzastaurin + Fulvestrant QD + BID
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5887
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Progression Free Survival (PFS)
    Comparison groups
    Placebo + Fulvestrant BID v Enzastaurin + Fulvestrant BID
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4516
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Progression Free Survival (PFS)
    Comparison groups
    Placebo + Fulvestrant BID v Enzastaurin + Fulvestrant QD
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7965
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of Participants Who Discontinued with Adverse Events (AE) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants Who Discontinued with Adverse Events (AE) and Serious Adverse Events (SAEs)
    End point description
    Clinically significant events were defined as serious AEs (SAEs) and other non-serious AEs, regardless of causality. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. Participants who discontinued due to an AE or SAE are reported.
    End point type
    Secondary
    End point timeframe
    From Baseline To Study Completion (Up to 3 years, 9 months)
    End point values
    		 Enzastaurin + Fulvestrant BID Enzastaurin + Fulvestrant QD Placebo + Fulvestrant BID Enzastaurin + Fulvestrant QD + BID
    Number of subjects analysed
    39 [17]
    55 [18]
    58 [19]
    94 [20]
    Units: participants
        Adverse Events (AEs)
    1
    2
    1
    3
        Serious Adverse Events (SAEs)
    0
    0
    1
    0
    Notes
    [17] - All randomized participants who received at least one dose of study drug.
    [18] - All randomized participants who received at least one dose of study drug.
    [19] - All randomized participants who received at least one dose of study drug.
    [20] - All randomized participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Enzastaurin Biomarkers and Disease State

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    End point title
    		 Percentage of Participants with Enzastaurin Biomarkers and Disease State
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline, Cycle 2 to Study Completion (Up to 3 Years, 9 Months)
    End point values
    		 Enzastaurin + Fulvestrant BID Enzastaurin + Fulvestrant QD Placebo + Fulvestrant BID Enzastaurin + Fulvestrant QD + BID
    Number of subjects analysed
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    Units: participants
    Notes
    [21] - Zero participants were analyzed due to insufficient samples being collected.
    [22] - Zero participants were analyzed due to insufficient samples being collected.
    [23] - Zero participants were analyzed due to insufficient samples being collected.
    [24] - Zero participants were analyzed due to insufficient samples being collected.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline To Study Completion (Up to 3 Years, 9 Months)
    Adverse event reporting additional description
    h6q_mc_s023
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Fulvestrant Plus Enzastaurin (QD + BID)
    Reporting group description
    		 -

    Reporting group title
    Fulvestrant Plus Enzastaurin (BID)
    Reporting group description
    		 -

    Reporting group title
    Fulvestrant Plus Enzastaurin (QD)
    Reporting group description
    		 -

    Reporting group title
    Fulvestrant Plus Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Fulvestrant Plus Enzastaurin (QD + BID) Fulvestrant Plus Enzastaurin (BID) Fulvestrant Plus Enzastaurin (QD) Fulvestrant Plus Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 94 (18.09%)
    9 / 39 (23.08%)
    8 / 55 (14.55%)
    11 / 58 (18.97%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    leiomyoma
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    metastases to skin
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    phlebitis
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    disease progression
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    oedema peripheral
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    depression
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    blood creatinine increased
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    femoral neck fracture
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    angina pectoris
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ischaemic cardiomyopathy
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    cerebrovascular accident
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ischaemic stroke
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 39 (5.13%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    lymphadenopathy
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    haemorrhoids
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    hepatic function abnormal
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Renal and urinary disorders
    hydronephrosis
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ureteric dilatation
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    device related infection
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fulvestrant Plus Enzastaurin (QD + BID) Fulvestrant Plus Enzastaurin (BID) Fulvestrant Plus Enzastaurin (QD) Fulvestrant Plus Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 94 (82.98%)
    31 / 39 (79.49%)
    47 / 55 (85.45%)
    50 / 58 (86.21%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    tumour pain
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    2 / 39 (5.13%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences all number
    6
    4
    2
    0
    Vascular disorders
    hot flush
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    14 / 94 (14.89%)
    8 / 39 (20.51%)
    6 / 55 (10.91%)
    5 / 58 (8.62%)
         occurrences all number
    248
    203
    45
    24
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    15 / 94 (15.96%)
    6 / 39 (15.38%)
    9 / 55 (16.36%)
    10 / 58 (17.24%)
         occurrences all number
    169
    124
    45
    54
    chest pain
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    0 / 39 (0.00%)
    3 / 55 (5.45%)
    5 / 58 (8.62%)
         occurrences all number
    9
    0
    9
    9
    fatigue
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    21 / 94 (22.34%)
    9 / 39 (23.08%)
    12 / 55 (21.82%)
    11 / 58 (18.97%)
         occurrences all number
    119
    37
    82
    68
    influenza like illness
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    2 / 39 (5.13%)
    2 / 55 (3.64%)
    1 / 58 (1.72%)
         occurrences all number
    7
    4
    3
    1
    malaise
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 39 (5.13%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    5
    5
    0
    0
    oedema peripheral
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    7 / 94 (7.45%)
    4 / 39 (10.26%)
    3 / 55 (5.45%)
    3 / 58 (5.17%)
         occurrences all number
    79
    58
    21
    16
    pyrexia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    7 / 94 (7.45%)
    4 / 39 (10.26%)
    3 / 55 (5.45%)
    3 / 58 (5.17%)
         occurrences all number
    20
    16
    4
    3
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    9 / 94 (9.57%)
    2 / 39 (5.13%)
    7 / 55 (12.73%)
    7 / 58 (12.07%)
         occurrences all number
    66
    46
    20
    21
    dysphonia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    1 / 39 (2.56%)
    3 / 55 (5.45%)
    2 / 58 (3.45%)
         occurrences all number
    24
    19
    5
    17
    dyspnoea
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    13 / 94 (13.83%)
    5 / 39 (12.82%)
    8 / 55 (14.55%)
    8 / 58 (13.79%)
         occurrences all number
    123
    91
    32
    18
    Psychiatric disorders
    insomnia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 39 (2.56%)
    1 / 55 (1.82%)
    3 / 58 (5.17%)
         occurrences all number
    7
    4
    3
    30
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    1 / 39 (2.56%)
    3 / 55 (5.45%)
    0 / 58 (0.00%)
         occurrences all number
    26
    10
    16
    0
    electrocardiogram qt prolonged
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    0 / 39 (0.00%)
    3 / 55 (5.45%)
    1 / 58 (1.72%)
         occurrences all number
    33
    0
    33
    4
    gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    1 / 39 (2.56%)
    3 / 55 (5.45%)
    1 / 58 (1.72%)
         occurrences all number
    29
    7
    22
    7
    weight decreased
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 39 (5.13%)
    0 / 55 (0.00%)
    0 / 58 (0.00%)
         occurrences all number
    7
    7
    0
    0
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    3 / 39 (7.69%)
    0 / 55 (0.00%)
    5 / 58 (8.62%)
         occurrences all number
    8
    8
    0
    11
    headache
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    11 / 94 (11.70%)
    4 / 39 (10.26%)
    7 / 55 (12.73%)
    7 / 58 (12.07%)
         occurrences all number
    35
    9
    26
    28
    paraesthesia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    2 / 39 (5.13%)
    1 / 55 (1.82%)
    1 / 58 (1.72%)
         occurrences all number
    40
    16
    24
    6
    sciatica
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    0 / 39 (0.00%)
    3 / 55 (5.45%)
    1 / 58 (1.72%)
         occurrences all number
    10
    0
    10
    10
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    9 / 94 (9.57%)
    4 / 39 (10.26%)
    5 / 55 (9.09%)
    4 / 58 (6.90%)
         occurrences all number
    49
    15
    34
    27
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 39 (0.00%)
    2 / 55 (3.64%)
    4 / 58 (6.90%)
         occurrences all number
    12
    0
    12
    5
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    8 / 94 (8.51%)
    3 / 39 (7.69%)
    5 / 55 (9.09%)
    4 / 58 (6.90%)
         occurrences all number
    17
    7
    10
    6
    abdominal pain upper
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    7 / 94 (7.45%)
    3 / 39 (7.69%)
    4 / 55 (7.27%)
    2 / 58 (3.45%)
         occurrences all number
    31
    10
    21
    5
    constipation
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    17 / 94 (18.09%)
    7 / 39 (17.95%)
    10 / 55 (18.18%)
    7 / 58 (12.07%)
         occurrences all number
    50
    17
    33
    20
    diarrhoea
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    20 / 94 (21.28%)
    6 / 39 (15.38%)
    14 / 55 (25.45%)
    10 / 58 (17.24%)
         occurrences all number
    76
    20
    56
    23
    dry mouth
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    2 / 39 (5.13%)
    1 / 55 (1.82%)
    1 / 58 (1.72%)
         occurrences all number
    17
    13
    4
    11
    dyspepsia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    3 / 39 (7.69%)
    1 / 55 (1.82%)
    2 / 58 (3.45%)
         occurrences all number
    10
    6
    4
    13
    faeces discoloured
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    2 / 39 (5.13%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences all number
    15
    12
    3
    0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 39 (0.00%)
    0 / 55 (0.00%)
    3 / 58 (5.17%)
         occurrences all number
    0
    0
    0
    15
    nausea
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    31 / 94 (32.98%)
    13 / 39 (33.33%)
    18 / 55 (32.73%)
    18 / 58 (31.03%)
         occurrences all number
    78
    34
    44
    60
    vomiting
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    10 / 94 (10.64%)
    4 / 39 (10.26%)
    6 / 55 (10.91%)
    6 / 58 (10.34%)
         occurrences all number
    17
    6
    11
    11
    Skin and subcutaneous tissue disorders
    dry skin
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 39 (0.00%)
    2 / 55 (3.64%)
    4 / 58 (6.90%)
         occurrences all number
    11
    0
    11
    33
    pruritus
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    3 / 39 (7.69%)
    1 / 55 (1.82%)
    1 / 58 (1.72%)
         occurrences all number
    33
    31
    2
    1
    rash
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    1 / 39 (2.56%)
    3 / 55 (5.45%)
    3 / 58 (5.17%)
         occurrences all number
    17
    4
    13
    5
    Renal and urinary disorders
    chromaturia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    9 / 94 (9.57%)
    3 / 39 (7.69%)
    6 / 55 (10.91%)
    1 / 58 (1.72%)
         occurrences all number
    94
    25
    69
    12
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    9 / 94 (9.57%)
    7 / 39 (17.95%)
    2 / 55 (3.64%)
    7 / 58 (12.07%)
         occurrences all number
    160
    138
    22
    36
    back pain
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    8 / 94 (8.51%)
    5 / 39 (12.82%)
    3 / 55 (5.45%)
    7 / 58 (12.07%)
         occurrences all number
    36
    22
    14
    21
    bone pain
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    9 / 94 (9.57%)
    2 / 39 (5.13%)
    7 / 55 (12.73%)
    10 / 58 (17.24%)
         occurrences all number
    37
    6
    31
    61
    musculoskeletal pain
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 39 (0.00%)
    1 / 55 (1.82%)
    3 / 58 (5.17%)
         occurrences all number
    2
    0
    2
    10
    myalgia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 39 (0.00%)
    2 / 55 (3.64%)
    5 / 58 (8.62%)
         occurrences all number
    8
    0
    8
    18
    osteoarthritis
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    2 / 39 (5.13%)
    1 / 55 (1.82%)
    0 / 58 (0.00%)
         occurrences all number
    39
    36
    3
    0
    pain in extremity
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    5 / 94 (5.32%)
    0 / 39 (0.00%)
    5 / 55 (9.09%)
    2 / 58 (3.45%)
         occurrences all number
    23
    0
    23
    7
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    2 / 39 (5.13%)
    2 / 55 (3.64%)
    4 / 58 (6.90%)
         occurrences all number
    56
    51
    5
    7
    cystitis
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    5 / 94 (5.32%)
    3 / 39 (7.69%)
    2 / 55 (3.64%)
    2 / 58 (3.45%)
         occurrences all number
    8
    6
    2
    2
    infection
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    4 / 94 (4.26%)
    2 / 39 (5.13%)
    2 / 55 (3.64%)
    2 / 58 (3.45%)
         occurrences all number
    8
    5
    3
    4
    nasopharyngitis
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    5 / 94 (5.32%)
    0 / 39 (0.00%)
    5 / 55 (9.09%)
    0 / 58 (0.00%)
         occurrences all number
    9
    0
    9
    0
    pharyngitis
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 39 (5.13%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    4
    4
    0
    2
    rhinitis
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    0 / 39 (0.00%)
    3 / 55 (5.45%)
    1 / 58 (1.72%)
         occurrences all number
    15
    0
    15
    2
    urinary tract infection
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 39 (2.56%)
    0 / 55 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    2
    2
    0
    8
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    5 / 94 (5.32%)
    2 / 39 (5.13%)
    3 / 55 (5.45%)
    2 / 58 (3.45%)
         occurrences all number
    25
    16
    9
    4
    hypercalcaemia
    alternative dictionary used: MedDRA 13.1
         subjects affected / exposed
    3 / 94 (3.19%)
    3 / 39 (7.69%)
    0 / 55 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    47
    47
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Apr 2007
    Overview of changes for protocol amendment a - modified inclusion criterion to clarify the definition of females with postmenopausal status and exclusion criterion to clarify the exclusion of participants receiving concurrent administration of any other antitumor therapy. Exclusion criterion included the following: -to clarify the evaluation methods for HR2 positive participants -to improve the safety of participants with known hypersensitivity to the drug or any of its component -to improve the safety of participants with a potential risk for osteoporosis, including those who have problems with the loss of the mineral contents of the bones Deleted blinding text Concomitant therapy section modified for clarity Serious Adverse Events deleted redundant text that will not be captured by CRF Deleted monocytes from list of required laboratory values.
    29 Sep 2008
    Protocol amendment (b): Participants received enzastaurin loading dose (1125 mg; 3 tablets, TID [9 tablets]) on Day 1 of Cycle 1 ONLY. Thereafter, enzastaurin (250 mg; 2 tablets) was administered orally BID in a 28-day cycle.

    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.
    The translational research component of the study was cancelled due to lack of efficacy in the experimental arm. Due to an amendment to the initial therapy, 250 mg BID dosing was added.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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