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    Clinical Trial Results:
    Phase II Study for the Evaluation of the Efficacy of Gemcitabine plus Erlotinib in Rash-positive Patients with Metastatic Pancreatic Cancer and Good Risk Factors

    Summary
    EudraCT number
    		 2011-005471-17
    Trial protocol
    		 DE  
    Global end of trial date
    01 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jun 2018
    First version publication date
    16 Jun 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RASH
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01729481
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Klinikum der Universität München-Großhadern
    Sponsor organisation address
    Marchioninistr. 15, München, Germany, 81377
    Public contact
    Study office, Klinikum der Universität München-Großhadern, 49 89440072208, Matthias.Wolff@med.uni-muenchen.de
    Scientific contact
    Study office, Klinikum der Universität München-Großhadern, 49 89440072208, Matthias.Wolff@med.uni-muenchen.de
    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
    16 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1-year survival rate of "good risk" patients who develop rash under treatment with gemcitabine/erlotinib
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable European and national regulations (including European Directive 2001/20/EC and German Drug Law (AMG)) and with the ethical principles laid down in the Declaration of Helsinki. Participating subjects signed the informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    11 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 150
    Worldwide total number of subjects
    150
    EEA total number of subjects
    150
    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)
    88
    From 65 to 84 years
    62
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 25 investigational sites in Germany were participating. 150 subjects were screened and enrolled at 20 of these 25 investigational sites. The first patient was enrolled 11-July-2012, the last patient 6-July-2015.

    Pre-assignment
    Screening details
    		 Main inclusion criteria: - Histologically confirmed metastatic adenocarcinoma of the pancreas (UICC stadium IV; any T, any N, M1 following TNM) - At least one measurable tumor lesion (CT or MRI) according to RECIST version 1.1 - ECOG PS 0 and 1 - Between 18 and 75 years of age - Bilirubin ≤ 1.5 ULN (biliary stent permitted)

    Pre-assignment period milestones
    Number of subjects started
    		 150
    Number of subjects completed
    		 144

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Violation in-/exclusion criteria (retrospectively): 1
    Reason: Number of subjects
    		 Death: 1
    Reason: Number of subjects
    		 Progression of tumor disease: 1
    Reason: Number of subjects
    		 Patient's wish: 1
    Reason: Number of subjects
    		 Loss of contact: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Period 1
    Period 1 title
    Run-in with Gemcitabin/Erlotinib
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Run-in
    Arm description
    		 Treatment with gemcitabine 1000 mg/^2 BSA weekly and erlotinib, 100 mg once daily for 4 weeks. Treatment was discontinued earlier in case of progression of the metastatic pancreatic adenocarcinoma, unacceptable toxicity or other reasons (patient’s wish, investigator’s decision).
    Arm type
    		 Run-in

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1000 mg/m^2 on D1, D8, D15, D21 of one 28-day cycle.

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily for 28 days.

    Number of subjects in period 1 [1]
    		Run-in
    Started
    144
    Completed
    116
    Not completed
    28
         Physician decision
    6
         Adverse event, non-fatal
    3
         Patient's wish
    7
         Death
    5
         Progression of tumor disease
    7
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Sample size calculation of 150 patients included 10% drop-outs. As 6 patients were screening failures , 144 patients entered the Run-in phase.
    Period 2
    Period 2 title
    Treatment according to ocurrence of rash
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (rash-positve)
    Arm description
    		 Patient who had developed skin rash after 4 weeks of treatment with gemcitabine 1000 mg/^2 BSA weekly and erlotinib 100 mg p.o. once daily in the Run-in phase (first 4 treatment weeks), continued treatment with gemcitabine 1000 mg/^2 weekly on D1, D7, D14 of each 28-day treatment cycle and erlotinib 100 mg p.o. once daily. Treatment was continued until progression of the metastatic pancreatic adenocarcinoma, unacceptable toxicity or other reasons (patient’s wish, investigator’s decision).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    1000 mg/m^2 BSA on D1, D8, D15 of each 28-day cycle

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg once daily

    Arm title
    		 Arm B (rash-negative)
    Arm description
    		 Patient who had developed no skin rash after 4 weeks of treatment with gemcitabine 1000 mg/^2 BSA weekly and erlotinib 100 mg p.o. once daily in the Run-in phase (first 4 treatment weeks), received further treatment with FOLFIRINOX (fluorouracil, folinic acid, irinotecan, oxaliplatin). Treatment was continued until progression of the metastatic pancreatic adenocarcinoma, unacceptable toxicity or other reasons (patient’s wish, investigator’s decision). Only rash-negative patients who were given FOLFIRINOX treatment after Run-in are included.
    Arm type
    		 treatment choice for RASH-negative patients

    Investigational medicinal product name
    Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection, Solvent for solution for infusion
    Routes of administration
    Intravenous bolus use , Intravenous drip use
    Dosage and administration details
    400 mg/m^2 BSA as bolus injection, followed by 2400 mg/m^2 BSA as continuous infusion over about 48 hours on D1/D2 of a 14-day cycle.

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion, Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    400 mg/m^2 BSA as intravenous infusion over about 2 hours on D1 of a 14-day cycle.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    180 mg/m^2 BSA as intravenous infusion over about 90 minutes on D1 of a 14-day cycle.

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    85 mg/m^2 BSA as intravenous infusion over about 2 hours on D1 of a 14-day cycle.

    Number of subjects in period 2
    		Arm A (rash-positve) Arm B (rash-negative)
    Started
    89
    27
    Completed
    89
    27

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Run-in with Gemcitabin/Erlotinib
    Reporting group description
    		 All patients of the Full-Analysis Population, who were administered at least one dose of gemcitabine or erlotinib during the Run-in period (first four weeks of treatment)

    Reporting group values
    		 Run-in with Gemcitabin/Erlotinib Total
    Number of subjects
    		 144 144
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 63.5 (24.0 to 75.0) -
    Gender categorical
    Units: Subjects
        Female
    		 57 57
        Male
    		 87 87
    ECOG Performance Status
    Units: Subjects
        ECOG PS 0
    		 87 87
        ECOG PS 1
    		 57 57
    Subject analysis sets

    Subject analysis set title
    Rash-positive (primary endpoint)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients, who are rash-positive after 4 weeks treatment with gemcitabine and erlotinib (all except one patient continued treatment with gemcitabine and erlotinib after the Run-in phase)

    Subject analysis set title
    Patients - efficacy assessable
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients of Full Analysis Set with: (a) at least two cycles for patients in arm A (i.e. cycle 1A+1B=2x28=56 days) and at least until cycle 2 for patients in arm B (i.e. cycle 1A+1+2=28+14+14=56days, (b) one restaging acc. to RECIST 1.1 during study treatment. Unless (a) and (b) are unsatisfied due to early progression/death

    Subject analysis set title
    All patients treated
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who have been treated with at least one dose of study medication (gemcitabine, erlotinib, FOLFIRINOX). One further patient was excluded from the Full Analysis due to later detected violation of inclusion- and exclusion criteria.

    Subject analysis sets values
    		 Rash-positive (primary endpoint) Patients - efficacy assessable All patients treated
    Number of subjects
    90
    123
    144
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    63.0 (24.0 to 75.0)
    63.0 (24.0 to 75.0)
    63.5 (24.0 to 75.0)
    Gender categorical
    Units: Subjects
        Female
    32
    47
    57
        Male
    58
    76
    87
    ECOG Performance Status
    Units: Subjects
        ECOG PS 0
    64
    78
    87
        ECOG PS 1
    26
    45
    57

    End points

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    End points reporting groups
    Reporting group title
    Run-in
    Reporting group description
    		 Treatment with gemcitabine 1000 mg/^2 BSA weekly and erlotinib, 100 mg once daily for 4 weeks. Treatment was discontinued earlier in case of progression of the metastatic pancreatic adenocarcinoma, unacceptable toxicity or other reasons (patient’s wish, investigator’s decision).
    Reporting group title
    Arm A (rash-positve)
    Reporting group description
    		 Patient who had developed skin rash after 4 weeks of treatment with gemcitabine 1000 mg/^2 BSA weekly and erlotinib 100 mg p.o. once daily in the Run-in phase (first 4 treatment weeks), continued treatment with gemcitabine 1000 mg/^2 weekly on D1, D7, D14 of each 28-day treatment cycle and erlotinib 100 mg p.o. once daily. Treatment was continued until progression of the metastatic pancreatic adenocarcinoma, unacceptable toxicity or other reasons (patient’s wish, investigator’s decision).

    Reporting group title
    Arm B (rash-negative)
    Reporting group description
    		 Patient who had developed no skin rash after 4 weeks of treatment with gemcitabine 1000 mg/^2 BSA weekly and erlotinib 100 mg p.o. once daily in the Run-in phase (first 4 treatment weeks), received further treatment with FOLFIRINOX (fluorouracil, folinic acid, irinotecan, oxaliplatin). Treatment was continued until progression of the metastatic pancreatic adenocarcinoma, unacceptable toxicity or other reasons (patient’s wish, investigator’s decision). Only rash-negative patients who were given FOLFIRINOX treatment after Run-in are included.

    Subject analysis set title
    Rash-positive (primary endpoint)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients, who are rash-positive after 4 weeks treatment with gemcitabine and erlotinib (all except one patient continued treatment with gemcitabine and erlotinib after the Run-in phase)

    Subject analysis set title
    Patients - efficacy assessable
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients of Full Analysis Set with: (a) at least two cycles for patients in arm A (i.e. cycle 1A+1B=2x28=56 days) and at least until cycle 2 for patients in arm B (i.e. cycle 1A+1+2=28+14+14=56days, (b) one restaging acc. to RECIST 1.1 during study treatment. Unless (a) and (b) are unsatisfied due to early progression/death

    Subject analysis set title
    All patients treated
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who have been treated with at least one dose of study medication (gemcitabine, erlotinib, FOLFIRINOX). One further patient was excluded from the Full Analysis due to later detected violation of inclusion- and exclusion criteria.

    Primary: 1-year survival rate in patients with skin rash

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    End point title
    		 1-year survival rate in patients with skin rash [1]
    End point description
    The primary endpoint is the 1-year survival rate for patients treated with gemcitabine + erlotinib developing skin rash of any grade during a four-week Run-in phase. Overall survival is calculated from the date of first adminstration of gemcitabine/erlotinib until date of death, censoring patients still alive with the date of last known contact (confirmatory analysis).
    End point type
    Primary
    End point timeframe
    Survival status of each participating patient is recorded for at least 18 months after the date of enrollment.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The alternative hypothesis of a one-year-survival-rate of 40% was to be differed from the null hypothesis of 25% within a two-sided test (significance level 0.05, power 83%; pre-specified analysis). The alternative hypothesis and the null hypothesis are based on the publicated historical data in patients treated with gemcitabine/erlotinib in the PA.3 study (Moore 2007) and in patients treated with FOLFIRINOX (Conroy 2011), thus the statistical hypothetical test compared with historical groups.
    End point values
    		 Rash-positive (primary endpoint)
    Number of subjects analysed
    90
    Units: number of patients alive
        40.0% (29.8-50.9%)
    36
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    Percentage of patients who experienced "Complete response" or "Partial response" according to RECIST 1.1 (exploratory analysis)
    End point type
    Secondary
    End point timeframe
    Evaluated every 8 weeks from the start of treatment until the end of treatment visit.
    End point values
    		 Arm B (rash-negative) Rash-positive (primary endpoint) Patients - efficacy assessable All patients treated
    Number of subjects analysed
    27
    90
    123
    144
    Units: number of subjects with ORR
        33.3% (16.5 to 54.0%)
    9
    0
    0
    0
        23.3% (15.1 to 33.4%)
    0
    21
    0
    0
        24.4%
    0
    0
    30
    0
        20.8%
    0
    0
    0
    30
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival is the time from the date of first administration of gemcitabin/erlotinib in Run-in until occurrence of progression or death of any cause. Patients without event will be censored with the last date known to be progression-free (exploratory analysis)
    End point type
    Secondary
    End point timeframe
    Progression is evaluated every 8 weeks from the start of treatment until the end of treatment visit by means of imaging procedures. Survival status of each participating patient is recorded for at least 18 months after the date of enrollment.
    End point values
    		 Arm B (rash-negative) Rash-positive (primary endpoint) Patients - efficacy assessable All patients treated
    Number of subjects analysed
    27
    90
    123
    144
    Units: Months
        arithmetic mean (confidence interval 95%)
    6.6 (2.6 to 9.6)
    3.8 (3.5 to 4.9)
    3.6 (2.8 to 5.0)
    3.6 (3.2 to 4.7)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival is calculated from the date of first application of gemcitabine/erlotinib until date of death, censoring patients still alive with the date of last known contact (exploratory analysis).
    End point type
    Secondary
    End point timeframe
    Survival status of each participating patient is recorded for at least 18 months after the date of enrollment.
    End point values
    		 Arm B (rash-negative) Rash-positive (primary endpoint) Patients - efficacy assessable All patients treated
    Number of subjects analysed
    27
    90
    123
    144
    Units: months
        median (confidence interval 95%)
    10.9 (6.6 to 14.0)
    10.1 (9.0 to 12.5)
    10.0 (9.0 to 12.1)
    9.7 (8.0 to 10.9)
    No statistical analyses for this end point

    Secondary: Disease-control rate (DCR)

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    End point title
    		 Disease-control rate (DCR)
    End point description
    Percentage of patients who experienced "Complete response" or "Partial response" or "Stable disease" according to RECIST 1.1 (exploratory analysis)
    End point type
    Secondary
    End point timeframe
    Evaluated every 8 weeks from the start of treatment until the end of treatment visit.
    End point values
    		 Arm B (rash-negative) Rash-positive (primary endpoint) Patients - efficacy assessable All patients treated
    Number of subjects analysed
    27
    90
    123
    144
    Units: Number of patients with DCR
        63.0%
    17
    0
    0
    0
        66.7%
    0
    60
    0
    0
        61,0%
    0
    0
    75
    0
        54,2%
    0
    0
    0
    78
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Date of signing informed consent until 28 days after last administration of study medication.
    Adverse event reporting additional description
    Patients who received at least one adminstration of gemcitabine or erlotinib were analyzed as Safety Population. Only treatment-emergent events were analyzed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Continued treatment with gemcitabin/erlotinib after Run-in
    Reporting group description
    		 Rash-positive patients: Continued treatment with gemcitabine 100 mg/m^2 BSA weekly i.v. in Week 1-3 of each 28-day cycle and erlotinib 100 mg p.o. once daily after the Run-in phase until progression or unacceptable toxicity. Only adverse events, experienced after Run-in during continued treatment with gemcitabine and erlotinib are taken into account.

    Reporting group title
    FOLFIRINOX after Run-in
    Reporting group description
    		 Treatment with FOLFIRINOX after the Run-in phase: Oxaliplatin 85 mg/m^2 on Day 1 of each 14-day cycle; i.v. Folinic acid 400 mg/m^2 on Day 1 of each 14-day cycle; i.v. Irinotecane 180 mg/m^2 on Day 1 of each 14-day cycle; i.v. 5-fluorouracil 400 mg/m² as bolus, followed by 2400 mg/m^2 as i.v. infusion over 46 hours Treatment until progression or unacceptable toxicity. Only adverse events, experienced after Run-in while receiving FOLFIRINOX treatment, are taken into account.

    Reporting group title
    Gemcitabine and erlotinib overall
    Reporting group description
    		 Patients who were administered at least one dose of gemcitabine or erlotinib in the Run-in phase (first 4 treatment weeks; gemcitabine 1000 mg/^2 BSA weekly and erlotinib 100 mg p.o. once daily) and/or continued application of gemcitabine and erlotinib (gemcitabine 1000 mg/^2 BSA on D1, D7, D14 of a 28-day cycle and erlotinib 100 mg p.o. once daily until progression or unacceptable toxicity). Only adverse event in these treatment periods with treatment with gemcitabin and erlotinib are taken into account. Those adverse events, experienced after Run-in while receiving FOLFIRINOX treatment, are not taken into account.

    Serious adverse events
    		 Continued treatment with gemcitabin/erlotinib after Run-in FOLFIRINOX after Run-in Gemcitabine and erlotinib overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 89 (47.19%)
    15 / 28 (53.57%)
    70 / 145 (48.28%)
         number of deaths (all causes)
    9
    2
    16
         number of deaths resulting from adverse events
    0
    1
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour associated fever
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
    Additional description: The pre-printed term was ""Thromboembolic events". Thus, the terms thrombosis, pulmonary embolism and jugular vein thrombosis are summarized under "Thrombosis".
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 28 (3.57%)
    6 / 145 (4.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical device implantation
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site haematoma
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 28 (0.00%)
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 28 (0.00%)
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 28 (7.14%)
    6 / 145 (4.14%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 2
    2 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    Impaired healing
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
    Additional description: Summarized pre-printed term "Pain" comprising summarized terms "Abdominal pain, back pain, chest pain, abdominal pain upper".
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 28 (7.14%)
    9 / 145 (6.21%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 28 (3.57%)
    5 / 145 (3.45%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
    Additional description: Summarized terms "Pneumonitis" and "Interstitial lung disease".
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 28 (3.57%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 28 (0.00%)
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 28 (0.00%)
    5 / 145 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
    Additional description: Terms "Blood bilirubin increased" and "jaundice"
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    5 / 145 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
    Additional description: Terms "Cachexia" and "Weight decreased"
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 28 (3.57%)
    0 / 145 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic complication
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 28 (3.57%)
    0 / 145 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
    Additional description: Summarized terms "Cerebrovascular accident" and "Cerebral infarction"
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 28 (3.57%)
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 28 (3.57%)
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 28 (3.57%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 28 (3.57%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 28 (3.57%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    2 / 89 (2.25%)
    2 / 28 (7.14%)
    4 / 145 (2.76%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 89 (3.37%)
    2 / 28 (7.14%)
    5 / 145 (3.45%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Duodenitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 28 (3.57%)
    0 / 145 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Bile duct stenosis
         subjects affected / exposed
    3 / 89 (3.37%)
    0 / 28 (0.00%)
    3 / 145 (2.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 28 (0.00%)
    5 / 145 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Perforation bile duct
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
    Additional description: The pre-printed term was infection without further differentiation. The term infection comprises among others also the terms "Cholangitis", "Peritonitis bacterial", "Atypical pneumonia".
         subjects affected / exposed
    16 / 89 (17.98%)
    3 / 28 (10.71%)
    22 / 145 (15.17%)
         occurrences causally related to treatment / all
    1 / 16
    1 / 4
    2 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 28 (0.00%)
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 28 (7.14%)
    0 / 145 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Continued treatment with gemcitabin/erlotinib after Run-in FOLFIRINOX after Run-in Gemcitabine and erlotinib overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    89 / 89 (100.00%)
    28 / 28 (100.00%)
    145 / 145 (100.00%)
    Investigations
    Weight decreased
         subjects affected / exposed
    26 / 89 (29.21%)
    13 / 28 (46.43%)
    37 / 145 (25.52%)
         occurrences all number
    30
    18
    45
    Blood bilirubin increased
         subjects affected / exposed
    31 / 89 (34.83%)
    4 / 28 (14.29%)
    51 / 145 (35.17%)
         occurrences all number
    33
    4
    54
    Blood alkaline phosphatase increased
         subjects affected / exposed
    26 / 89 (29.21%)
    9 / 28 (32.14%)
    38 / 145 (26.21%)
         occurrences all number
    28
    11
    40
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    12 / 89 (13.48%)
    2 / 28 (7.14%)
    15 / 145 (10.34%)
         occurrences all number
    15
    2
    18
    C-reactive protein increased
         subjects affected / exposed
    18 / 89 (20.22%)
    6 / 28 (21.43%)
    25 / 145 (17.24%)
         occurrences all number
    22
    8
    30
    Blood creatinine increased
         subjects affected / exposed
    21 / 89 (23.60%)
    4 / 28 (14.29%)
    28 / 145 (19.31%)
         occurrences all number
    26
    16
    33
    Gamma-glutamyltransferase increased
    Additional description: Terms "Gamma-glutamyltransferase" and "Gamma-glutamyltransferase increased"
         subjects affected / exposed
    52 / 89 (58.43%)
    21 / 28 (75.00%)
    79 / 145 (54.48%)
         occurrences all number
    60
    27
    89
    Protein total decreased
         subjects affected / exposed
    7 / 89 (7.87%)
    5 / 28 (17.86%)
    10 / 145 (6.90%)
         occurrences all number
    7
    6
    12
    Aspartate aminotransferase increased
         subjects affected / exposed
    21 / 89 (23.60%)
    4 / 28 (14.29%)
    30 / 145 (20.69%)
         occurrences all number
    21
    6
    32
    Hepatic enzyme increased
    Additional description: Summarized pre-printed term "Liver values increased (ALT)" and term "Hepatic enzyme increased" and term "Transaminases" and term "Alanine aminotransferase increased".
         subjects affected / exposed
    79 / 89 (88.76%)
    20 / 28 (71.43%)
    117 / 145 (80.69%)
         occurrences all number
    98
    27
    140
    Blood urea increased
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 28 (3.57%)
    5 / 145 (3.45%)
         occurrences all number
    6
    4
    6
    Vascular disorders
    Hypertension
    Additional description: Summarized terms "Hypertension" and "Blood pressure increased".
         subjects affected / exposed
    8 / 89 (8.99%)
    3 / 28 (10.71%)
    11 / 145 (7.59%)
         occurrences all number
    9
    3
    13
    Thrombosis
    Additional description: The pre-printed term was ""Thromboembolic events". Thus, the terms thrombosis, pulmonary embolism and jugular vein thrombosis are summarized under "Thrombosis".
         subjects affected / exposed
    8 / 89 (8.99%)
    4 / 28 (14.29%)
    11 / 145 (7.59%)
         occurrences all number
    10
    4
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 89 (11.24%)
    4 / 28 (14.29%)
    15 / 145 (10.34%)
         occurrences all number
    11
    4
    16
    Dysgeusia
         subjects affected / exposed
    7 / 89 (7.87%)
    3 / 28 (10.71%)
    13 / 145 (8.97%)
         occurrences all number
    8
    5
    14
    Peripheral sensory neuropathy
         subjects affected / exposed
    13 / 89 (14.61%)
    16 / 28 (57.14%)
    18 / 145 (12.41%)
         occurrences all number
    13
    35
    18
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    87 / 89 (97.75%)
    25 / 28 (89.29%)
    135 / 145 (93.10%)
         occurrences all number
    90
    33
    143
    Leukopenia
         subjects affected / exposed
    63 / 89 (70.79%)
    10 / 28 (35.71%)
    98 / 145 (67.59%)
         occurrences all number
    88
    22
    130
    Neutropenia
         subjects affected / exposed
    26 / 89 (29.21%)
    7 / 28 (25.00%)
    38 / 145 (26.21%)
         occurrences all number
    31
    18
    46
    Lymphopenia
    Additional description: Summarized terms "Lymphopenia" and "Lymphocyte count decreased".
         subjects affected / exposed
    9 / 89 (10.11%)
    4 / 28 (14.29%)
    13 / 145 (8.97%)
         occurrences all number
    11
    4
    15
    Thrombocytopenia
         subjects affected / exposed
    51 / 89 (57.30%)
    14 / 28 (50.00%)
    96 / 145 (66.21%)
         occurrences all number
    65
    22
    125
    Thrombocytosis
         subjects affected / exposed
    6 / 89 (6.74%)
    5 / 28 (17.86%)
    8 / 145 (5.52%)
         occurrences all number
    6
    6
    8
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    6 / 89 (6.74%)
    0 / 28 (0.00%)
    9 / 145 (6.21%)
         occurrences all number
    6
    0
    9
    Fatigue
         subjects affected / exposed
    48 / 89 (53.93%)
    19 / 28 (67.86%)
    89 / 145 (61.38%)
         occurrences all number
    55
    43
    97
    Feeling cold
         subjects affected / exposed
    3 / 89 (3.37%)
    2 / 28 (7.14%)
    3 / 145 (2.07%)
         occurrences all number
    4
    2
    4
    General physical health deterioration
         subjects affected / exposed
    4 / 89 (4.49%)
    3 / 28 (10.71%)
    10 / 145 (6.90%)
         occurrences all number
    5
    3
    11
    Oedema peripheral
    Additional description: Terms "Oedema peripheral" and "Oedema lower leg"
         subjects affected / exposed
    26 / 89 (29.21%)
    8 / 28 (28.57%)
    40 / 145 (27.59%)
         occurrences all number
    39
    10
    47
    Pain
    Additional description: Summarized pre-printed term "Pain" comprising summarized terms "Abdominal pain, back pain, chest pain, abdominal pain upper" et others.
         subjects affected / exposed
    54 / 89 (60.67%)
    23 / 28 (82.14%)
    104 / 145 (71.72%)
         occurrences all number
    67
    34
    123
    Pyrexia
         subjects affected / exposed
    16 / 89 (17.98%)
    3 / 28 (10.71%)
    27 / 145 (18.62%)
         occurrences all number
    20
    3
    32
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    23 / 89 (25.84%)
    6 / 28 (21.43%)
    35 / 145 (24.14%)
         occurrences all number
    29
    15
    42
    Diarrhoea
         subjects affected / exposed
    30 / 89 (33.71%)
    13 / 28 (46.43%)
    59 / 145 (40.69%)
         occurrences all number
    35
    23
    69
    Ascites
         subjects affected / exposed
    6 / 89 (6.74%)
    1 / 28 (3.57%)
    7 / 145 (4.83%)
         occurrences all number
    7
    1
    8
    Dry mouth
         subjects affected / exposed
    4 / 89 (4.49%)
    2 / 28 (7.14%)
    8 / 145 (5.52%)
         occurrences all number
    4
    2
    8
    Dyspepsia
         subjects affected / exposed
    6 / 89 (6.74%)
    2 / 28 (7.14%)
    8 / 145 (5.52%)
         occurrences all number
    7
    3
    10
    Stomatitis
    Additional description: The term "Stomatitis" comprises stomatitis and mucositis at another site.
         subjects affected / exposed
    14 / 89 (15.73%)
    8 / 28 (28.57%)
    26 / 145 (17.93%)
         occurrences all number
    15
    19
    27
    Nausea
         subjects affected / exposed
    49 / 89 (55.06%)
    23 / 28 (82.14%)
    82 / 145 (56.55%)
         occurrences all number
    59
    43
    96
    Vomiting
         subjects affected / exposed
    21 / 89 (23.60%)
    13 / 28 (46.43%)
    36 / 145 (24.83%)
         occurrences all number
    23
    16
    43
    Flatulence
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 28 (0.00%)
    5 / 145 (3.45%)
         occurrences all number
    5
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 89 (6.74%)
    2 / 28 (7.14%)
    6 / 145 (4.14%)
         occurrences all number
    6
    2
    6
    Dyspnoea
         subjects affected / exposed
    14 / 89 (15.73%)
    5 / 28 (17.86%)
    17 / 145 (11.72%)
         occurrences all number
    17
    5
    20
    Epistaxis
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 28 (0.00%)
    7 / 145 (4.83%)
         occurrences all number
    5
    0
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    22 / 89 (24.72%)
    10 / 28 (35.71%)
    25 / 145 (17.24%)
         occurrences all number
    23
    20
    27
    Dry skin
         subjects affected / exposed
    13 / 89 (14.61%)
    5 / 28 (17.86%)
    19 / 145 (13.10%)
         occurrences all number
    16
    10
    23
    Night sweats
         subjects affected / exposed
    4 / 89 (4.49%)
    1 / 28 (3.57%)
    8 / 145 (5.52%)
         occurrences all number
    4
    1
    8
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 89 (5.62%)
    4 / 28 (14.29%)
    6 / 145 (4.14%)
         occurrences all number
    6
    7
    7
    Pruritus
         subjects affected / exposed
    10 / 89 (11.24%)
    2 / 28 (7.14%)
    21 / 145 (14.48%)
         occurrences all number
    11
    2
    22
    Rash
         subjects affected / exposed
    15 / 89 (16.85%)
    3 / 28 (10.71%)
    17 / 145 (11.72%)
         occurrences all number
    19
    3
    23
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 89 (2.25%)
    2 / 28 (7.14%)
    2 / 145 (1.38%)
         occurrences all number
    2
    3
    2
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    6 / 89 (6.74%)
    0 / 28 (0.00%)
    6 / 145 (4.14%)
         occurrences all number
    8
    0
    8
    Infections and infestations
    Infection
    Additional description: The pre-printed term was infection without further differentiation. The term "Infection" comprises among others also the terms "Cholangitis", "Peritonitis bacterial", "Atypical pneumonia".
         subjects affected / exposed
    21 / 89 (23.60%)
    3 / 28 (10.71%)
    35 / 145 (24.14%)
         occurrences all number
    24
    3
    38
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    31 / 89 (34.83%)
    6 / 28 (21.43%)
    47 / 145 (32.41%)
         occurrences all number
    38
    11
    56
    Hypokalaemia
    Additional description: Summarized terms "Hypokalaemia" and "Blood potassium decreased".
         subjects affected / exposed
    5 / 89 (5.62%)
    6 / 28 (21.43%)
    12 / 145 (8.28%)
         occurrences all number
    6
    12
    14
    Hyperglycaemia
    Additional description: Summarized terms "Hyperglycaemia" and "Blood glucose increased".
         subjects affected / exposed
    2 / 89 (2.25%)
    3 / 28 (10.71%)
    5 / 145 (3.45%)
         occurrences all number
    2
    4
    5
    Hyponatraemia
    Additional description: Summarized terms "Hyponatraemia" and "Blood sodium decreased".
         subjects affected / exposed
    7 / 89 (7.87%)
    6 / 28 (21.43%)
    9 / 145 (6.21%)
         occurrences all number
    8
    6
    9
    Hypocalcaemia
         subjects affected / exposed
    2 / 89 (2.25%)
    2 / 28 (7.14%)
    3 / 145 (2.07%)
         occurrences all number
    3
    3
    4
    Hypoalbuminaemia
    Additional description: Summarized terms "Hypoalbuminaemia" and "Blood albumin decreased".
         subjects affected / exposed
    12 / 89 (13.48%)
    3 / 28 (10.71%)
    14 / 145 (9.66%)
         occurrences all number
    13
    7
    16

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

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

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