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    Clinical Trial Results:
    A Randomized Phase 3 Study of Enzastaurin versus Lomustine in the Treatment of Recurrent, Intracranial Glioblastoma Multiforme

    Summary
    EudraCT number
    		 2005-004627-18
    Trial protocol
    		 AT   ES   DE   BE   GB   IT  
    Global end of trial date
    23 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2018
    First version publication date
    29 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H6Q-MC-JCBF
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00295815
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 9817
    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, 877 CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 877 285 4559,
    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, 877 CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 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
    23 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective is to compare enzastaurin versus lomustine in terms of PFS time in patients with recurrent, intracranial GBM (WHO Stage IV).
    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
    10 Jan 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Ethical reason
    Long term follow-up duration
    		 8 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Australia: 33
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    India: 5
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    United States: 77
    Worldwide total number of subjects
    266
    EEA total number of subjects
    131
    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)
    221
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 No Text Entered

    Pre-assignment
    Screening details
    		 No Text Entered

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 500 mg Enzastaurin
    Arm description
    		 500 mg enzastaurin administered daily oral dose (four 125-mg tablets once a day) starting on Day 2 with an 1125-mg loading dose (three 125-mg tablets taken 3 times a day).
    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
    500 mg enzastaurin administered daily (four 125-mg tablets once a day) starting on Day 2 with an 1125-mg loading dose (three 125-mg tablets taken 3 times a day).

    Arm title
    		 Lomustine
    Arm description
    		 10 mg, 40 mg, or 100 mg lomustine administered orally as 100 to 130 mg/m2 on Day 1 of each 6-week treatment cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lomustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg, 40 mg, or 100 mg lomustine administered orally as 100 to 130 mg/m2 on Day 1 of each 6-week treatment cycle.

    Number of subjects in period 1
    		500 mg Enzastaurin Lomustine
    Started
    174
    92
    Received at least one dose of study drug
    167
    84
    Completed
    157
    74
    Not completed
    17
    18
         Consent withdrawn by subject
    5
    4
         Physician decision
    -
    2
         Not Treated
    7
    10
         Sponsor Decision
    4
    1
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    500 mg Enzastaurin
    Reporting group description
    		 500 mg enzastaurin administered daily oral dose (four 125-mg tablets once a day) starting on Day 2 with an 1125-mg loading dose (three 125-mg tablets taken 3 times a day).

    Reporting group title
    Lomustine
    Reporting group description
    		 10 mg, 40 mg, or 100 mg lomustine administered orally as 100 to 130 mg/m2 on Day 1 of each 6-week treatment cycle.

    Reporting group values
    		 500 mg Enzastaurin Lomustine Total
    Number of subjects
    		 174 92 266
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    All participants who received at least one dose of study drug.
    Units: years
        arithmetic mean (standard deviation)
    		 55.6 ± 10.98 54.0 ± 12.52 -
    Gender categorical
    Units: Subjects
        Female
    		 58 36 94
        Male
    		 116 56 172
    Ethnicity
    Units: Subjects
        African
    		 1 1 2
        Caucasian
    		 164 85 249
        East Asian
    		 2 0 2
        Hispanic
    		 4 5 9
        West Asian
    		 3 1 4

    End points

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    End points reporting groups
    Reporting group title
    500 mg Enzastaurin
    Reporting group description
    		 500 mg enzastaurin administered daily oral dose (four 125-mg tablets once a day) starting on Day 2 with an 1125-mg loading dose (three 125-mg tablets taken 3 times a day).

    Reporting group title
    Lomustine
    Reporting group description
    		 10 mg, 40 mg, or 100 mg lomustine administered orally as 100 to 130 mg/m2 on Day 1 of each 6-week treatment cycle.

    Subject analysis set title
    250 mg Enzastaurin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    500 mg enzastaurin administered daily.

    Subject analysis set title
    High Expresssion Enzastaurin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    High Expresssion Enzastaurin

    Subject analysis set title
    Low Expresssion Enzastaurin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Low Expresssion Enzastaurin

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS is the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1 or death from any cause. Progressive disease (PD) was identified by either a radiologic assessment (MRI) or evidence of neurologic progression. A worsening of the radiologic assessment or neurologic examination findings was presumed evidence of PD. The date on which a participant's disease progressed would be the earlier date derived from radiologic progression or neurologic progression. Analysis Population Description: All participants who received at least one dose of drug. Participants censored were: 500 mg Enzastaurin=18 and Lomustine=22.
    End point type
    Primary
    End point timeframe
    From Date of Randomization until Disease Progression or Death Due to Any Cause Up To 13 Months
    End point values
    		 500 mg Enzastaurin Lomustine
    Number of subjects analysed
    174
    92
    Units: months
        median (confidence interval 95%)
    1.51 (1.45 to 2.10)
    1.64 (1.48 to 2.79)
    Statistical analysis title
    		 Enzastaurin vs Lomustine PFS
    Comparison groups
    Lomustine v 500 mg Enzastaurin
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.7

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS defined as the time from the date of randomization to the date of death due to any cause. For participants not known to have died as of the data cutoff date, OS will be censored at the last contact date. Analysis Population Description: All participants who received at least one dose of study drug. Participants censored were: 500 Enzastaurin= 53 and Lomustine= 33.
    End point type
    Secondary
    End point timeframe
    From Date of Randomization until Death Due to Any Cause Up To 16 Months
    End point values
    		 500 mg Enzastaurin Lomustine
    Number of subjects analysed
    174
    92
    Units: Months
        median (confidence interval 95%)
    6.60 (5.22 to 7.75)
    7.13 (6.01 to 8.80)
    Statistical analysis title
    		 Enzastaurin vs Lomustine OS
    Comparison groups
    500 mg Enzastaurin v Lomustine
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.65

    Secondary: Number of participants Who Achieved Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Response Rates [ORR])

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    End point title
    		 Number of participants Who Achieved Best Overall Tumor Response of Complete Response (CR) or Partial Response (PR) (Objective Response Rates [ORR])
    End point description
    ORR is the percentage of participants with a confirmed CR or PR, as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions.
    End point type
    Secondary
    End point timeframe
    From Date of Randomization to Disease Progression or Death Up to 13 Months
    End point values
    		 500 mg Enzastaurin Lomustine
    Number of subjects analysed
    174
    92
    Units: participants
    5
    4
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of objective tumor response was measured from the date that measurement criteria are first met for an objective tumor response until the first date of objective PD or death from any cause, whichever occurs first. For responders not known to have died or have objective PD as of the data cut-off date, duration of objective response will be censored at the date of the last objective progression-free disease assessment. Progressive disease (PD) was identified by either a radiologic assessment (MRI) or evidence of neurologic progression. A worsening of the radiologic assessment or neurologic examination findings was presumed evidence of PD. The date on which a participant's disease progressed would be the earlier date derived from radiologic progression or neurologic progression.
    End point type
    Secondary
    End point timeframe
    Time of Response to Time of Measured PD or Death Up to 10 Months
    End point values
    		 500 mg Enzastaurin Lomustine
    Number of subjects analysed
    5
    4 [1]
    Units: months
        median (confidence interval 95%)
    7.87 (6.80 to 9.63)
    9999 (2.79 to 9999)
    Notes
    [1] - 9999=Data Not Available (N/A)
    No statistical analyses for this end point

    Secondary: Time to Deterioration of Patient-reported Functional Assessment of Cancer Therapy – Brain (FACT-Br) Trial Outcome Index (TOI)

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    End point title
    		 Time to Deterioration of Patient-reported Functional Assessment of Cancer Therapy – Brain (FACT-Br) Trial Outcome Index (TOI)
    End point description
    Time to deterioration (TtD) for each participant is defined as a decrease in the TOI score that is at least the minimally important difference, as compared to the participant’s baseline score. Time to deterioration is measured from the date of randomization to the first date of a deterioration in the TOI (as defined by a decrease from baseline in the TOI that is at least the minimally important difference) or of death from any cause. For participants who receive subsequent therapy prior to an observation of deterioration, TtD will be censored at the date of initiation of a subsequent therapy. For participants not known to have died or have an observation of deterioration as of the data cut-off date, TtD will be censored at the date of the last deterioration-free assessment. Analysis Population Description: All randomized participants who had evaluable data. Number of participants censored were: 500 mg Enzastaurin =73 and Lomustine =40.
    End point type
    Secondary
    End point timeframe
    Randomization to the First Date of a Deterioration in the TOI Up To 14 Months
    End point values
    		 500 mg Enzastaurin Lomustine
    Number of subjects analysed
    159
    82
    Units: Months
        median (confidence interval 95%)
    2.27 (1.71 to 3.35)
    2.33 (1.94 to 3.68)
    No statistical analyses for this end point

    Secondary: Lost productivity: Number of participants employed prior to diagnosis and after last visit

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    End point title
    		 Lost productivity: Number of participants employed prior to diagnosis and after last visit
    End point description
    To describe the burden of disease, work status (retired, part-time, full-time, or not employed) of the participant was assessed. Analysis Population Description: All participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Prior to Diagnosis Until Last Patient Visit Up To 16 Months
    End point values
    		 500 mg Enzastaurin Lomustine
    Number of subjects analysed
    171 [2]
    90 [3]
    Units: percentage of participants
    number (not applicable)
        Employed prior to diagnosis
    45.0
    46.7
        Retired Prior to diagnosis
    35.7
    32.2
        Not Employed After Last Visit
    31.8
    44.4
        Retired after last visit
    49.1
    40.7
    Notes
    [2] - The small n for "Not Employed After Last Visit" and "Retired after last visit" was 110.
    [3] - The small n for "Not Employed After Last Visit" and "Retired after last visit" was 54.
    No statistical analyses for this end point

    Secondary: Assess Biomarkers: PFS by High Protein Expression Level Versus a Low Protein Expression Level

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    End point title
    		 Assess Biomarkers: PFS by High Protein Expression Level Versus a Low Protein Expression Level
    End point description
    Assess Biomarkers: PFS by high protein expression level versus a low protein expression level
    End point type
    Secondary
    End point timeframe
    Prior to Diagnosis Until Last Patient Visit Up To 16 Months
    End point values
    		 High Expresssion Enzastaurin Low Expresssion Enzastaurin
    Number of subjects analysed
    174 [4]
    174 [5]
    Units: months
    median (confidence interval 95%)
        PKCb2_Cytoplasm (PKCb2_C)
    1.45 (1.41 to 1.61)
    1.51 (1.41 to 2.73)
        PKCb2_Nucleus (PKCb2_N)
    1.41 (1.38 to 1.51)
    1.54 (1.41 to 2.73)
        pCREB_Nucleus (pCREB_N)
    1.48 (1.41 to 1.61)
    1.45 (1.41 to 2.27)
        pGSK3_Cytoplasm (pGSK3_C)
    1.45 (1.41 to 2.79)
    1.45 (1.41 to 1.54)
        pGSK3_Nucleus (pGSK3_N)
    1.41 (1.38 to 2.86)
    1.46 (1.41 to 1.54)
        pS6_Cytoplasm (pS6_C)
    1.48 (1.41 to 1.61)
    1.45 (1.41 to 2.27)
    Notes
    [4] - The small n for biomarkers are: PKCb2_C=55,PKCb2_N=23, pCREB_N=73, pGSK3_C=34, pGSK3_N=27, pS6_C=45
    [5] - The small n for biomarkers are: PKCb2_C=41, PKCb2_N=73, pCREB_N=24, pGSK3_C=62, pGSK3_N=69,pS6_C=52
    Statistical analysis title
    		 PKCb2_Cytoplasm
    Statistical analysis description
    There were 174 participants in the enzastaurin arm. The "subject in this analysis value =348" below in incorrect due to database adding numbers for both cohorts (low expression and high expression) together
    Comparison groups
    Low Expresssion Enzastaurin v High Expresssion Enzastaurin
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.357
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 2.093
    Statistical analysis title
    		 PKCb2_Nucleus
    Statistical analysis description
    There were 174 participants in the enzastaurin arm. The "subject in this analysis value =348" below in incorrect due to database adding numbers for both cohorts (low expression and high expression) together.
    Comparison groups
    High Expresssion Enzastaurin v Low Expresssion Enzastaurin
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.007
         upper limit
    		 2.704
    Statistical analysis title
    		 pCREB_Nucleus
    Statistical analysis description
    There were 174 participants in the enzastaurin arm. The "subject in this analysis value =348" below in incorrect due to database adding numbers for both cohorts (low expression and high expression) together.
    Comparison groups
    High Expresssion Enzastaurin v Low Expresssion Enzastaurin
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.712
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.436
         upper limit
    		 1.162
    Statistical analysis title
    		 pGSK3_Cytoplasm
    Statistical analysis description
    There were 174 participants in the enzastaurin arm. The "subject in this analysis value =348" below in incorrect due to database adding numbers for both cohorts (low expression and high expression) together.
    Comparison groups
    High Expresssion Enzastaurin v Low Expresssion Enzastaurin
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.944
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.611
         upper limit
    		 1.46
    Statistical analysis title
    		 pGSK3_Nucleus
    Statistical analysis description
    There were 174 participants in the enzastaurin arm. The "subject in this analysis value =348" below in incorrect due to database adding numbers for both cohorts (low expression and high expression) together.
    Comparison groups
    High Expresssion Enzastaurin v Low Expresssion Enzastaurin
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.946
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.517
    Statistical analysis title
    		 pS6_Cytoplasm
    Statistical analysis description
    There were 174 participants in the enzastaurin arm. The "subject in this analysis value =348" below in incorrect due to database adding numbers for both cohorts (low expression and high expression) together.
    Comparison groups
    High Expresssion Enzastaurin v Low Expresssion Enzastaurin
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.137
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.743
         upper limit
    		 1.74

    Secondary: Number of participants Neurologic Exam Scores by Time

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    End point title
    		 Number of participants Neurologic Exam Scores by Time
    End point description
    Neurologic Function: 0 - No neurologic symptoms; fully active at home/work without assistance. 1 - Minor neurologic symptoms; fully active at home/work without assistance. 2 - Moderate neurologic symptoms; fully active at home/work but requires assistance. 3 -Moderate neurologic symptoms; less than fully active at home/work and requires assistance.
    End point type
    Secondary
    End point timeframe
    Baseline Through 16 Months
    End point values
    		 500 mg Enzastaurin Lomustine
    Number of subjects analysed
    174
    92
    Units: participants
        Number of patients with score <3 at Baseline
    119
    63
        Number of patients with score <3 at 90 days
    100
    50
        Number of patients with score <3 at 180 days
    43
    28
        Number of patients with score >=3 at Baseline
    25
    14
        Number of patients with score >=3 at 90 days
    47
    29
        Number of patients with score >=3 at 180 days
    17
    12
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ) Cycle 1 Day 21

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    End point title
    		 Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ) Cycle 1 Day 21 [6]
    End point description
    Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ). Analysis population Description: All participants who received at least one dose of study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1: 1 to 5 hours; Day 21: Predose, 3 to 8 hours postdose; Cycle 4, Day 1:Predose
    Notes
    [6] - 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: PK data was analyzed for Enzastaurin only.
    End point values
    		 500 mg Enzastaurin
    Number of subjects analysed
    72
    Units: nanomole/Liter
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 21: LY317615
    291 ± 129
        Cycle 1 Day 21: LSN326020
    514 ± 66
        Cycle 1 Day 21:Total Analyte (LY317615+ LSN326020)
    860 ± 78
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ) Cycle 4 Day 1

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    End point title
    		 Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ) Cycle 4 Day 1 [7]
    End point description
    Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ) Cycle 4 Day 1. Analysis population Description: All participants who received at least one dose of study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1: 1 to 5 hours; Day 21: Predose, 3 to 8 hours postdose; Cycle 4, Day 1:Predose
    Notes
    [7] - 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: PK data was analyzed for Enzastaurin only.
    End point values
    		 500 mg Enzastaurin
    Number of subjects analysed
    6 [8]
    Units: nanomole/Liter
    geometric mean (geometric coefficient of variation)
        Cycle 4 Day 1: LY317615
    152 ± 95
        Cycle 4 Day 1: LSN326020
    437 ± 53
        Cycle 4 Day 1: Total Analyte (LY317615 +LSN326020)
    598 ± 62
    Notes
    [8] - Cycle 4 Day 1
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ) 250 mg Cycle 1 Day 21

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    End point title
    		 Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ) 250 mg Cycle 1 Day 21
    End point description
    Pharmacokinetic (PK): Minimum Observed Drug Concentration During a Dosing Interval at Steady State (Cmin,ss ) Cycle 1 Day 21. Analysis Population Description: All participants who received at least one dose of study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1: 1 to 5 hours; Day 21: Predose, 3 to 8 hours postdose; Cycle 4, Day 1:Predose
    End point values
    		 250 mg Enzastaurin
    Number of subjects analysed
    1 [9]
    Units: nanomole/Liter
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 21: LY317615
    109 ± 9999
        Cycle 1 Day 21: LSN326020
    455 ± 9999
        Cycle 1 Day 21: Total Analyte (LY317615+ LSN32602)
    563 ± 9999
    Notes
    [9] - 9999=Data Not Available (N/A)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    H6Q-MC-JCBF
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Lomustine
    Reporting group description
    		 10 mg, 40 mg, or 100 mg lomustine administered orally as 100 to 130 mg/m2 on Day 1 of each 6-week treatment cycle.

    Reporting group title
    Enzastaurin
    Reporting group description
    		 500 mg enzastaurin administered daily oral dose (four 125-mg tablets once a day) starting on Day 2 with an 1125-mg loading dose (three 125-mg tablets taken 3 times a day).

    Serious adverse events
    		 Lomustine Enzastaurin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 83 (28.92%)
    56 / 167 (33.53%)
         number of deaths (all causes)
    3
    10
         number of deaths resulting from adverse events
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    tumour haemorrhage
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    aortic thrombosis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    deep vein thrombosis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    6 / 167 (3.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haematoma
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    cyst drainage
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    chest pain
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    general physical health deterioration
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oedema peripheral
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    immobile
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    aspiration
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cough
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    hypoxia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    laryngeal ulceration
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pharyngolaryngeal pain
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 83 (2.41%)
    7 / 167 (4.19%)
         occurrences causally related to treatment / all
    0 / 4
    3 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    respiratory failure
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    disorientation
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mental status changes
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ammonia increased
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    electrocardiogram t wave inversion
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutrophil count decreased
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    platelet count decreased
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    brain herniation
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fall
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    femoral neck fracture
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    radiation injury
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal compression fracture
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    angina pectoris
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cardiopulmonary failure
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    supraventricular tachycardia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    aphasia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    brain oedema
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 83 (2.41%)
    6 / 167 (3.59%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    cerebral haematoma
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebral haemorrhage
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    2 / 2
    convulsion
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    5 / 83 (6.02%)
    12 / 167 (7.19%)
         occurrences causally related to treatment / all
    0 / 9
    2 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coordination abnormal
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    depressed level of consciousness
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dizziness
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysarthria
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    epilepsy
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    grand mal convulsion
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhage intracranial
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    headache
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 83 (2.41%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hemiparesis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intracranial pressure increased
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    loss of consciousness
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    motor dysfunction
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neurological symptom
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    partial seizures
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    postictal paralysis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sensorimotor disorder
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sensory loss
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    somnolence
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    status epilepticus
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    febrile neutropenia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    3 / 83 (3.61%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    3 / 83 (3.61%)
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    7 / 7
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal haematoma
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    abdominal pain upper
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anal fistula
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysphagia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    faecal incontinence
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophagitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    angioneurotic oedema
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    urinary incontinence
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    muscular weakness
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 167 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cellulitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    3 / 83 (3.61%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    encephalitis herpes
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    erysipelas
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    escherichia infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastrointestinal fungal infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower respiratory tract infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 167 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    meningitis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    meningitis bacterial
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 83 (2.41%)
    4 / 167 (2.40%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory tract infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    skin infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    3 / 167 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    wound infection
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    dehydration
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diabetes mellitus
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperglycaemia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    5 / 167 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 167 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lomustine Enzastaurin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 83 (79.52%)
    134 / 167 (80.24%)
    Investigations
    haemoglobin decreased
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    5 / 83 (6.02%)
    4 / 167 (2.40%)
         occurrences all number
    20
    15
    neutrophil count decreased
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    5 / 83 (6.02%)
    1 / 167 (0.60%)
         occurrences all number
    10
    4
    Injury, poisoning and procedural complications
    contusion
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    2 / 83 (2.41%)
    10 / 167 (5.99%)
         occurrences all number
    6
    35
    Nervous system disorders
    convulsion
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    6 / 83 (7.23%)
    16 / 167 (9.58%)
         occurrences all number
    17
    37
    headache
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    16 / 83 (19.28%)
    31 / 167 (18.56%)
         occurrences all number
    50
    78
    hemiparesis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    6 / 83 (7.23%)
    4 / 167 (2.40%)
         occurrences all number
    21
    10
    memory impairment
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    5 / 83 (6.02%)
    8 / 167 (4.79%)
         occurrences all number
    25
    26
    somnolence
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    11 / 167 (6.59%)
         occurrences all number
    3
    22
    speech disorder
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    6 / 83 (7.23%)
    12 / 167 (7.19%)
         occurrences all number
    14
    38
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    20 / 83 (24.10%)
    26 / 167 (15.57%)
         occurrences all number
    67
    84
    oedema peripheral
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    7 / 83 (8.43%)
    18 / 167 (10.78%)
         occurrences all number
    26
    57
    Blood and lymphatic system disorders
    leukopenia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    10 / 83 (12.05%)
    3 / 167 (1.80%)
         occurrences all number
    25
    6
    neutropenia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    15 / 83 (18.07%)
    0 / 167 (0.00%)
         occurrences all number
    32
    0
    thrombocytopenia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    35 / 83 (42.17%)
    11 / 167 (6.59%)
         occurrences all number
    98
    24
    Gastrointestinal disorders
    constipation
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    5 / 83 (6.02%)
    16 / 167 (9.58%)
         occurrences all number
    8
    44
    diarrhoea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    4 / 83 (4.82%)
    14 / 167 (8.38%)
         occurrences all number
    6
    32
    faeces discoloured
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 83 (0.00%)
    9 / 167 (5.39%)
         occurrences all number
    0
    32
    nausea
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    18 / 83 (21.69%)
    18 / 167 (10.78%)
         occurrences all number
    37
    33
    vomiting
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    6 / 83 (7.23%)
    14 / 167 (8.38%)
         occurrences all number
    6
    22
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    3 / 83 (3.61%)
    10 / 167 (5.99%)
         occurrences all number
    7
    23
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 83 (1.20%)
    10 / 167 (5.99%)
         occurrences all number
    3
    26
    confusional state
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    10 / 83 (12.05%)
    16 / 167 (9.58%)
         occurrences all number
    23
    30
    depression
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    5 / 83 (6.02%)
    3 / 167 (1.80%)
         occurrences all number
    17
    10
    insomnia
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    6 / 83 (7.23%)
    8 / 167 (4.79%)
         occurrences all number
    20
    21
    Renal and urinary disorders
    urinary incontinence
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    6 / 83 (7.23%)
    7 / 167 (4.19%)
         occurrences all number
    14
    15
    Musculoskeletal and connective tissue disorders
    muscular weakness
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    7 / 83 (8.43%)
    14 / 167 (8.38%)
         occurrences all number
    24
    74

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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 study was terminated due to futility.
    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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