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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Evaluating the Efficacy of ABT-888 in Combination with Temozolomide Versus Temozolomide Alone in Subjects with Metastatic Melanoma

    Summary
    EudraCT number
    		 2008-004941-27
    Trial protocol
    		 GB  
    Global end of trial date
    19 Jan 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Mar 2017
    First version publication date
    02 Feb 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    The correction clarifies the time frames for the endpoints.

    Trial information

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    Trial identification
    Sponsor protocol code
    M10-440
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00804908
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Servicees, AbbVie, 001 800-633-9110,
    Scientific contact
    Mark D McKee, MD, AbbVie, mark.mckee@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy of ABT-888 in combination with temozolomide versus temozolomide alone in subjects with metastatic melanoma.
    Protection of trial subjects
    Subject read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2009
    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
    Australia: 53
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    United Kingdom: 61
    Country: Number of subjects enrolled
    United States: 183
    Worldwide total number of subjects
    346
    EEA total number of subjects
    61
    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)
    201
    From 65 to 84 years
    140
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 346 subjects were randomized; 2 subjects did not receive study drug and were excluded from the safety analysis.

    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
    Yes

    Arm title
    		 Placebo for ABT-888 BID + TMZ QD
    Arm description
    		 Placebo for ABT-888 twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    temozolomide
    Investigational medicinal product code
    Other name
    Temodar, Temodal
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide capsule administered orally once daily for 5 days every 28 days

    Investigational medicinal product name
    placebo for ABT-888
    Investigational medicinal product code
    Other name
    veliparib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for ABT-888 capsule administered orally twice daily for 7 days every 28 days

    Arm title
    		 ABT-888 20 mg BID + TMZ QD
    Arm description
    		 ABT-888 20 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    temozolomide
    Investigational medicinal product code
    Other name
    Temodar, Temodal
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide capsule administered orally once daily for 5 days every 28 days

    Investigational medicinal product name
    ABT-888
    Investigational medicinal product code
    Other name
    veliparib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-888 capsule administered orally twice daily for 7 days every 28 days

    Arm title
    		 ABT-888 40 mg BID + TMZ QD
    Arm description
    		 ABT-888 40 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    temozolomide
    Investigational medicinal product code
    Other name
    Temodar, Temodal
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Temozolomide capsule administered orally once daily for 5 days every 28 days

    Investigational medicinal product name
    ABT-888
    Investigational medicinal product code
    Other name
    veliparib
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-888 capsule administered orally twice daily for 7 days every 28 days

    Number of subjects in period 1
    		Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Started
    115
    116
    115
    Completed
    0
    0
    1
    Not completed
    115
    116
    114
         Not specified
    115
    116
    114

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo for ABT-888 BID + TMZ QD
    Reporting group description
    		 Placebo for ABT-888 twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Reporting group title
    ABT-888 20 mg BID + TMZ QD
    Reporting group description
    		 ABT-888 20 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Reporting group title
    ABT-888 40 mg BID + TMZ QD
    Reporting group description
    		 ABT-888 40 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Reporting group values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD Total
    Number of subjects
    		 115 116 115 346
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.4 ± 14.13 58.6 ± 12.55 62.3 ± 13.14 -
    Gender, Male/Female
    Units:
        Female
    		 36 45 38 119
        Male
    		 79 71 77 227

    End points

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    End points reporting groups
    Reporting group title
    Placebo for ABT-888 BID + TMZ QD
    Reporting group description
    		 Placebo for ABT-888 twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Reporting group title
    ABT-888 20 mg BID + TMZ QD
    Reporting group description
    		 ABT-888 20 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Reporting group title
    ABT-888 40 mg BID + TMZ QD
    Reporting group description
    		 ABT-888 40 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Primary: Progression-Free Survival (PFS): Time to event

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    End point title
    		 Progression-Free Survival (PFS): Time to event
    End point description
    PFS: the number of days from the date that the subject was randomized to the date the subject experienced a confirmed event of disease progression (radiological, as determined by the central imaging center; or clinical, as determined by the investigator), or to the date of death (all causes of mortality) if disease progression was not reached. All events were included whether the subject was still taking or had discontinued study drug. Events of death were included for subjects who had not experienced a confirmed event of disease progression, provided the death occurred within 8 weeks of the last available disease progression assessment. The distribution of PFS, as determined by the central imaging center (radiological)/ investigator (clinical), was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% confidence intervals (95% CIs) for the quartiles for the PFS distribution are provided. 9999=Not calculable due to insufficient progression events.
    End point type
    Primary
    End point timeframe
    Every Cycle (28 Days) until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months.
    End point values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Number of subjects analysed
    115 [1]
    116 [2]
    115 [3]
    Units: days
    number (confidence interval 95%)
        25th Percentile
    54 (50 to 56)
    56 (53 to 58)
    53 (51 to 56)
        50th Percentile
    60 (57 to 111)
    113 (92 to 168)
    110 (57 to 125)
        75th Percentile
    163 (113 to 283)
    225 (169 to 9999)
    226 (173 to 9999)
    Notes
    [1] - ITT population defined as all randomized subjects.
    [2] - ITT population defined as all randomized subjects.
    [3] - ITT population defined as all randomized subjects.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Comparisons between treatment groups were performed using a log-rank test stratified by baseline lactate dehydrogenase (LDH) status (0 to 1 ULN; >1 to ≤ 2 ULN) and history of previously treated brain metastases (with, without). Hochberg testing procedure for multiplicity adjustment.
    Comparison groups
    Placebo for ABT-888 BID + TMZ QD v ABT-888 40 mg BID + TMZ QD
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.233
    Method
    		 stratified log-rank
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Comparisons between treatment groups were performed using a Comparisons between treatment groups were performed using a log-rank test stratified by baseline lactate dehydrogenase (LDH) status (0 to 1 ULN; >1 to ≤ 2 ULN) and history of previously treated brain metastases (with, without). Hochberg testing procedure for multiplicity adjustment.
    Comparison groups
    Placebo for ABT-888 BID + TMZ QD v ABT-888 20 mg BID + TMZ QD
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.071
    Method
    		 stratified log-rank
    Confidence interval

    Secondary: Overall Survival (OS): Time to Event

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    End point title
    		 Overall Survival (OS): Time to Event
    End point description
    OS: the number of days from the date the subject was randomized to the date of death. All deaths were included, whether the subject was still taking or had discontinued study drug. If a subject had not died and was lost to follow-up, data were censored at the last study visit or contact date, or date the subject was last known to be alive, whichever was later; if the subject was not lost to follow-up, data were censored at the last study visit or contact date, whichever was later. The distribution of OS was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the OS distribution are provided. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ groups were statistically significantly better than the Placebo + TMZ group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints. 9999-Not calculable due to insufficient survival events.
    End point type
    Secondary
    End point timeframe
    Per protocol, survival follow-up information was to be obtained every 3 months for up to 18 months after the final visit for the subject. The maximum observed follow-up at the overall survival analysis time was 21.0 months.
    End point values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Number of subjects analysed
    115 [4]
    116 [5]
    115 [6]
    Units: days
    number (confidence interval 95%)
        25th Percentile
    207 (155 to 241)
    204 (175 to 247)
    181 (154 to 266)
        50th Percentile
    390 (299 to 436)
    327 (274 to 399)
    412 (346 to 483)
        75th Percentile
    559 (476 to 598)
    9999 (492 to 9999)
    9999 (9999 to 9999)
    Notes
    [4] - ITT population defined as all randomized subjects.
    [5] - ITT population defined as all randomized subjects.
    [6] - ITT population defined as all randomized subjects.
    No statistical analyses for this end point

    Secondary: 12-Month Overall Survival (OS) Rate

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    End point title
    		 12-Month Overall Survival (OS) Rate
    End point description
    The 12-month overall survival rate was defined as the percentage of participants surviving at 12 months. The distribution of 12-month OS rate was estimated using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the PFS distribution are provided. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values.
    End point type
    Secondary
    End point timeframe
    Per protocol, survival was to be assessed every 4 weeks or as needed after participant is registered as off-study for up to 18 months. The maximum observed follow-up at the overall survival analysis time was 21.0 months.
    End point values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Number of subjects analysed
    115 [7]
    116 [8]
    115 [9]
    Units: percentage of subjects
        number (confidence interval 95%)
    52.6 (43.1 to 61.3)
    43.5 (34.3 to 52.3)
    54.1 (44.5 to 62.7)
    Notes
    [7] - ITT population defined as all randomized participants.
    [8] - ITT population defined as all randomized participants.
    [9] - ITT population defined as all randomized participants.
    No statistical analyses for this end point

    Secondary: 6-month Progression-Free Survival Rate

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    End point title
    		 6-month Progression-Free Survival Rate
    End point description
    The 6-month progression-free survival rate was defined as the percentage of participants without disease progression at 6 months. The distribution of 6-month progression-free survival rate, as determined by the central imaging center (radiological)/ investigator (clinical), was estimated using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the PFS distribution are provided. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values.
    End point type
    Secondary
    End point timeframe
    Every Cycle (28 Days) until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months.
    End point values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Number of subjects analysed
    115 [10]
    116 [11]
    115 [12]
    Units: percentage of subjects
        number (confidence interval 95%)
    19.1 (10.9 to 29)
    32.8 (22 to 44.1)
    30.7 (20.3 to 41.7)
    Notes
    [10] - ITT population defined as all randomized participants.
    [11] - ITT population defined as all randomized participants.
    [12] - ITT population defined as all randomized participants.
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    The objective response rate was defined as the percentage of participants with a confirmed CR or PR based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values.
    End point type
    Secondary
    End point timeframe
    Every 2 cycles (8 weeks) until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months.
    End point values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Number of subjects analysed
    115 [13]
    116 [14]
    115 [15]
    Units: percentage of subjects
        number (confidence interval 95%)
    7 (3.1 to 13.2)
    10.3 (5.5 to 17.4)
    9.6 (4.9 to 16.5)
    Notes
    [13] - All subjects in the ITT population (defined as all randomized participants) with measurable disease.
    [14] - All subjects in the ITT population (defined as all randomized participants) with measurable disease.
    [15] - All subjects in the ITT population (defined as all randomized participants) with measurable disease.
    No statistical analyses for this end point

    Secondary: Time to Disease Progression

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    End point title
    		 Time to Disease Progression
    End point description
    The distribution of time to disease progression, as determined by the central imaging center (radiological)/ investigator (clinical), was estimated for each treatment group using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the PFS distribution are provided. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values. 9999=Not calculable due to insufficient progression events
    End point type
    Secondary
    End point timeframe
    Every Cycle (28 Days), until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months.
    End point values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Number of subjects analysed
    115 [16]
    116 [17]
    115 [18]
    Units: days
    number (confidence interval 95%)
        25th Percentile
    54 (50 to 56)
    56 (53 to 57)
    53 (51 to 56)
        50th Percentile
    60 (57 to 111)
    113 (92 to 168)
    110 (57 to 125)
        75th Percentile
    163 (113 to 283)
    225 (169 to 9999)
    226 (173 to 9999)
    Notes
    [16] - ITT population defined as all randomized participants.
    [17] - ITT population defined as all randomized participants.
    [18] - ITT population defined as all randomized participants.
    No statistical analyses for this end point

    Secondary: Disease Control Rate

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    End point title
    		 Disease Control Rate
    End point description
    The disease control rate was defined as the percentage of subjects who had at least stable disease (complete response, partial response, or stable disease) through the end of Week 8. Per protocol, because neither the ABT-888 20 mg BID + TMZ nor ABT-888 40 mg BID + TMZ treatment groups were statistically significantly better than the Placebo + TMZ treatment group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Number of subjects analysed
    115 [19]
    116 [20]
    115 [21]
    Units: percentage of subjects
        number (confidence interval 95%)
    48.7 (39.3 to 58.2)
    62.9 (53.5 to 71.7)
    59.1 (49.6 to 68.2)
    Notes
    [19] - ITT population defined as all randomized participants.
    [20] - ITT population defined as all randomized participants.
    [21] - ITT population defined as all randomized participants.
    No statistical analyses for this end point

    Secondary: Time to neurological/brain metastases progression

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    End point title
    		 Time to neurological/brain metastases progression
    End point description
    Time to neurological/brain metastases progression, defined as the number of days from randomization to the date the subject experienced an event of neurological/brain metastases progression, was estimated using Kaplan-Meier methodology. Point estimates and 95% CIs for the quartiles for the distribution are provided. All events of progression were included, whether the event occurred while the subject was still taking study drug. If a subject did not experience an event, data were censored at the date of the last available brain CT scan; for subjects with no postbaseline brain CT scans, data were censored at randomization. Per protocol, because neither the ABT-888 20 mg BID+TMZ nor ABT-888 40 mg BID+TMZ groups were statistically significantly better than the Placebo + TMZ group for the primary endpoint of PFS, confirmatory statistical testing was not continued for any secondary endpoints, regardless of the observed P values. 9999=Not calculable due to insufficient progression events.
    End point type
    Secondary
    End point timeframe
    Every 2 cycles (8 weeks) until disease progression was observed or another reason for discontinuation of assessments was identified by the investigator. The maximum observed followup duration at the progression-free survival analysis time was 9.7 months.
    End point values
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 20 mg BID + TMZ QD ABT-888 40 mg BID + TMZ QD
    Number of subjects analysed
    115 [22]
    116 [23]
    115 [24]
    Units: days
    number (confidence interval 95%)
        25th Percentile
    60 (34 to 9999)
    119 (48 to 9999)
    184 (51 to 9999)
        50th Percentile
    9999 (60 to 9999)
    9999 (119 to 9999)
    184 (184 to 9999)
        75th Percentile
    9999 (9999 to 9999)
    9999 (119 to 9999)
    9999 (184 to 9999)
    Notes
    [22] - ITT population defined as all randomized participants.
    [23] - ITT population defined as all randomized participants.
    [24] - ITT population defined as all randomized participants.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs (TEAEs) were collected from first dose of study drug until 30 days after the last dose of study drug (up to 5.6 years); SAEs were collected from the time informed consent was obtained (up to 5.7 years).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo for ABT-888 BID + TMZ QD
    Reporting group description
    		 Placebo for ABT-888 twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Reporting group title
    ABT-888 40 mg BID + TMZ QD
    Reporting group description
    		 ABT-888 40 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Reporting group title
    ABT-888 20 mg BID + TMZ QD
    Reporting group description
    		 ABT-888 20 mg twice daily (BID) for 7 days every 28 days plus temozolomide (TMZ; by body surface area) 150 mg/m2 once daily (QD) for 5 days every 28 days.

    Serious adverse events
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 40 mg BID + TMZ QD ABT-888 20 mg BID + TMZ QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 113 (24.78%)
    31 / 115 (26.96%)
    27 / 116 (23.28%)
         number of deaths (all causes)
    4
    4
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    2 / 113 (1.77%)
    2 / 115 (1.74%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gliosarcoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    2 / 113 (1.77%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 113 (0.00%)
    4 / 115 (3.48%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 113 (1.77%)
    3 / 115 (2.61%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 113 (0.88%)
    3 / 115 (2.61%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 113 (3.54%)
    4 / 115 (3.48%)
    3 / 116 (2.59%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth swelling
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 113 (1.77%)
    1 / 115 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 113 (1.77%)
    1 / 115 (0.87%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral prolapse
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 115 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 113 (1.77%)
    2 / 115 (1.74%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo for ABT-888 BID + TMZ QD ABT-888 40 mg BID + TMZ QD ABT-888 20 mg BID + TMZ QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 113 (99.12%)
    113 / 115 (98.26%)
    116 / 116 (100.00%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    6 / 113 (5.31%)
    3 / 115 (2.61%)
    3 / 116 (2.59%)
         occurrences all number
    13
    4
    5
    Weight decreased
         subjects affected / exposed
    7 / 113 (6.19%)
    6 / 115 (5.22%)
    7 / 116 (6.03%)
         occurrences all number
    7
    7
    7
    Platelet count decreased
         subjects affected / exposed
    4 / 113 (3.54%)
    10 / 115 (8.70%)
    12 / 116 (10.34%)
         occurrences all number
    9
    34
    28
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    6 / 113 (5.31%)
    0 / 115 (0.00%)
    0 / 116 (0.00%)
         occurrences all number
    7
    0
    0
    Tumour pain
         subjects affected / exposed
    1 / 113 (0.88%)
    6 / 115 (5.22%)
    3 / 116 (2.59%)
         occurrences all number
    1
    7
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    17 / 113 (15.04%)
    15 / 115 (13.04%)
    19 / 116 (16.38%)
         occurrences all number
    28
    21
    23
    Dysgeusia
         subjects affected / exposed
    8 / 113 (7.08%)
    11 / 115 (9.57%)
    15 / 116 (12.93%)
         occurrences all number
    8
    12
    16
    Lethargy
         subjects affected / exposed
    7 / 113 (6.19%)
    6 / 115 (5.22%)
    6 / 116 (5.17%)
         occurrences all number
    13
    14
    7
    Headache
         subjects affected / exposed
    30 / 113 (26.55%)
    25 / 115 (21.74%)
    22 / 116 (18.97%)
         occurrences all number
    56
    49
    28
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 113 (7.96%)
    13 / 115 (11.30%)
    19 / 116 (16.38%)
         occurrences all number
    10
    23
    24
    Leukopenia
         subjects affected / exposed
    5 / 113 (4.42%)
    8 / 115 (6.96%)
    8 / 116 (6.90%)
         occurrences all number
    8
    22
    19
    Neutropenia
         subjects affected / exposed
    7 / 113 (6.19%)
    26 / 115 (22.61%)
    24 / 116 (20.69%)
         occurrences all number
    9
    53
    59
    Lymphopenia
         subjects affected / exposed
    5 / 113 (4.42%)
    6 / 115 (5.22%)
    4 / 116 (3.45%)
         occurrences all number
    9
    22
    9
    Thrombocytopenia
         subjects affected / exposed
    19 / 113 (16.81%)
    56 / 115 (48.70%)
    49 / 116 (42.24%)
         occurrences all number
    32
    155
    146
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 113 (3.54%)
    6 / 115 (5.22%)
    5 / 116 (4.31%)
         occurrences all number
    4
    7
    6
    Chills
         subjects affected / exposed
    4 / 113 (3.54%)
    8 / 115 (6.96%)
    8 / 116 (6.90%)
         occurrences all number
    6
    8
    8
    Influenza like illness
         subjects affected / exposed
    4 / 113 (3.54%)
    1 / 115 (0.87%)
    6 / 116 (5.17%)
         occurrences all number
    4
    1
    7
    Fatigue
         subjects affected / exposed
    73 / 113 (64.60%)
    77 / 115 (66.96%)
    75 / 116 (64.66%)
         occurrences all number
    130
    161
    139
    Pain
         subjects affected / exposed
    8 / 113 (7.08%)
    12 / 115 (10.43%)
    10 / 116 (8.62%)
         occurrences all number
    10
    16
    17
    Oedema peripheral
         subjects affected / exposed
    1 / 113 (0.88%)
    4 / 115 (3.48%)
    9 / 116 (7.76%)
         occurrences all number
    1
    4
    12
    Pyrexia
         subjects affected / exposed
    6 / 113 (5.31%)
    4 / 115 (3.48%)
    7 / 116 (6.03%)
         occurrences all number
    6
    5
    7
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 113 (2.65%)
    6 / 115 (5.22%)
    4 / 116 (3.45%)
         occurrences all number
    3
    6
    5
    Abdominal pain
         subjects affected / exposed
    8 / 113 (7.08%)
    15 / 115 (13.04%)
    11 / 116 (9.48%)
         occurrences all number
    9
    24
    17
    Constipation
         subjects affected / exposed
    62 / 113 (54.87%)
    62 / 115 (53.91%)
    60 / 116 (51.72%)
         occurrences all number
    103
    112
    84
    Diarrhoea
         subjects affected / exposed
    24 / 113 (21.24%)
    26 / 115 (22.61%)
    27 / 116 (23.28%)
         occurrences all number
    30
    50
    45
    Dry mouth
         subjects affected / exposed
    6 / 113 (5.31%)
    0 / 115 (0.00%)
    3 / 116 (2.59%)
         occurrences all number
    6
    0
    3
    Dyspepsia
         subjects affected / exposed
    12 / 113 (10.62%)
    8 / 115 (6.96%)
    8 / 116 (6.90%)
         occurrences all number
    13
    12
    10
    Nausea
         subjects affected / exposed
    75 / 113 (66.37%)
    82 / 115 (71.30%)
    83 / 116 (71.55%)
         occurrences all number
    148
    183
    162
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 115 (1.74%)
    10 / 116 (8.62%)
         occurrences all number
    0
    3
    10
    Vomiting
         subjects affected / exposed
    53 / 113 (46.90%)
    30 / 115 (26.09%)
    42 / 116 (36.21%)
         occurrences all number
    90
    52
    75
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 113 (14.16%)
    18 / 115 (15.65%)
    28 / 116 (24.14%)
         occurrences all number
    22
    24
    33
    Dyspnoea
         subjects affected / exposed
    11 / 113 (9.73%)
    17 / 115 (14.78%)
    17 / 116 (14.66%)
         occurrences all number
    13
    18
    17
    Epistaxis
         subjects affected / exposed
    5 / 113 (4.42%)
    10 / 115 (8.70%)
    1 / 116 (0.86%)
         occurrences all number
    5
    13
    1
    Oropharyngeal pain
         subjects affected / exposed
    6 / 113 (5.31%)
    5 / 115 (4.35%)
    7 / 116 (6.03%)
         occurrences all number
    7
    7
    7
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    5 / 113 (4.42%)
    8 / 115 (6.96%)
    2 / 116 (1.72%)
         occurrences all number
    7
    12
    2
    Erythema
         subjects affected / exposed
    2 / 113 (1.77%)
    3 / 115 (2.61%)
    7 / 116 (6.03%)
         occurrences all number
    2
    3
    11
    Night sweats
         subjects affected / exposed
    7 / 113 (6.19%)
    3 / 115 (2.61%)
    7 / 116 (6.03%)
         occurrences all number
    7
    3
    7
    Hyperhidrosis
         subjects affected / exposed
    6 / 113 (5.31%)
    2 / 115 (1.74%)
    3 / 116 (2.59%)
         occurrences all number
    8
    2
    3
    Pruritus
         subjects affected / exposed
    15 / 113 (13.27%)
    6 / 115 (5.22%)
    7 / 116 (6.03%)
         occurrences all number
    16
    9
    8
    Rash
         subjects affected / exposed
    6 / 113 (5.31%)
    11 / 115 (9.57%)
    10 / 116 (8.62%)
         occurrences all number
    8
    15
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    12 / 113 (10.62%)
    14 / 115 (12.17%)
    12 / 116 (10.34%)
         occurrences all number
    14
    15
    12
    Anxiety
         subjects affected / exposed
    7 / 113 (6.19%)
    5 / 115 (4.35%)
    6 / 116 (5.17%)
         occurrences all number
    8
    5
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 113 (11.50%)
    14 / 115 (12.17%)
    17 / 116 (14.66%)
         occurrences all number
    21
    24
    20
    Back pain
         subjects affected / exposed
    10 / 113 (8.85%)
    14 / 115 (12.17%)
    21 / 116 (18.10%)
         occurrences all number
    12
    21
    29
    Groin pain
         subjects affected / exposed
    3 / 113 (2.65%)
    6 / 115 (5.22%)
    4 / 116 (3.45%)
         occurrences all number
    4
    6
    4
    Muscle spasms
         subjects affected / exposed
    1 / 113 (0.88%)
    6 / 115 (5.22%)
    2 / 116 (1.72%)
         occurrences all number
    1
    8
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    6 / 113 (5.31%)
    1 / 115 (0.87%)
    7 / 116 (6.03%)
         occurrences all number
    10
    1
    8
    Musculoskeletal pain
         subjects affected / exposed
    11 / 113 (9.73%)
    9 / 115 (7.83%)
    11 / 116 (9.48%)
         occurrences all number
    11
    16
    11
    Myalgia
         subjects affected / exposed
    7 / 113 (6.19%)
    8 / 115 (6.96%)
    4 / 116 (3.45%)
         occurrences all number
    7
    13
    4
    Pain in extremity
         subjects affected / exposed
    11 / 113 (9.73%)
    10 / 115 (8.70%)
    13 / 116 (11.21%)
         occurrences all number
    12
    12
    15
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    5 / 113 (4.42%)
    3 / 115 (2.61%)
    7 / 116 (6.03%)
         occurrences all number
    5
    3
    8
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 113 (6.19%)
    10 / 115 (8.70%)
    8 / 116 (6.90%)
         occurrences all number
    7
    10
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    37 / 113 (32.74%)
    36 / 115 (31.30%)
    26 / 116 (22.41%)
         occurrences all number
    53
    56
    30
    Hyperglycaemia
         subjects affected / exposed
    6 / 113 (5.31%)
    5 / 115 (4.35%)
    4 / 116 (3.45%)
         occurrences all number
    8
    8
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Dec 2008
    The main purpose of this amendment was to clarify inclusion criteria (men must agree to contraception) and modify the starting dose of temozolomide (TMZ) from 200 mg/m2/day to 10 mg/m2/day.
    22 May 2009
    The main purpose of this amendment was to increase the number of subjects from 180 to 300 and clarify inclusion (history of brain metasteses, prior and excluded anticancer therapy) and exclusion (prior whole brain radiation therapy [WBRT]) criteria.
    22 Apr 2010
    The main purpose of this amendment was to clarify ABT-888 dosing, time frame for collection of survival and post-treatment therapy information, update the actual number of subjects enrolled from 300 to 346, clarify the frequency of brain magnetic resonance imaging for subjects with a history of previously treated metastasis, and clarify discontinuation criteria.
    15 Mar 2012
    The main purpose of this amendment was to decrease the number of required study procedures (tumor assessments, serial biopsies, and pharmacodynamic sampling no longer required); clarify the final visit date and assessments to be performed at final visit; and define the stop date for collection of survival assessments.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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