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    Clinical Trial Results:
    A Randomized, Phase 3 Study of Eryaspase in Combination with Chemotherapy versus Chemotherapy Alone as Second-Line Treatment in Patients with Pancreatic Adenocarcinoma

    Summary
    EudraCT number
    		 2018-000572-15
    Trial protocol
    		 FI   SE   ES   AT   DE   NL   DK   BE   IT  
    Global end of trial date
    18 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 May 2023
    First version publication date
    20 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GRASPANC-2018-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03665441
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Erytech Pharma
    Sponsor organisation address
    Bioserra 60 Av Rockefeller, Lyon, France, 69008
    Public contact
    Anu Gupta, ERYTECH Pharma, 1 7327424937, anu.gupta@erytech.com
    Scientific contact
    Iman El-Hariry, ERYTECH Pharma, 1 617 9592131, iman.elhariry@erytech.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
    30 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to determine whether the addition of eryaspase to chemotherapy improves overall survival (OS) in second-line treatment of pancreatic adenocarcinoma compared to chemotherapy alone.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. An independent data monitoring committed reviewed the interim results from the study as well as safety on a regular basis during the trial. The IDMC had the potential to stop the study in case of safety concerns or for lack of efficacy.
    Background therapy
    		 Patients could receive one of 2 chemotherapy regimen, Gemcitabine and Abraxane or Irinotecan-based therapy. The choice of the chemotherapy regimen was determined by the prior treatment patient received in the first-line setting. Thus: − If a patient received prior gemcitabine/Abraxane in the first-line setting, then on disease progression, the patient was assigned to FOLFIRI (or Onivyde/5-FU/LV) in the current study. − If a patient received prior irinotecan-based therapy (FOLinic acid-Fluorouracil-IRInotecan-Oxaliplatin; FOLFIRINOX), then on disease progression, the patient was assigned to gemcitabine/Abraxane in the current study. − If patient received neither, the chemotherapy was investigator chose one of the 2 regimen.
    Evidence for comparator
    		 In the second-line setting, there remains a lack of consensus regarding the standard of care. Treatment options are dependent on the risk-benefit balance for the patient and the treatment received in the first line. In 2017, treatment guidelines were updated to recommend that the combination of nanoliposomal irinotecan (Onivyde®) with fluoropyrimidine regimens (i.e., 5-FU with LV) can be considered an active and tolerable treatment option in fit patients (ECOG PS less than 2) previously treated with gemcitabine-based therapy. This combination extended survival by 1.9 months compared with patients treated with 5-FU in combination with LV. No formal recommendations are available for patients who have progressed on first-line FOLFIRINOX; although gemcitabine is widely used in this setting.
    Actual start date of recruitment
    01 Sep 2018
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 170
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 25
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 211
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    United States: 39
    Worldwide total number of subjects
    512
    EEA total number of subjects
    470
    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)
    282
    From 65 to 84 years
    229
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 512 patient were randomized 1:1 to receive eryaspase with chemotherapy or chemotherapy alone. Of these, 494 patients received treatment.

    Pre-assignment
    Screening details
    		 684 patients were screened to enroll 512 patients who met the eligibility criteria. Key eligibility criteria included patients who were 18 years of age or older, had pancreatic adenocarcinoma, Stage III or IV disease, had failed 1 line of systemic therapy in advanced setting and had measurable disease per RECIST 1.1 and in good general health.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eryaspase + chemotherapy
    Arm description
    		 Patients randomized to Arm A receive eryaspase in combination with gemcitabine and Abraxane or irinotecan and 5-FU/LV.
    Arm type
    		 Experimental

    Investigational medicinal product name
    eryaspase
    Investigational medicinal product code
    Other name
    L-asparaginase encapsulated in RBCs, GRASPA, ERY001
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eryaspase (100 U/kg) was administered every 2 weeks (Day 1 and Day 15 of 4 week cycle) in combination with standard chemotherapy, gemcitabine and Abraxane of irinotecan and 5-FU/LV. Prior to administration, an irregular antibody test and crossmatch test was completed. Eryaspase was administered until disease progression or intolerable toxicity or a patient discontinues treatment for other reasons.

    Investigational medicinal product name
    Gemcitabine and Abraxane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine and Abraxane were administered on Days 1, 8, and 15 of each 4-week cycle as follows: • Abraxane: 125 mg/m2 IV over 30-40 minutes, followed by • Gemcitabine: 1000 mg/m2 IV over 30 minutes.

    Investigational medicinal product name
    Irinotecan (or Onivyde) and 5-flourouracil and Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRI (irinotecan, 5-FU, and leucovorin) was administered every 2 weeks on Day 1 and Day 15 of each 4-week cycle as follows: • Irinotecan 180 mg/m2 IV infusion • Leucovorin 400 mg/m² IV infusion over 2 hours, • 5-FU 400 mg/m² IV bolus injection over 2-4 minutes, immediately following leucovorin infusion, and • 5-FU 2400 mg/m² IV continuous infusion over 46 hours, immediately following bolus 5-FU Or Onivyde (irinotecan nanoliposomal) + 5-FU/leucovorin were administered on Days 1 and 15 of each 4-week cycle as follows: • Onivyde 70 mg/m2 IV over 90 minutes • Leucovorin 400 mg/m2 IV over 30 minutes, and • 5-FU 2400 mg/m2 over 46 hours

    Arm title
    		 Chemotherapy alone
    Arm description
    		 Patients randomized to Arm B receive either gemcitabine and Abraxane or irinotecan and 5-FU/LV.
    Arm type
    		 Standard of Care

    Investigational medicinal product name
    Gemcitabine and Abraxane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine and Abraxane were administered on Days 1, 8, and 15 of each 4-week cycle as follows: • Abraxane: 125 mg/m2 IV over 30-40 minutes, followed by • Gemcitabine: 1000 mg/m2 IV over 30 minutes.

    Investigational medicinal product name
    Irinotecan (or Onivyde) and 5-flourouracil and Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRI (irinotecan, 5-FU, and leucovorin) was administered every 2 weeks on Day 1 and Day 15 of each 4-week cycle as follows: • Irinotecan 180 mg/m2 IV infusion • Leucovorin 400 mg/m² IV infusion over 2 hours, • 5-FU 400 mg/m² IV bolus injection over 2-4 minutes, immediately following leucovorin infusion, and • 5-FU 2400 mg/m² IV continuous infusion over 46 hours, immediately following bolus 5-FU Or Onivyde (irinotecan nanoliposomal) + 5-FU/leucovorin were administered on Days 1 and 15 of each 4-week cycle as follows: • Onivyde 70 mg/m2 IV over 90 minutes • Leucovorin 400 mg/m2 IV over 30 minutes, and • 5-FU 2400 mg/m2 over 46 hours

    Number of subjects in period 1
    		Eryaspase + chemotherapy Chemotherapy alone
    Started
    255
    257
    Completed
    209
    211
    Not completed
    46
    46
         On treatment
    9
    6
         Consent withdrawn by subject
    4
    11
         Survival Follow up
    30
    27
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eryaspase + chemotherapy
    Reporting group description
    		 Patients randomized to Arm A receive eryaspase in combination with gemcitabine and Abraxane or irinotecan and 5-FU/LV.

    Reporting group title
    Chemotherapy alone
    Reporting group description
    		 Patients randomized to Arm B receive either gemcitabine and Abraxane or irinotecan and 5-FU/LV.

    Reporting group values
    		 Eryaspase + chemotherapy Chemotherapy alone Total
    Number of subjects
    		 255 257 512
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 140 142 282
        Adults (65 years and older)
    		 115 115 230
    Gender categorical
    Units: Subjects
        Female
    		 121 124 245
        Male
    		 134 133 267
    Geographical Region
    Units: Subjects
        Europe
    		 236 237 473
        USA
    		 19 20 39
    ECOG
    Units: Subjects
        ECOG=0
    		 107 105 212
        ECOG=1
    		 148 152 300
    Time from initial diagnosis of advanced disease to randomization (months)
    Units: Subjects
        <6 months
    		 79 74 153
        >=6 months
    		 176 183 359
    Chemotherapy regimen in study
    Units: Subjects
        Gemcitabine and Abraxane
    		 148 148 296
        Irinotecan and 5-FU/LV
    		 107 109 216
    Subject analysis sets

    Subject analysis set title
    Final Analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all patients who were randomized to study treatment, regardless of whether they received study medication.

    Subject analysis set title
    Final Analysis - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population is defined as all patients who received at least one dose of study drug.

    Subject analysis set title
    Final Analysis - Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol population is defined as a subset of ITT patients who receive at least one dose of study medication and had no major protocol deviation in inclusion/exclusion criteria.

    Subject analysis set title
    Final Analysis - PRO
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PRO population will consist of all patients who receive at least one dose of the study treatment and provide answers to at least some items of the EORTC QLQ-C30 at Cycle 1 Day 1 (i.e, baseline) and a time point after the date of first dose of study treatment.

    Subject analysis set title
    Final Analysis - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic analysis set will include all randomized patients who received at least one dose of eryaspase and who have at least one post-baseline PK assessment.

    Subject analysis sets values
    		 Final Analysis Final Analysis - Safety Final Analysis - Per Protocol Final Analysis - PRO Final Analysis - PK
    Number of subjects
    512
    494
    491
    457
    226
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    282
    272
    271
    249
    127
        Adults (65 years and older)
    230
    222
    220
    209
    99
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    245
    260
    259
    242
    117
        Male
    267
    234
    232
    215
    109
    Geographical Region
    Units: Subjects
        Europe
    473
    458
    455
    427
    207
        USA
    39
    36
    36
    30
    19
    ECOG
    Units: Subjects
        ECOG=0
    212
    196
    195
    184
    95
        ECOG=1
    300
    298
    296
    273
    131
    Time from initial diagnosis of advanced disease to randomization (months)
    Units: Subjects
        <6 months
    153
    152
    151
    140
    74
        >=6 months
    359
    342
    340
    317
    152
    Chemotherapy regimen in study
    Units: Subjects
        Gemcitabine and Abraxane
    296
    283
    280
    270
    135
        Irinotecan and 5-FU/LV
    216
    211
    211
    187
    91

    End points

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    End points reporting groups
    Reporting group title
    Eryaspase + chemotherapy
    Reporting group description
    		 Patients randomized to Arm A receive eryaspase in combination with gemcitabine and Abraxane or irinotecan and 5-FU/LV.

    Reporting group title
    Chemotherapy alone
    Reporting group description
    		 Patients randomized to Arm B receive either gemcitabine and Abraxane or irinotecan and 5-FU/LV.

    Subject analysis set title
    Final Analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population comprised all patients who were randomized to study treatment, regardless of whether they received study medication.

    Subject analysis set title
    Final Analysis - Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population is defined as all patients who received at least one dose of study drug.

    Subject analysis set title
    Final Analysis - Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol population is defined as a subset of ITT patients who receive at least one dose of study medication and had no major protocol deviation in inclusion/exclusion criteria.

    Subject analysis set title
    Final Analysis - PRO
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PRO population will consist of all patients who receive at least one dose of the study treatment and provide answers to at least some items of the EORTC QLQ-C30 at Cycle 1 Day 1 (i.e, baseline) and a time point after the date of first dose of study treatment.

    Subject analysis set title
    Final Analysis - PK
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic analysis set will include all randomized patients who received at least one dose of eryaspase and who have at least one post-baseline PK assessment.

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    OS defined as the time elapsed between randomization and death from any cause. Patients who are not known to have died prior to data cut-off will be censored at the date of last contact or clinical cut-off, whichever comes first.
    End point type
    Primary
    End point timeframe
    36 months
    End point values
    		 Eryaspase + chemotherapy Chemotherapy alone
    Number of subjects analysed
    255 [1]
    257 [2]
    Units: months
        median (confidence interval 95%)
    7.5 (6.5 to 8.3)
    6.7 (5.4 to 7.5)
    Notes
    [1] - ITT population
    [2] - ITT population
    Statistical analysis title
    		 OS ITT population
    Statistical analysis description
    OS is measured from the date of randomization to the date of death from any cause. Patients who are not known to have died are censored at the date of last contact or date of clinical cut-off, whichever comes first. The stratification factors include ECOG performance status (0 or 1), Chemotherapy regimen (gemcitabine/Abraxane or irinotecan-based treatment [FOLFIRI or its equivalent Onivyde/5-FU/LV]), and Time interval since initial diagnosis of advanced disease (<6 months or >=6 months).
    Comparison groups
    Eryaspase + chemotherapy v Chemotherapy alone
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.11
    Notes
    [3] - The two-sided p-value for the time to event analysis is associated with the stratified log-rank statistic. The null hypothesis is rejected if the two-sided p-value for the test <=0.046.

    Secondary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    PFS is defined as the interval time from the date of randomization until objective disease progression per modified RECIST 1.1, or death from any cause in the absence of disease progression, whichever occurs first. PFS is compared between the two treatment arms using the same methods of analysis as for OS.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 Eryaspase + chemotherapy Chemotherapy alone
    Number of subjects analysed
    255
    257
    Units: month
        median (confidence interval 95%)
    3.7 (3.4 to 4.1)
    3.4 (2.0 to 3.7)
    Statistical analysis title
    		 PFS ITT population
    Statistical analysis description
    Stratified log-rank test, with the stratification variable being ECOG performance status (0 or 1), Chemotherapy regimen (gemcitabine/Abraxane or irinotecan-based treatment [FOLFIRI or its equivalent Onivyde/5-FU/LV]) and Time interval since initial diagnosis of advanced disease (<6 months or >=6 months).
    Comparison groups
    Chemotherapy alone v Eryaspase + chemotherapy
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.07
    Notes
    [4] - The two-sided p-value for the time to event analysis is associated with the stratified log-rank statistic. The null hypothesis is rejected if the two-sided p-value for this test and proceeding OS test are <=0.046.

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    ORR is defined as the proportion of patients who achieve objective tumor response (CR or PR) per modified RECIST 1.1.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 Eryaspase + chemotherapy Chemotherapy alone
    Number of subjects analysed
    255
    257
    Units: subjects
    41
    32
    Statistical analysis title
    		 ORR ITT Population
    Statistical analysis description
    ORR is defined as the proportion of patients who achieve objective tumor response (CR or PR) per modified RECIST 1.1. The 95% CI is calculated using the binomial exact (Clopper-Pearson) method and 2-sided p-value is from the stratified Cochran-Mantel-Haenszel test. The stratification factors are ECOG, chemotherapy regimen, and time interval since initial diagnosis of advanced disease. The null hypothesis is rejected if the 2-sided p-value for this test and proceeding OS and PFS are <=0.046.
    Comparison groups
    Eryaspase + chemotherapy v Chemotherapy alone
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.242
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 2.24

    Secondary: Disease Control Rate

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    End point title
    		 Disease Control Rate
    End point description
    DCR is defined as the proportion of patients who achieve CR, PR or SD per modified RECIST 1.1. The denominator for DCR is the number of ITT patients in the treatment group.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 Eryaspase + chemotherapy Chemotherapy alone
    Number of subjects analysed
    255
    257
    Units: subjects
    147
    126
    Statistical analysis title
    		 DCR ITT Population
    Comparison groups
    Chemotherapy alone v Eryaspase + chemotherapy
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.047
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - The DCR for each treatment group, along with 95% CIs will be calculated. The DCRs will be compared using a stratified CMH test with the same strata as for the primary analysis for OS.

    Secondary: Duration of Response ITT population with ORR

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    End point title
    		 Duration of Response ITT population with ORR
    End point description
    DoR is measured from the first reporting of CR or PR per modified RECIST 1.1 until the first date of progression, death, or censoring; Patients who were not known to have disease progression or died were censored to the date of last assessment.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 Eryaspase + chemotherapy Chemotherapy alone
    Number of subjects analysed
    41
    32
    Units: months
        median (confidence interval 95%)
    5.7 (3.9 to 7.4)
    5.8 (2.8 to 7.4)
    No statistical analyses for this end point

    Secondary: Global Health Status time to event worsening analysis - PRO population

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    End point title
    		 Global Health Status time to event worsening analysis - PRO population
    End point description
    The time to first Worsening is the date of randomization to the date of first Worsening occurred. Patients who did not have any Worsening were censored at date of last measurement or at baseline if no measurement was available post-baseline.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 Eryaspase + chemotherapy Chemotherapy alone
    Number of subjects analysed
    228
    229
    Units: months
        median (confidence interval 95%)
    4.0 (3.1 to 5.1)
    3.6 (2.8 to 4.7)
    No statistical analyses for this end point

    Secondary: Global Health Status time to event improvement analysis - PRO population

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    End point title
    		 Global Health Status time to event improvement analysis - PRO population
    End point description
    The time to first improvement is the date of randomization to the date of first improvement occurred. Patients who did not have any improvement were censored at date of last measurement or at baseline if no measurement was available post-baseline.
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 Eryaspase + chemotherapy Chemotherapy alone
    Number of subjects analysed
    228
    229
    Units: months
        median (confidence interval 95%)
    10.6 (3.8 to 12.1)
    5.6 (3.8 to 6.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Collected from time of informed consent until 90 days after last study treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Eryaspase + chemotherapy
    Reporting group description
    		 Patients randomized to Arm A receive eryaspase in combination with gemcitabine and Abraxane or irinotecan and 5-FU/LV.

    Reporting group title
    Chemotherapy alone
    Reporting group description
    		 Patients randomized to Arm B receive either gemcitabine and Abraxane or irinotecan and 5-FU/LV.

    Serious adverse events
    		 Eryaspase + chemotherapy Chemotherapy alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    122 / 248 (49.19%)
    105 / 246 (42.68%)
         number of deaths (all causes)
    202
    206
         number of deaths resulting from adverse events
    14
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 248 (4.03%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    3 / 10
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    7 / 248 (2.82%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    4 / 7
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inadequate analgesia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Alloimmunisation
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (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
    Pulmonary embolism
         subjects affected / exposed
    10 / 248 (4.03%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 248 (0.81%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 248 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         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
    3 / 248 (1.21%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Pancreatic enzymes abnormal
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic transfusion reaction
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (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 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 248 (0.40%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    4 / 248 (1.61%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalopathy
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 248 (0.81%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 248 (0.40%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 248 (1.21%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal obstruction
         subjects affected / exposed
    9 / 248 (3.63%)
    11 / 246 (4.47%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    7 / 248 (2.82%)
    9 / 246 (3.66%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 9
         deaths causally related to treatment / all
    1 / 2
    0 / 4
    Diarrhoea
         subjects affected / exposed
    6 / 248 (2.42%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    5 / 6
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    6 / 248 (2.42%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 248 (0.81%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral disorder
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric varices
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic duct stenosis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestine perforation
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    13 / 248 (5.24%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         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
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    4 / 248 (1.61%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    11 / 248 (4.44%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    0 / 11
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 248 (1.21%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 248 (1.61%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aeromonas infection
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    2 / 248 (0.81%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infection
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 248 (0.40%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 248 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perihepatic abscess
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (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
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 248 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 248 (0.81%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food intolerance
         subjects affected / exposed
    0 / 248 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 248 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Eryaspase + chemotherapy Chemotherapy alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    248 / 248 (100.00%)
    242 / 246 (98.37%)
    Investigations
    Weight decreased
         subjects affected / exposed
    35 / 248 (14.11%)
    14 / 246 (5.69%)
         occurrences all number
    35
    14
    Transaminases increased
         subjects affected / exposed
    30 / 248 (12.10%)
    18 / 246 (7.32%)
         occurrences all number
    30
    18
    Blood albumin decreased
         subjects affected / exposed
    15 / 248 (6.05%)
    16 / 246 (6.50%)
         occurrences all number
    15
    16
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    16 / 248 (6.45%)
    13 / 246 (5.28%)
         occurrences all number
    16
    13
    Blood alkaline phosphatase increased
         subjects affected / exposed
    15 / 248 (6.05%)
    10 / 246 (4.07%)
         occurrences all number
    15
    10
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    69 / 248 (27.82%)
    62 / 246 (25.20%)
         occurrences all number
    69
    62
    Headache
         subjects affected / exposed
    29 / 248 (11.69%)
    14 / 246 (5.69%)
         occurrences all number
    29
    14
    Dysgeusia
         subjects affected / exposed
    20 / 248 (8.06%)
    14 / 246 (5.69%)
         occurrences all number
    20
    14
    Dizziness
         subjects affected / exposed
    12 / 248 (4.84%)
    10 / 246 (4.07%)
         occurrences all number
    12
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    186 / 248 (75.00%)
    173 / 246 (70.33%)
         occurrences all number
    186
    173
    Pyrexia
         subjects affected / exposed
    73 / 248 (29.44%)
    56 / 246 (22.76%)
         occurrences all number
    73
    56
    Oedema
         subjects affected / exposed
    65 / 248 (26.21%)
    47 / 246 (19.11%)
         occurrences all number
    65
    47
    Chills
         subjects affected / exposed
    17 / 248 (6.85%)
    6 / 246 (2.44%)
         occurrences all number
    17
    6
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    108 / 248 (43.55%)
    93 / 246 (37.80%)
         occurrences all number
    108
    93
    Thrombocytopenia
         subjects affected / exposed
    75 / 248 (30.24%)
    72 / 246 (29.27%)
         occurrences all number
    75
    72
    Leukopenia
         subjects affected / exposed
    28 / 248 (11.29%)
    16 / 246 (6.50%)
         occurrences all number
    28
    16
    Lymphopenia
         subjects affected / exposed
    19 / 248 (7.66%)
    10 / 246 (4.07%)
         occurrences all number
    19
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    133 / 248 (53.63%)
    107 / 246 (43.50%)
         occurrences all number
    133
    107
    Nausea
         subjects affected / exposed
    132 / 248 (53.23%)
    89 / 246 (36.18%)
         occurrences all number
    132
    89
    Abdominal pain
         subjects affected / exposed
    96 / 248 (38.71%)
    84 / 246 (34.15%)
         occurrences all number
    96
    84
    Constipation
         subjects affected / exposed
    69 / 248 (27.82%)
    62 / 246 (25.20%)
         occurrences all number
    69
    62
    Vomiting
         subjects affected / exposed
    69 / 248 (27.82%)
    57 / 246 (23.17%)
         occurrences all number
    69
    57
    Oral disorder
         subjects affected / exposed
    58 / 248 (23.39%)
    60 / 246 (24.39%)
         occurrences all number
    58
    60
    Flatulence
         subjects affected / exposed
    19 / 248 (7.66%)
    8 / 246 (3.25%)
         occurrences all number
    19
    8
    Ascites
         subjects affected / exposed
    15 / 248 (6.05%)
    7 / 246 (2.85%)
         occurrences all number
    15
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    15 / 248 (6.05%)
    5 / 246 (2.03%)
         occurrences all number
    15
    5
    Dyspepsia
         subjects affected / exposed
    12 / 248 (4.84%)
    7 / 246 (2.85%)
         occurrences all number
    12
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    34 / 248 (13.71%)
    24 / 246 (9.76%)
         occurrences all number
    34
    24
    Epistaxis
         subjects affected / exposed
    21 / 248 (8.47%)
    16 / 246 (6.50%)
         occurrences all number
    21
    16
    Cough
         subjects affected / exposed
    14 / 248 (5.65%)
    11 / 246 (4.47%)
         occurrences all number
    14
    11
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    18 / 248 (7.26%)
    10 / 246 (4.07%)
         occurrences all number
    18
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    64 / 248 (25.81%)
    51 / 246 (20.73%)
         occurrences all number
    64
    51
    Rash
         subjects affected / exposed
    18 / 248 (7.26%)
    10 / 246 (4.07%)
         occurrences all number
    18
    10
    Pruritus
         subjects affected / exposed
    11 / 248 (4.44%)
    13 / 246 (5.28%)
         occurrences all number
    11
    13
    Dry skin
         subjects affected / exposed
    15 / 248 (6.05%)
    7 / 246 (2.85%)
         occurrences all number
    15
    7
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    16 / 248 (6.45%)
    19 / 246 (7.72%)
         occurrences all number
    16
    19
    Anxiety
         subjects affected / exposed
    13 / 248 (5.24%)
    13 / 246 (5.28%)
         occurrences all number
    13
    13
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    37 / 248 (14.92%)
    24 / 246 (9.76%)
         occurrences all number
    37
    24
    Arthralgia
         subjects affected / exposed
    22 / 248 (8.87%)
    21 / 246 (8.54%)
         occurrences all number
    22
    21
    Myalgia
         subjects affected / exposed
    25 / 248 (10.08%)
    16 / 246 (6.50%)
         occurrences all number
    25
    16
    Pain in extremity
         subjects affected / exposed
    12 / 248 (4.84%)
    10 / 246 (4.07%)
         occurrences all number
    12
    10
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    12 / 248 (4.84%)
    13 / 246 (5.28%)
         occurrences all number
    12
    13
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 248 (4.84%)
    10 / 246 (4.07%)
         occurrences all number
    12
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    76 / 248 (30.65%)
    60 / 246 (24.39%)
         occurrences all number
    76
    60
    Hypokalaemia
         subjects affected / exposed
    29 / 248 (11.69%)
    26 / 246 (10.57%)
         occurrences all number
    29
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2019
    Key changes included: Clearly defined objectives and study endpoints. Extension of safety assessments from 30 days to 90 days or start of new anti-cancer treatment. Detail acceptable birth control methods. Aligned pre-testing and dosing guidance for UGT1A1 and DPD deficiency as per product labels for irinotecan and 5-FU. Clarified Onivyde dosing. Update of specific toxicity management. Other clarifications and administrative changes per sites questions.
    06 Feb 2021
    Key changes included: Reduced frequency of ECG assessment during study. COVID-19 impact to waive certain assessments, use of facilities not defined in the clinical information forms, documentation of protocol deviations resulting from COVID-19 impact, and allowing of remote monitoring visits in case of site visit and travel restrictions.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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