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    Clinical Trial Results:
    A Randomized Controlled Study of Yondelis (Trabectedin) or Dacarbazine for the Treatment of Advanced Liposarcoma or Leiomyosarcoma

    Summary
    EudraCT number
    		 2016-000929-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    05 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Nov 2016
    First version publication date
    03 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ET743-SAR-3007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01343277
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    05 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of study was to evaluate whether overall survival (OS) for the trabectedin group was superior to the dacarbazine group for subjects with advanced liposarcoma or leiomyosarcoma (L-sarcoma) who were previously treated (in any order) with at least: a) an anthracycline and ifosfamide containing regimen, or b) an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Adverse events of clinical interest (eg, thrombocytopenia and bleeding, neutropenia and infections [including sepsis or septic shock], creatine phosphokinase (CPK) elevations or rhabdomyolysis, catheter-related complications, liver injury, multi-organ failures, cardiac disorders, and renal disorders were reported throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 May 2011
    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: 23
    Country: Number of subjects enrolled
    Brazil: 12
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    United States: 539
    Worldwide total number of subjects
    577
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    445
    From 65 to 84 years
    131
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 577 subjects were planned (380 subjects in the trabectedin group and 190 subjects in the dacarbazine group). Out of them 534 subjects completed the study (367 subjects in the trabectedin group and 167 subjects in the dacarbazine group).

    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
    		 Trabectedin
    Arm description
    		 Subjects received trabectedin 1.5 milligram per meter square (mg/m^2) as a 24-hour intravenous (i.v.) infusion once every 3 weeks (q3wk 24-h).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trabectedin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received trabectedin 1.5 milligram per meter square per meter square (mg/m^2) as a 24-hour intravenous (i.v.) infusion once every 3 weeks (q3wk 24-h).

    Arm title
    		 Dacarbazine
    Arm description
    		 Subjects received dacarbazine 1 gram per meter square (g/m^2) as a 20- 120 minutes intravenous (i.v.) infusion once every 3 weeks (q3wk).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received dacarbazine 1 gram per meter square (g/m^2) as a 20- 120 minutes intravenous (i.v.) infusion once every 3 weeks (q3wk).

    Number of subjects in period 1
    		Trabectedin Dacarbazine
    Started
    384
    193
    Completed
    367
    167
    Not completed
    17
    26
         Withdraw consent for follow-up
    12
    23
         Lost to follow-up
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trabectedin
    Reporting group description
    		 Subjects received trabectedin 1.5 milligram per meter square (mg/m^2) as a 24-hour intravenous (i.v.) infusion once every 3 weeks (q3wk 24-h).

    Reporting group title
    Dacarbazine
    Reporting group description
    		 Subjects received dacarbazine 1 gram per meter square (g/m^2) as a 20- 120 minutes intravenous (i.v.) infusion once every 3 weeks (q3wk).

    Reporting group values
    		 Trabectedin Dacarbazine Total
    Number of subjects
    		 384 193 577
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 1 1
        Adults (18-64 years)
    		 290 155 445
        From 65 to 84 years
    		 94 37 131
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ( 11.04 ) 54.1 ( 11.92 ) -
    Title for Gender
    Units: subjects
        Female
    		 262 140 402
        Male
    		 122 53 175

    End points

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    End points reporting groups
    Reporting group title
    Trabectedin
    Reporting group description
    		 Subjects received trabectedin 1.5 milligram per meter square (mg/m^2) as a 24-hour intravenous (i.v.) infusion once every 3 weeks (q3wk 24-h).

    Reporting group title
    Dacarbazine
    Reporting group description
    		 Subjects received dacarbazine 1 gram per meter square (g/m^2) as a 20- 120 minutes intravenous (i.v.) infusion once every 3 weeks (q3wk).

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the subject is alive or the vital status is unknown, the participant will be censored at the date the subject will be last known to be alive. Analysis population included all the randomized subjects up to final analysis cut-off date (05 January 2015).
    End point type
    Primary
    End point timeframe
    Approximately 3 years 8 months (From Study start date [27 May 2011] up to final analysis data cut-off [05 January 2015]
    End point values
    		 Trabectedin Dacarbazine
    Number of subjects analysed
    384
    193
    Units: Months
        median (confidence interval 95%)
    13.73 (12.16 to 16)
    13.14 (9.1 to 16.23)
    Statistical analysis title
    		 Overall Survival Analysis
    Comparison groups
    Trabectedin v Dacarbazine
    Number of subjects included in analysis
    577
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.492
    Method
    		 Unstratified log rank test
    Parameter type
    		 Log hazard ratio
    Point estimate
    0.927
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.748
         upper limit
    		 1.15

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    The Progression-Free Survival (PFS) was assessed as median number of months from baseline until the first documented sign of disease progression (increase in disease; radiographic, clinical, or both) or death due to any cause, whichever occurred earlier. Independent Data Monitoring Committee performed ongoing safety monitoring and conducted the interim analysis after 189 death events and 329 PFS events were observed. Analysis population included all the randomized subjects evaluated up to interim analysis cut-off date (16 September 2013).
    End point type
    Secondary
    End point timeframe
    Approximately 2 years 4 months (From Study start date [27 May 2011] up to interim analysis data cut-off [16 September 2013])
    End point values
    		 Trabectedin Dacarbazine
    Number of subjects analysed
    345
    173
    Units: Months
        median (confidence interval 95%)
    4.21 (2.99 to 4.83)
    1.54 (1.48 to 2.6)
    Statistical analysis title
    		 Progression-Free Survival Analysis
    Comparison groups
    Trabectedin v Dacarbazine
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Unstratified log rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.436
         upper limit
    		 0.696

    Secondary: Time to Progression

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    End point title
    		 Time to Progression
    End point description
    Time interval in months between the date of randomization and the date of disease progression or death due to progression, whichever occurred first. Independent Data Monitoring Committee performed ongoing safety monitoring and conducted the interim analysis after 189 death events and 329 PFS events were observed. Analysis population included all the randomized subjects up to interim analysis cut-off date (16 September 2013).
    End point type
    Secondary
    End point timeframe
    Approximately 2 years 4 months (From Study start date [27 May 2011] up to interim analysis data cut-off [16 September 2013])
    End point values
    		 Trabectedin Dacarbazine
    Number of subjects analysed
    345
    173
    Units: Months
        median (confidence interval 95%)
    4.24 (3.22 to 4.93)
    1.54 (1.48 to 2.6)
    Statistical analysis title
    		 Time to Progression Analysis
    Comparison groups
    Trabectedin v Dacarbazine
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Unstratified log rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.522
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.412
         upper limit
    		 0.661

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    The objective response rate (ORR) is defined as the percentage of subjects who achieved a Complete response (CR) or partial response (PR) as best responses. according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST). CR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions taking as reference the Baseline sum diameters. Confirmed responses are those that persist on repeat imaging study for at least 4 weeks after initial documentation of response. Independent Data Monitoring Committee performed ongoing safety monitoring and conducted the interim analysis after 189 death events and 329 PFS events were observed. Analysis population included all the randomized subjects up to interim analysis cut-off date (16 September 2013).
    End point type
    Secondary
    End point timeframe
    Approximately 2 years 4 months (From Study start date [27 May 2011] up to interim analysis data cut-off [16 September 2013])
    End point values
    		 Trabectedin Dacarbazine
    Number of subjects analysed
    345
    173
    Units: Percentage of subjects
        median (confidence interval 95%)
    9.9 (6.9 to 13.5)
    6.9 (3.6 to 11.8)
    Statistical analysis title
    		 Objective Response Rate Analysis
    Comparison groups
    Trabectedin v Dacarbazine
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3269
    Method
    		 Fisher′s exact test.
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.467
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.717
         upper limit
    		 3.197

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response is defined as the time from the date of initial documentation of a response (CR or PR) to the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death. Independent Data Monitoring Committee performed ongoing safety monitoring and conducted the interim analysis after 189 death events and 329 PFS events were observed. Analysis population included all the randomized subjects up to interim analysis cut-off date (16 September 2013). The value 999 indicated the not estimable data value.
    End point type
    Secondary
    End point timeframe
    Approximately 2 years 4 months (From Study start date [27 May 2011] up to interim analysis data cut-off [16 September 2013])
    End point values
    		 Trabectedin Dacarbazine
    Number of subjects analysed
    34
    12
    Units: Months
        median (confidence interval 95%)
    6.47 (3.58 to 7.62)
    4.17 (2.14 to 999)
    Statistical analysis title
    		 Duration of Response Analysis
    Comparison groups
    Trabectedin v Dacarbazine
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1415
    Method
    		 Unstratified log rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.471
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.168
         upper limit
    		 1.318

    Secondary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Safety population included all the treated subjects.
    End point type
    Secondary
    End point timeframe
    Approximately 3 years 8 months (From Study start date [27 May 2011] up to final analysis data cut-off [05 January 2015])
    End point values
    		 Trabectedin Dacarbazine
    Number of subjects analysed
    378
    172
    Units: Subjects
        Serious Adverse Events (SAEs)
    155
    52
        Adverse Events (AEs)
    375
    166
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 3 years 8 months (From Study start date [27 May 2011] up to final analysis data cut-off [05 January 2015])
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Dacarbazine
    Reporting group description
    		 Subjects received dacarbazine 1 gram per meter square (g/m^2) as a 20- 120 minutes intravenous (i.v.) infusion once every 3 weeks (q3wk).

    Reporting group title
    Trabectedin
    Reporting group description
    		 Subjects received trabectedin 1.5 milligram per meter square (mg/m^2) as a 24-hour intravenous (i.v.) infusion once every 3 weeks (q3wk 24-h).

    Serious adverse events
    		 Dacarbazine Trabectedin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 172 (30.23%)
    155 / 378 (41.01%)
         number of deaths (all causes)
    5
    25
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Ascites
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Pain
         subjects affected / exposed
    3 / 172 (1.74%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory Collapse
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 172 (0.58%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism Venous
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 172 (0.58%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jugular Vein Thrombosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Temporal Arteritis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous Thrombosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip Surgery
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         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
         subjects affected / exposed
    0 / 172 (0.00%)
    5 / 378 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Site Inflammation
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 172 (1.74%)
    5 / 378 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    Device Breakage
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Failure
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 172 (0.58%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait Disturbance
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised Oedema
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Site Extravasation
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-Organ Failure
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Necrosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 172 (1.16%)
    12 / 378 (3.17%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in Device
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal Fistula
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal Haemorrhage
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (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
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchial Obstruction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 172 (1.16%)
    13 / 378 (3.44%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    3 / 172 (1.74%)
    5 / 378 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 172 (0.58%)
    6 / 378 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Arrest
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory Distress
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory Failure
         subjects affected / exposed
    1 / 172 (0.58%)
    6 / 378 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Tachypnoea
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 172 (0.00%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 172 (0.00%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Lactic Acid Increased
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection Fraction Decreased
         subjects affected / exposed
    0 / 172 (0.00%)
    5 / 378 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Function Test Abnormal
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoglobin Blood Increased
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    1 / 172 (0.58%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    2 / 172 (1.16%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin I Increased
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Access Complication
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Cardiac Disorder
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 172 (0.00%)
    7 / 378 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Ventricular Dysfunction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    2 / 172 (1.16%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyramidal Tract Syndrome
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    2 / 172 (1.16%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 172 (1.16%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 172 (2.33%)
    15 / 378 (3.97%)
         occurrences causally related to treatment / all
    0 / 4
    11 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    2 / 172 (1.16%)
    12 / 378 (3.17%)
         occurrences causally related to treatment / all
    0 / 2
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 172 (1.74%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathic Haemolytic Anaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 172 (0.58%)
    9 / 378 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 172 (1.74%)
    7 / 378 (1.85%)
         occurrences causally related to treatment / all
    0 / 3
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual Impairment
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Hernia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    8 / 172 (4.65%)
    13 / 378 (3.44%)
         occurrences causally related to treatment / all
    0 / 8
    2 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 172 (0.58%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 172 (0.00%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Obstruction
         subjects affected / exposed
    2 / 172 (1.16%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal Obstruction
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Ulcer
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-Abdominal Haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestinal Obstruction
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 172 (1.74%)
    15 / 378 (3.97%)
         occurrences causally related to treatment / all
    0 / 4
    14 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction Gastric
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal Obstruction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Pain
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    3 / 172 (1.74%)
    9 / 378 (2.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 172 (1.74%)
    15 / 378 (3.97%)
         occurrences causally related to treatment / all
    0 / 4
    14 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal Vein Thrombosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive Uropathy
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    1 / 172 (0.58%)
    12 / 378 (3.17%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 14
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Renal Tubular Necrosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Obstruction
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    2 / 172 (1.16%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Range of Motion Decreased
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Swelling
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    2 / 172 (1.16%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 172 (0.00%)
    4 / 378 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Soft Tissue Necrosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Site Infection
         subjects affected / exposed
    1 / 172 (0.58%)
    8 / 378 (2.12%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Infection
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Enterococcal Bacteraemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney Infection
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 172 (0.00%)
    6 / 378 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 172 (0.00%)
    8 / 378 (2.12%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Septic Shock
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Staphylococcal Bacteraemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 172 (1.16%)
    7 / 378 (1.85%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection Staphylococcal
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal Infection
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Abscess
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased Appetite
         subjects affected / exposed
    1 / 172 (0.58%)
    3 / 378 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 172 (1.74%)
    15 / 378 (3.97%)
         occurrences causally related to treatment / all
    0 / 3
    12 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to Thrive
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid Overload
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid Retention
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 378 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 378 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperlipasaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 378 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 378 (0.26%)
         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
    		 Dacarbazine Trabectedin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    166 / 172 (96.51%)
    375 / 378 (99.21%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    12 / 172 (6.98%)
    186 / 378 (49.21%)
         occurrences all number
    16
    529
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    10 / 172 (5.81%)
    141 / 378 (37.30%)
         occurrences all number
    11
    343
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    16 / 172 (9.30%)
    87 / 378 (23.02%)
         occurrences all number
    21
    194
    Blood Bilirubin Increased
         subjects affected / exposed
    5 / 172 (2.91%)
    34 / 378 (8.99%)
         occurrences all number
    6
    58
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    2 / 172 (1.16%)
    54 / 378 (14.29%)
         occurrences all number
    2
    134
    Blood Creatinine Increased
         subjects affected / exposed
    3 / 172 (1.74%)
    47 / 378 (12.43%)
         occurrences all number
    4
    103
    Lymphocyte Count Decreased
         subjects affected / exposed
    4 / 172 (2.33%)
    21 / 378 (5.56%)
         occurrences all number
    5
    92
    Neutrophil Count Decreased
         subjects affected / exposed
    24 / 172 (13.95%)
    93 / 378 (24.60%)
         occurrences all number
    64
    306
    Platelet Count Decreased
         subjects affected / exposed
    29 / 172 (16.86%)
    61 / 378 (16.14%)
         occurrences all number
    117
    267
    Weight Decreased
         subjects affected / exposed
    5 / 172 (2.91%)
    27 / 378 (7.14%)
         occurrences all number
    6
    34
    White Blood Cell Count Decreased
         subjects affected / exposed
    20 / 172 (11.63%)
    96 / 378 (25.40%)
         occurrences all number
    51
    371
    Vascular disorders
    Flushing
         subjects affected / exposed
    9 / 172 (5.23%)
    19 / 378 (5.03%)
         occurrences all number
    10
    32
    Hot Flush
         subjects affected / exposed
    10 / 172 (5.81%)
    13 / 378 (3.44%)
         occurrences all number
    10
    18
    Hypertension
         subjects affected / exposed
    2 / 172 (1.16%)
    22 / 378 (5.82%)
         occurrences all number
    2
    61
    Hypotension
         subjects affected / exposed
    7 / 172 (4.07%)
    19 / 378 (5.03%)
         occurrences all number
    7
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 172 (12.21%)
    46 / 378 (12.17%)
         occurrences all number
    26
    55
    Dysgeusia
         subjects affected / exposed
    11 / 172 (6.40%)
    34 / 378 (8.99%)
         occurrences all number
    12
    38
    Headache
         subjects affected / exposed
    33 / 172 (19.19%)
    94 / 378 (24.87%)
         occurrences all number
    42
    143
    Hypoaesthesia
         subjects affected / exposed
    3 / 172 (1.74%)
    22 / 378 (5.82%)
         occurrences all number
    4
    33
    Paraesthesia
         subjects affected / exposed
    9 / 172 (5.23%)
    22 / 378 (5.82%)
         occurrences all number
    10
    28
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    48 / 172 (27.91%)
    149 / 378 (39.42%)
         occurrences all number
    106
    416
    Leukopenia
         subjects affected / exposed
    11 / 172 (6.40%)
    43 / 378 (11.38%)
         occurrences all number
    16
    119
    Neutropenia
         subjects affected / exposed
    31 / 172 (18.02%)
    111 / 378 (29.37%)
         occurrences all number
    65
    361
    Thrombocytopenia
         subjects affected / exposed
    33 / 172 (19.19%)
    70 / 378 (18.52%)
         occurrences all number
    90
    311
    General disorders and administration site conditions
    Catheter Site Pain
         subjects affected / exposed
    1 / 172 (0.58%)
    19 / 378 (5.03%)
         occurrences all number
    1
    30
    Chest Pain
         subjects affected / exposed
    6 / 172 (3.49%)
    19 / 378 (5.03%)
         occurrences all number
    6
    25
    Chills
         subjects affected / exposed
    11 / 172 (6.40%)
    34 / 378 (8.99%)
         occurrences all number
    15
    41
    Fatigue
         subjects affected / exposed
    90 / 172 (52.33%)
    260 / 378 (68.78%)
         occurrences all number
    156
    553
    Influenza Like Illness
         subjects affected / exposed
    6 / 172 (3.49%)
    19 / 378 (5.03%)
         occurrences all number
    6
    22
    Oedema Peripheral
         subjects affected / exposed
    21 / 172 (12.21%)
    107 / 378 (28.31%)
         occurrences all number
    25
    143
    Pain
         subjects affected / exposed
    9 / 172 (5.23%)
    18 / 378 (4.76%)
         occurrences all number
    10
    21
    Pyrexia
         subjects affected / exposed
    27 / 172 (15.70%)
    64 / 378 (16.93%)
         occurrences all number
    35
    91
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    16 / 172 (9.30%)
    30 / 378 (7.94%)
         occurrences all number
    19
    35
    Abdominal Pain
         subjects affected / exposed
    29 / 172 (16.86%)
    58 / 378 (15.34%)
         occurrences all number
    34
    76
    Abdominal Pain Upper
         subjects affected / exposed
    8 / 172 (4.65%)
    19 / 378 (5.03%)
         occurrences all number
    11
    22
    Constipation
         subjects affected / exposed
    52 / 172 (30.23%)
    140 / 378 (37.04%)
         occurrences all number
    73
    199
    Diarrhoea
         subjects affected / exposed
    40 / 172 (23.26%)
    130 / 378 (34.39%)
         occurrences all number
    50
    213
    Dry Mouth
         subjects affected / exposed
    13 / 172 (7.56%)
    22 / 378 (5.82%)
         occurrences all number
    14
    28
    Dyspepsia
         subjects affected / exposed
    12 / 172 (6.98%)
    30 / 378 (7.94%)
         occurrences all number
    15
    31
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    11 / 172 (6.40%)
    12 / 378 (3.17%)
         occurrences all number
    11
    13
    Nausea
         subjects affected / exposed
    85 / 172 (49.42%)
    282 / 378 (74.60%)
         occurrences all number
    142
    571
    Stomatitis
         subjects affected / exposed
    6 / 172 (3.49%)
    21 / 378 (5.56%)
         occurrences all number
    6
    28
    Vomiting
         subjects affected / exposed
    35 / 172 (20.35%)
    167 / 378 (44.18%)
         occurrences all number
    48
    303
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    36 / 172 (20.93%)
    85 / 378 (22.49%)
         occurrences all number
    42
    104
    Dyspnoea
         subjects affected / exposed
    33 / 172 (19.19%)
    91 / 378 (24.07%)
         occurrences all number
    42
    133
    Dyspnoea Exertional
         subjects affected / exposed
    4 / 172 (2.33%)
    26 / 378 (6.88%)
         occurrences all number
    5
    28
    Nasal Congestion
         subjects affected / exposed
    6 / 172 (3.49%)
    23 / 378 (6.08%)
         occurrences all number
    9
    27
    Oropharyngeal Pain
         subjects affected / exposed
    4 / 172 (2.33%)
    19 / 378 (5.03%)
         occurrences all number
    4
    24
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    9 / 172 (5.23%)
    13 / 378 (3.44%)
         occurrences all number
    9
    14
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    13 / 172 (7.56%)
    40 / 378 (10.58%)
         occurrences all number
    16
    45
    Depression
         subjects affected / exposed
    7 / 172 (4.07%)
    30 / 378 (7.94%)
         occurrences all number
    9
    31
    Insomnia
         subjects affected / exposed
    16 / 172 (9.30%)
    55 / 378 (14.55%)
         occurrences all number
    17
    75
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 172 (8.72%)
    57 / 378 (15.08%)
         occurrences all number
    15
    73
    Back Pain
         subjects affected / exposed
    28 / 172 (16.28%)
    65 / 378 (17.20%)
         occurrences all number
    35
    84
    Bone Pain
         subjects affected / exposed
    12 / 172 (6.98%)
    20 / 378 (5.29%)
         occurrences all number
    12
    22
    Muscular Weakness
         subjects affected / exposed
    4 / 172 (2.33%)
    25 / 378 (6.61%)
         occurrences all number
    5
    36
    Musculoskeletal Pain
         subjects affected / exposed
    14 / 172 (8.14%)
    29 / 378 (7.67%)
         occurrences all number
    14
    31
    Myalgia
         subjects affected / exposed
    11 / 172 (6.40%)
    47 / 378 (12.43%)
         occurrences all number
    13
    56
    Pain in Extremity
         subjects affected / exposed
    15 / 172 (8.72%)
    47 / 378 (12.43%)
         occurrences all number
    21
    74
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    10 / 172 (5.81%)
    24 / 378 (6.35%)
         occurrences all number
    12
    28
    Urinary Tract Infection
         subjects affected / exposed
    8 / 172 (4.65%)
    29 / 378 (7.67%)
         occurrences all number
    9
    34
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    36 / 172 (20.93%)
    138 / 378 (36.51%)
         occurrences all number
    43
    182
    Dehydration
         subjects affected / exposed
    17 / 172 (9.88%)
    43 / 378 (11.38%)
         occurrences all number
    17
    50
    Hyperglycaemia
         subjects affected / exposed
    5 / 172 (2.91%)
    30 / 378 (7.94%)
         occurrences all number
    21
    75
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 172 (4.07%)
    32 / 378 (8.47%)
         occurrences all number
    8
    70
    Hypocalcaemia
         subjects affected / exposed
    3 / 172 (1.74%)
    27 / 378 (7.14%)
         occurrences all number
    3
    55
    Hypokalaemia
         subjects affected / exposed
    22 / 172 (12.79%)
    53 / 378 (14.02%)
         occurrences all number
    34
    104
    Hyponatraemia
         subjects affected / exposed
    7 / 172 (4.07%)
    26 / 378 (6.88%)
         occurrences all number
    8
    52

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2010
    The amendment includes the inclusion of subjects 15 years of age or older; the prohibition of subject crossover from the dacarbazine group to the trabectedin group; proactive reviews of cases of sepsis; and minor editorial changes and clarifications. No subjects had been enrolled at the time of the first amendment.
    24 Jun 2011
    The amendment includes the clarification that assessments for disease status were to be conducted consistently and on schedule; additional dosing instructions for subjects with abnormal liver function tests; treatment windows for the placement of the central venous catheter and dosing; clarification to allow administration of colony stimulating factors (CSFs) during Cycle 1, specification that alkaline phosphatase (ALP) liver fraction or 5’ nucleotidase was to be measured when ALP was more than (>) 2.5 x upper limit of normal (ULN); the option to use echocardiograms if multigated acquisition (MUGA) was not available; and minor editorial changes and clarifications. One subject was enrolled at the time of the second amendment; however, both the first and second amendments were adopted before any study-related procedures had begun.
    12 Jun 2012
    The protocol changes in the third amendment included: a change to allow anthracycline and ifosfamide containing regimens or an anthracycline containing regimen and 1 additional cytotoxic chemotherapy (in any order); the provision for de-bulking surgery and the criteria to be met for such surgery; an update to the definition of progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1); an update to the most recent version of the M.D. Anderson Symptom Inventory (MDASI) questionnaire, and minor editorial changes and clarifications. There were 58 subjects enrolled at the time of the third amendment.

    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.
    No notable study limitations were identified by the Sponsor.
    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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