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    Clinical Trial Results:
    A Randomized, Open-Label Study Comparing the Combination of YONDELIS® and DOXIL®/CAELYX® with DOXIL®/CAELYX® Monotherapy for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

    Summary
    EudraCT number
    2012-004808-34
    Trial protocol
    GB   PL  
    Global end of trial date
    18 Jan 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Mar 2019
    First version publication date
    07 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ET743OVC3006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01846611
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920, Route 202 South, Raritan, NJ, United States, 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
    18 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to compare the overall survival (OS) after treatment with trabectedin+DOXIL combination therapy to that observed after treatment with DOXIL monotherapy for subjects with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who had received 2 previous lines of platinum-based chemotherapy
    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. Vital sign measurements (temperature, pulse/heart rate, respiration rate, and blood pressure) were obtained at the screening phase of the study. Safety was evaluated based on adverse events (AEs); clinical laboratory tests (hematology, serum chemistry, and serum or urine pregnancy testing); electrocardiograms (ECGs) and LVEF (either multigated acquisition [MUGA] scans or 2-dimensional echocardiograms [2D-ECHO]); and physical examinations (including height and weight measurements).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Oct 2013
    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
    South Africa: 11
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    United States: 204
    Country: Number of subjects enrolled
    Australia: 29
    Country: Number of subjects enrolled
    China: 27
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    New Zealand: 18
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Russian Federation: 246
    Worldwide total number of subjects
    576
    EEA total number of subjects
    30
    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)
    362
    From 65 to 84 years
    212
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Total 576 subjects randomized, 289 subjects in trabectedin+DOXIL arm, 287 subjects in DOXIL arm. 8 subjects did not received study drug (3 subjects in trabectedin+DOXIL arm, 5 subjects in DOXIL arm) due to worsening of health status (5 subjects) or withdrawal of subject consent (3 subjects). 568 subjects received at least 1 dose of study drug.

    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 + DOXIL
    Arm description
    Subjects received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Subjects were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.
    Arm type
    Experimental

    Investigational medicinal product name
    DOXIL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received DOXIL 30 mg/m^2 administered as an IV infusion over approximately 90 minutes.

    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 1.1 mg/m^2 of Trabectedin administered as an IV infusion for 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks.

    Investigational medicinal product name
    Dexamethasone IV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.

    Arm title
    DOXIL
    Arm description
    Subjects received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    DOXIL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1.

    Number of subjects in period 1
    Trabectedin + DOXIL DOXIL
    Started
    289
    287
    Completed
    250
    241
    Not completed
    39
    46
         Consent withdrawn by subject
    16
    21
         Unspecified
    19
    19
         Lost to follow-up
    4
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trabectedin + DOXIL
    Reporting group description
    Subjects received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Subjects were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.

    Reporting group title
    DOXIL
    Reporting group description
    Subjects received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.

    Reporting group values
    Trabectedin + DOXIL DOXIL Total
    Number of subjects
    289 287 576
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    179 183 362
        From 65 to 74 years
    93 81 174
        From 75 and above
    17 23 40
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    59.8 ± 10.16 59.9 ± 10.35 -
    Title for Gender
    Units: subjects
        Female
    289 287 576

    End points

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    End points reporting groups
    Reporting group title
    Trabectedin + DOXIL
    Reporting group description
    Subjects received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Subjects were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.

    Reporting group title
    DOXIL
    Reporting group description
    Subjects received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS defined as the time between the date of randomization and the date of death. Subjects who died, regardless of the cause of death, were considered to have had an event. All randomized analysis set included all subjects who were randomized to study treatment independent of whether they received study drug.
    End point type
    Primary
    End point timeframe
    Up to 4.3 years
    End point values
    Trabectedin + DOXIL DOXIL
    Number of subjects analysed
    289
    287
    Units: months
        median (confidence interval 95%)
    23.82 (20.30 to 26.12)
    22.21 (18.10 to 24.67)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Trabectedin + DOXIL v DOXIL
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5236
    Method
    Unstratified log rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.925
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.727
         upper limit
    1.177

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS defined as the time between the date of randomization and the date of disease progression or death. PFS was assessed using the response evaluation criteria in solid tumors (RECIST) Version 1.1. As per criteria progressive disease in case of target lesions means at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). Progressive disease in case of non-target lesions means unequivocal progression of existing non-target lesions. In both cases the appearance of one or more new lesions is also considered progression. All randomized analysis set included all subjects who were randomized to study treatment independent of whether they received study drug.
    End point type
    Secondary
    End point timeframe
    Up to 4.3 years
    End point values
    Trabectedin + DOXIL DOXIL
    Number of subjects analysed
    289
    287
    Units: months
        median (confidence interval 95%)
    7.52 (6.93 to 9.43)
    7.26 (6.14 to 7.59)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Trabectedin + DOXIL v DOXIL
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5174
    Method
    Unstratified log rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.935
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.762
         upper limit
    1.147

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    ORR defined as the percentage of subjects with measurable disease achieving a best overall response of either complete response (CR) or partial response (PR) based on RECIST. CR: disappearance of all target and non-target lesions and normalization of tumor marker levels in non-target lesions. PR: at least a 30 percent (%) decrease in the sum of longest diameter (LD) of target lesions or persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. All randomized analysis set included all subjects who were randomized to study treatment independent of whether they received study drug.
    End point type
    Secondary
    End point timeframe
    Up to 4.3 years
    End point values
    Trabectedin + DOXIL DOXIL
    Number of subjects analysed
    289
    287
    Units: Percentage of subjects
        number (confidence interval 95%)
    46.0 (40.2 to 52.0)
    35.9 (30.3 to 41.7)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Trabectedin + DOXIL v DOXIL
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0142
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.523
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.075
         upper limit
    2.158

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 4.3 years
    Adverse event reporting additional description
    Safety population included all-treated subjects who received at least 1 dose of study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Trabectedin + DOXIL
    Reporting group description
    Subjects received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Subjects were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.

    Reporting group title
    DOXIL
    Reporting group description
    Subjects received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.

    Serious adverse events
    Trabectedin + DOXIL DOXIL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    118 / 289 (40.83%)
    58 / 287 (20.21%)
         number of deaths (all causes)
    132
    131
         number of deaths resulting from adverse events
    Vascular disorders
    Capillary Leak Syndrome
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    3 / 289 (1.04%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flushing
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Venous Thrombosis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    2 / 289 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphangiosis Carcinomatosa
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant Pleural Effusion
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Abdominal Wall
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Central Nervous System
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic Syndrome
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Cell Carcinoma
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         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 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Site Inflammation
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         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 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 289 (1.38%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Fatigue
         subjects affected / exposed
    4 / 289 (1.38%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza Like Illness
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    2 / 289 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Oedema Peripheral
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    9 / 289 (3.11%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    5 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic Fluid Collection
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic Ulcer
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Stoma Complication
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Related Reaction
         subjects affected / exposed
    0 / 289 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    14 / 289 (4.84%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    16 / 16
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    9 / 289 (3.11%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    11 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection Fraction Decreased
         subjects affected / exposed
    2 / 289 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    5 / 289 (1.73%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    3 / 289 (1.04%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    4 / 289 (1.38%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (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
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 289 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    4 / 289 (1.38%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    2 / 289 (0.69%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    6 / 289 (2.08%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 289 (3.11%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    17 / 17
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    14 / 289 (4.84%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    16 / 16
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 289 (1.04%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    12 / 289 (4.15%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    15 / 15
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    10 / 289 (3.46%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    13 / 13
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    6 / 289 (2.08%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 289 (1.04%)
    8 / 287 (2.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    5 / 289 (1.73%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 289 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Obstruction
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 289 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    3 / 289 (1.04%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    8 / 289 (2.77%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Colitis
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral Pain
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral Pruritus
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    4 / 289 (1.38%)
    14 / 287 (4.88%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stomatitis
         subjects affected / exposed
    0 / 289 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 289 (3.46%)
    7 / 287 (2.44%)
         occurrences causally related to treatment / all
    10 / 13
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    4 / 289 (1.38%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal Failure
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-Induced Liver Injury
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis Toxic
         subjects affected / exposed
    2 / 289 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device Malfunction
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         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
    Back Pain
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate Antidiuretic Hormone Secretion
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    6 / 289 (2.08%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid Overload
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 289 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Wall Abscess
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Site Infection
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 289 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    3 / 289 (1.04%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Sepsis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter Bacteraemia
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    2 / 289 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral Candidiasis
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 289 (0.69%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis Bacterial
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    2 / 289 (0.69%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 289 (1.38%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal Sepsis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 289 (1.38%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    5 / 289 (1.73%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    2 / 5
    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
    Trabectedin + DOXIL DOXIL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    282 / 289 (97.58%)
    270 / 287 (94.08%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 289 (7.61%)
    7 / 287 (2.44%)
         occurrences all number
    41
    27
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    151 / 289 (52.25%)
    12 / 287 (4.18%)
         occurrences all number
    486
    16
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    100 / 289 (34.60%)
    11 / 287 (3.83%)
         occurrences all number
    234
    17
    Bilirubin Conjugated Increased
         subjects affected / exposed
    24 / 289 (8.30%)
    2 / 287 (0.70%)
         occurrences all number
    32
    3
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    73 / 289 (25.26%)
    16 / 287 (5.57%)
         occurrences all number
    163
    35
    Blood Creatinine Increased
         subjects affected / exposed
    20 / 289 (6.92%)
    21 / 287 (7.32%)
         occurrences all number
    35
    39
    Blood Bilirubin Increased
         subjects affected / exposed
    24 / 289 (8.30%)
    3 / 287 (1.05%)
         occurrences all number
    33
    3
    Ejection Fraction Decreased
         subjects affected / exposed
    20 / 289 (6.92%)
    10 / 287 (3.48%)
         occurrences all number
    23
    10
    Neutrophil Count Decreased
         subjects affected / exposed
    52 / 289 (17.99%)
    37 / 287 (12.89%)
         occurrences all number
    211
    135
    Platelet Count Decreased
         subjects affected / exposed
    52 / 289 (17.99%)
    16 / 287 (5.57%)
         occurrences all number
    197
    35
    Weight Decreased
         subjects affected / exposed
    13 / 289 (4.50%)
    16 / 287 (5.57%)
         occurrences all number
    21
    18
    White Blood Cell Count Decreased
         subjects affected / exposed
    33 / 289 (11.42%)
    29 / 287 (10.10%)
         occurrences all number
    139
    113
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    41 / 289 (14.19%)
    34 / 287 (11.85%)
         occurrences all number
    57
    41
    Dyspnoea
         subjects affected / exposed
    44 / 289 (15.22%)
    28 / 287 (9.76%)
         occurrences all number
    69
    37
    Oropharyngeal Pain
         subjects affected / exposed
    16 / 289 (5.54%)
    17 / 287 (5.92%)
         occurrences all number
    25
    19
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    135 / 289 (46.71%)
    70 / 287 (24.39%)
         occurrences all number
    417
    194
    Leukopenia
         subjects affected / exposed
    53 / 289 (18.34%)
    38 / 287 (13.24%)
         occurrences all number
    275
    157
    Neutropenia
         subjects affected / exposed
    149 / 289 (51.56%)
    104 / 287 (36.24%)
         occurrences all number
    948
    424
    Thrombocytopenia
         subjects affected / exposed
    63 / 289 (21.80%)
    18 / 287 (6.27%)
         occurrences all number
    298
    33
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    35 / 289 (12.11%)
    20 / 287 (6.97%)
         occurrences all number
    46
    23
    Headache
         subjects affected / exposed
    38 / 289 (13.15%)
    29 / 287 (10.10%)
         occurrences all number
    61
    35
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    39 / 289 (13.49%)
    16 / 287 (5.57%)
         occurrences all number
    146
    30
    Mucosal Inflammation
         subjects affected / exposed
    22 / 289 (7.61%)
    33 / 287 (11.50%)
         occurrences all number
    28
    81
    Fatigue
         subjects affected / exposed
    171 / 289 (59.17%)
    113 / 287 (39.37%)
         occurrences all number
    519
    214
    Oedema Peripheral
         subjects affected / exposed
    32 / 289 (11.07%)
    22 / 287 (7.67%)
         occurrences all number
    52
    31
    Pyrexia
         subjects affected / exposed
    38 / 289 (13.15%)
    26 / 287 (9.06%)
         occurrences all number
    51
    38
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    18 / 289 (6.23%)
    8 / 287 (2.79%)
         occurrences all number
    19
    8
    Insomnia
         subjects affected / exposed
    19 / 289 (6.57%)
    16 / 287 (5.57%)
         occurrences all number
    23
    20
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    20 / 289 (6.92%)
    15 / 287 (5.23%)
         occurrences all number
    34
    25
    Abdominal Pain
         subjects affected / exposed
    54 / 289 (18.69%)
    44 / 287 (15.33%)
         occurrences all number
    92
    71
    Ascites
         subjects affected / exposed
    12 / 289 (4.15%)
    17 / 287 (5.92%)
         occurrences all number
    20
    25
    Constipation
         subjects affected / exposed
    82 / 289 (28.37%)
    61 / 287 (21.25%)
         occurrences all number
    127
    95
    Diarrhoea
         subjects affected / exposed
    59 / 289 (20.42%)
    47 / 287 (16.38%)
         occurrences all number
    91
    80
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    12 / 289 (4.15%)
    15 / 287 (5.23%)
         occurrences all number
    12
    19
    Dyspepsia
         subjects affected / exposed
    23 / 289 (7.96%)
    18 / 287 (6.27%)
         occurrences all number
    36
    25
    Nausea
         subjects affected / exposed
    212 / 289 (73.36%)
    114 / 287 (39.72%)
         occurrences all number
    687
    235
    Stomatitis
         subjects affected / exposed
    52 / 289 (17.99%)
    91 / 287 (31.71%)
         occurrences all number
    99
    229
    Vomiting
         subjects affected / exposed
    141 / 289 (48.79%)
    54 / 287 (18.82%)
         occurrences all number
    276
    86
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    32 / 289 (11.07%)
    22 / 287 (7.67%)
         occurrences all number
    34
    24
    Dry Skin
         subjects affected / exposed
    22 / 289 (7.61%)
    21 / 287 (7.32%)
         occurrences all number
    29
    23
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    58 / 289 (20.07%)
    117 / 287 (40.77%)
         occurrences all number
    124
    313
    Rash
         subjects affected / exposed
    22 / 289 (7.61%)
    26 / 287 (9.06%)
         occurrences all number
    37
    56
    Rash Maculo-Papular
         subjects affected / exposed
    8 / 289 (2.77%)
    24 / 287 (8.36%)
         occurrences all number
    15
    46
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    25 / 289 (8.65%)
    12 / 287 (4.18%)
         occurrences all number
    32
    18
    Back Pain
         subjects affected / exposed
    24 / 289 (8.30%)
    15 / 287 (5.23%)
         occurrences all number
    29
    19
    Muscular Weakness
         subjects affected / exposed
    16 / 289 (5.54%)
    9 / 287 (3.14%)
         occurrences all number
    21
    15
    Myalgia
         subjects affected / exposed
    16 / 289 (5.54%)
    6 / 287 (2.09%)
         occurrences all number
    24
    8
    Pain in Extremity
         subjects affected / exposed
    8 / 289 (2.77%)
    16 / 287 (5.57%)
         occurrences all number
    8
    20
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    83 / 289 (28.72%)
    52 / 287 (18.12%)
         occurrences all number
    183
    111
    Dehydration
         subjects affected / exposed
    21 / 289 (7.27%)
    9 / 287 (3.14%)
         occurrences all number
    33
    14
    Hypoalbuminaemia
         subjects affected / exposed
    21 / 289 (7.27%)
    8 / 287 (2.79%)
         occurrences all number
    32
    11
    Hypokalaemia
         subjects affected / exposed
    22 / 289 (7.61%)
    12 / 287 (4.18%)
         occurrences all number
    33
    24
    Hypomagnesaemia
         subjects affected / exposed
    19 / 289 (6.57%)
    6 / 287 (2.09%)
         occurrences all number
    52
    7
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    12 / 289 (4.15%)
    15 / 287 (5.23%)
         occurrences all number
    12
    24

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Mar 2013
    The main reason of this amendment was to revise inclusion criterion.
    29 Aug 2013
    The overall reasons for the amendment are to extend the use of contraceptives from 3 months to 6 months after the study, to increase the creatinine clearance rate from greater than equal to (>=) 40 millilitres per minute/1.73 meter square (mL/min/1.73 m^2) to >=60 mL/min/1.73 m^2, and to add a prohibition regarding subjects receiving a yellow fever vaccine.
    09 Jan 2018
    The overall reason for the amendment was the sponsor’s decision to amend the study protocol was based on the Independent Data Monitoring Committee (IDMC) recommendation to discontinue the study based on the results of a futility analysis of overall survival (OS), in which the prespecified futility threshold was crossed. In addition, the amendment will allow study subjects deriving clinical benefit to continue on single-agent DOXIL per local standard of care.

    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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