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    Clinical Trial Results:
    RAMSES / FLOT7 Perioperative RAMucirumab in combination with FLOT versus FLOT alone for reSEctable eSophagogastric adenocarcinoma RAMSES - a phase II/III trial of the AIO

    Summary
    EudraCT number
    		 2015-003118-26
    Trial protocol
    		 DE   IT  
    Global end of trial date
    20 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2023
    First version publication date
    23 Sep 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RAMSES/FLOT7
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02661971
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
    Sponsor organisation address
    Steinbacher Hohl 2-26, Frankfurt am Main Mitte-West, Frankfurt am Main, Germany, 60488
    Public contact
    Dr. Claudia Pauligk, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest, info@ikf-khnw.de
    Scientific contact
    Dr. Claudia Pauligk, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest, info@ikf-khnw.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
    22 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of this trial was to evaluate the efficacy and safety of the combination of perioperative FLOT with the anti-VEGFR antibody ramucirumab in patients with resectable esophagogastric adenocarcinoma.
    Protection of trial subjects
    This clinical study was designed and shall be implemented and reported in accordance with the protocol, the AMG (Arzneimittelgesetz), the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki. The trial was authorized/approved by the competent authority (Paul-Ehrlich-Institut, PEI) and the competent ethics committee responsible for the trial (“federführende Ethikkommission”). Before recruitment into the clinical trial, each patient was informed that participation in the study is completely voluntary, and that he or she may withdraw his or her participation in the trial at any time without any declaration of reasons, which will not lead to any disadvantage for the respective patient. The eligibility of a new patient was determined by the local investigator during regular clinical visits. The examinations for the study and the inclusion of the patient were done after detailed written and oral education about aims, methods, anticipated benefits and potential hazards of the study by use of the informed consent forms and after given written consent of the patient. Safety of FLOT/Ramucirumab was monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported. An independent data safety and monitoring board (DSMB) was responsible for assessment of reports summarizing safety data or study results and gave recommendations for planned protocol amendments.
    Background therapy
    		 -
    Evidence for comparator
    		 FLOT, a docetaxel-based triple combination consisting of 5-FU, leucovorin, oxaliplatin and docetaxel, is one of the most intensively evaluated regimen for gastric and GEJ cancer. It has been evaluated in the perooperative setting, the metastatic and limited metastatic settings, in elderly and in operable patients. FLOT is regarded as a standard chemotherapy regimen for gastric cancer in Germany. Ramucirumab is a human monoclonal antibody that specifically binds VEGF-R2. The binding of ramucirumab to VEGF-R2 prevents its interaction with the activating ligands VEGF-A, VEGF-C, and VEGF-D. Ramucirumab was approved for advanced or metastatic esophagogastric adenocarcinoma after previous chemotherapy.
    Actual start date of recruitment
    12 Jul 2016
    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
    Germany: 170
    Country: Number of subjects enrolled
    Italy: 10
    Worldwide total number of subjects
    180
    EEA total number of subjects
    180
    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)
    130
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 180 patients for enrolled the phase II part between JULY 2016 and NOV 2019 in 50 centres in Germany and 10 centres in Italy. Approx. 758 additional patients were planned for phase III. However, the trial was terminated after phase II part and not transitioned into phase III.

    Pre-assignment
    Screening details
    		 Patients with locally advanced adenocarcinoma of the stomach and gastroesophageal junction type I-III (i.e. cT2 any N or any T N-positive) with exclusion of distant metastases were included in this trial. Due to safety concerns, patients with GEJ type I as well as with planned transthoracic esophagectomy at study entry were excluded after NOV2017

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - FLOT
    Arm description
    		 4 pre-operative treatments of FLOT (docetaxel, oxaliplatin, leucovorin & 5-fluorouracil) on d1, d15, d29 and d43, plus additional 4 post-operative FLOT treatments after surgery (start 6 to 8 weeks after surgery) on d1, d15, d29, d43 of the post-operative treatment phase
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Administration 50 mg/m², iv over 1 h d1, d15, d29, d43 pre- and post-operative

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Infusion , Injection
    Dosage and administration details
    85 mg/m² in 500 ml 5% Glucose, iv over 2h

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    folinic acid
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Infusion , Injection
    Dosage and administration details
    200 mg/m² in 250 ml NaCl 0.9%, iv over 30 min

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    5-FU
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Injection , Infusion
    Dosage and administration details
    2600 mg/m², iv over 24 h

    Arm title
    		 Arm B - FLOT/Ramucirumab
    Arm description
    		 Patients received Ramucirumab at indicated days as well as the FLOT regimen, which was administered identical to Arm A as described above. Surgery in Arm B was planned to occur 4 to 6 weeks after d1 of last FLOT/ramucirumab dose (but never earlier than 4 weeks after d1 of last FLOT/ramucirumab dose). Patients received FLOT + Ramucirumab for 8 weeks in the post-operative treatment phase followed by 16 additional doses of Ramucirumab as a monotherapy every 2 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Administration 50 mg/m², iv over 1 h d1, d15, d29, d43 pre- and post-operative

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Infusion , Injection
    Dosage and administration details
    85 mg/m² in 500 ml 5% Glucose, iv over 2h

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    folinic acid
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Infusion , Injection
    Dosage and administration details
    200 mg/m² in 250 ml NaCl 0.9%, iv over 30 min

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    5-FU
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Infusion , Injection
    Dosage and administration details
    2600 mg/m², iv over 24 h

    Investigational medicinal product name
    Ramucirumab
    Investigational medicinal product code
    SUB32795
    Other name
    Cyramza
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    8mg/kg, iv over 1 h, d1

    Number of subjects in period 1
    		Arm A - FLOT Arm B - FLOT/Ramucirumab
    Started
    91
    89
    started pre-OP treatment
    90
    88
    underwent surgery
    85
    87
    started post-OP treatment
    57
    64
    started maintenance
    0 [1]
    43
    Completed
    46
    24
    Not completed
    45
    65
         Consent withdrawn by subject
    13
    18
         Physician decision
    1
    3
         death
    3
    9
         Adverse event, non-fatal
    14
    19
         unplanned hospitalization
    -
    1
         histological report from 26.09.2017 declared no ca
    1
    -
         Lost to follow-up
    1
    -
         Sponsor decision
    -
    4
         Lack of efficacy
    12
    11
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: No maintenance phase was planned in Arm A

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - FLOT
    Reporting group description
    		 4 pre-operative treatments of FLOT (docetaxel, oxaliplatin, leucovorin & 5-fluorouracil) on d1, d15, d29 and d43, plus additional 4 post-operative FLOT treatments after surgery (start 6 to 8 weeks after surgery) on d1, d15, d29, d43 of the post-operative treatment phase

    Reporting group title
    Arm B - FLOT/Ramucirumab
    Reporting group description
    		 Patients received Ramucirumab at indicated days as well as the FLOT regimen, which was administered identical to Arm A as described above. Surgery in Arm B was planned to occur 4 to 6 weeks after d1 of last FLOT/ramucirumab dose (but never earlier than 4 weeks after d1 of last FLOT/ramucirumab dose). Patients received FLOT + Ramucirumab for 8 weeks in the post-operative treatment phase followed by 16 additional doses of Ramucirumab as a monotherapy every 2 weeks.

    Reporting group values
    		 Arm A - FLOT Arm B - FLOT/Ramucirumab Total
    Number of subjects
    		 91 89 180
    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))
    		 51 (35 to 70) 60 (36 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24 48
        Male
    		 67 65 132
    ECOG
    Units: Subjects
        ECOG 0
    		 73 59 132
        ECOG 1
    		 18 30 48
    Primary localisation
    Adenocarcinomas of the gastro-esophageal junction were classified according to the Siewert classification as tumors having their center 5 cm proximal or distal of the anatomical cardia
    Units: Subjects
        GEJ type I
    		 12 16 28
        GEJ type II
    		 29 24 53
        GEJ type III
    		 7 8 15
        Stomach, corpus or antrum
    		 43 41 84
    cT stage
    Clinical tumor stage (cT) and clinical nodal (cN) stage were assessed by endoscopic ultrasound and CT or MRI and classified according to the seventh version of the International Union against Cancer tumor–node–metastasis classification
    Units: Subjects
        T1
    		 0 1 1
        T2
    		 17 13 30
        T3
    		 70 67 137
        T4
    		 2 2 4
        T4a
    		 2 6 8
    cN stage
    Clinical tumor stage (cT) and clinical nodal (cN) stage were assessed by endoscopic ultrasound and CT or MRI and classified according to the seventh version of the International Union against Cancer tumor–node–metastasis classification.
    Units: Subjects
        N-
    		 23 17 40
        N+
    		 68 72 140
    Barrett's carcinoma
    Barrett's carcinoma was defined as the presence of Barrett's mucosa in tumors of the gastro-esophageal junction as assessed by either baseline endoscopy or pathological examination. Stomach tumors were automatically regarded non-Barrett
    Units: Subjects
        Yes
    		 10 8 18
        No
    		 72 77 149
        Unclear
    		 6 4 10
        Missing
    		 3 0 3
    Lauren's type
    Units: Subjects
        Diffuse
    		 36 30 66
        Intestinal
    		 31 33 64
        Mixed
    		 11 9 20
        Not evaluable acc. to Lauren
    		 8 14 22
        Missing
    		 5 3 8
    Signet-ring cells
    Defined as the presence of any signet-ring cells.
    Units: Subjects
        Yes
    		 39 33 72
        No
    		 50 54 104
        Missing
    		 2 2 4
    Grading according to WHO
    WHO grading increases with the lack of cellular differentiation, reflecting how much the tumor cells differ from the cells of the normal tissue they have originated from
    Units: Subjects
        G1
    		 4 3 7
        G2
    		 22 27 49
        G3
    		 58 54 112
        Missing
    		 7 5 12
    HER2 status
    Units: Subjects
        HER2 positive
    		 2 0 2
        HER2 negative
    		 87 85 172
        Missing
    		 2 4 6
    Subject analysis sets

    Subject analysis set title
    mITT Arm A
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    includes all patients in Arm A who were randomized except for those with GEJ type I or in whom transthoracic esophagectomy was planned at study entry.

    Subject analysis set title
    mITT Arm B
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    includes all patients in Arm B who were randomized except for those with GEJ type I or in whom transthoracic esophagectomy was planned at study entry.

    Subject analysis sets values
    		 mITT Arm A mITT Arm B
    Number of subjects
    79
    73
    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))
    59 (35 to 70)
    61 (36 to 70)
    Gender categorical
    Units: Subjects
        Female
    23
    23
        Male
    56
    50
    ECOG
    Units: Subjects
        ECOG 0
    63
    50
        ECOG 1
    16
    23
    Primary localisation
    Adenocarcinomas of the gastro-esophageal junction were classified according to the Siewert classification as tumors having their center 5 cm proximal or distal of the anatomical cardia
    Units: Subjects
        GEJ type I
    0
    0
        GEJ type II
    29
    24
        GEJ type III
    7
    8
        Stomach, corpus or antrum
    43
    41
    cT stage
    Clinical tumor stage (cT) and clinical nodal (cN) stage were assessed by endoscopic ultrasound and CT or MRI and classified according to the seventh version of the International Union against Cancer tumor–node–metastasis classification
    Units: Subjects
        T1
    0
    1
        T2
    15
    12
        T3
    60
    54
        T4
    2
    1
        T4a
    2
    5
    cN stage
    Clinical tumor stage (cT) and clinical nodal (cN) stage were assessed by endoscopic ultrasound and CT or MRI and classified according to the seventh version of the International Union against Cancer tumor–node–metastasis classification.
    Units: Subjects
        N-
    20
    15
        N+
    59
    58
    Barrett's carcinoma
    Barrett's carcinoma was defined as the presence of Barrett's mucosa in tumors of the gastro-esophageal junction as assessed by either baseline endoscopy or pathological examination. Stomach tumors were automatically regarded non-Barrett
    Units: Subjects
        Yes
    2
    4
        No
    68
    67
        Unclear
    6
    2
        Missing
    3
    0
    Lauren's type
    Units: Subjects
        Diffuse
    36
    28
        Intestinal
    24
    24
        Mixed
    9
    8
        Not evaluable acc. to Lauren
    7
    11
        Missing
    3
    2
    Signet-ring cells
    Defined as the presence of any signet-ring cells.
    Units: Subjects
        Yes
    37
    31
        No
    40
    41
        Missing
    2
    1
    Grading according to WHO
    WHO grading increases with the lack of cellular differentiation, reflecting how much the tumor cells differ from the cells of the normal tissue they have originated from
    Units: Subjects
        G1
    2
    3
        G2
    17
    17
        G3
    53
    49
        Missing
    7
    4
    HER2 status
    Units: Subjects
        HER2 positive
    0
    0
        HER2 negative
    77
    69
        Missing
    2
    4

    End points

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    End points reporting groups
    Reporting group title
    Arm A - FLOT
    Reporting group description
    		 4 pre-operative treatments of FLOT (docetaxel, oxaliplatin, leucovorin & 5-fluorouracil) on d1, d15, d29 and d43, plus additional 4 post-operative FLOT treatments after surgery (start 6 to 8 weeks after surgery) on d1, d15, d29, d43 of the post-operative treatment phase

    Reporting group title
    Arm B - FLOT/Ramucirumab
    Reporting group description
    		 Patients received Ramucirumab at indicated days as well as the FLOT regimen, which was administered identical to Arm A as described above. Surgery in Arm B was planned to occur 4 to 6 weeks after d1 of last FLOT/ramucirumab dose (but never earlier than 4 weeks after d1 of last FLOT/ramucirumab dose). Patients received FLOT + Ramucirumab for 8 weeks in the post-operative treatment phase followed by 16 additional doses of Ramucirumab as a monotherapy every 2 weeks.

    Subject analysis set title
    mITT Arm A
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    includes all patients in Arm A who were randomized except for those with GEJ type I or in whom transthoracic esophagectomy was planned at study entry.

    Subject analysis set title
    mITT Arm B
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    includes all patients in Arm B who were randomized except for those with GEJ type I or in whom transthoracic esophagectomy was planned at study entry.

    Primary: Pathological complete and subtotal response

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    End point title
    		 Pathological complete and subtotal response
    End point description
    The pathological complete response (pCR) and subtotal response (pSR) rate was chosen as primary endpoint for the phase II part of the trial and was defined as the proportion of patients with pCR as evaluated blinded by central pathologist referring to the total number of patients of the
    End point type
    Primary
    End point timeframe
    The relevant time point for the primary study endpoint was reached upon completion of surgery. Patients with a pCR or pSR at this timepoint added to the rate of the primary endpoint.
    End point values
    		 Arm A - FLOT Arm B - FLOT/Ramucirumab mITT Arm A mITT Arm B
    Number of subjects analysed
    91
    89
    79
    73
    Units: Subjects
        Yes
    28
    24
    23
    19
        No
    63
    65
    56
    54
    Statistical analysis title
    		 Fisher Exact Test
    Comparison groups
    mITT Arm A v mITT Arm B
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.719
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Margin-free (R0) resection

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    End point title
    		 Margin-free (R0) resection
    End point description
    R0 resection rate was defined as the percentage of patients achieving a R0 (margin-free) resection referring to the total number of patients randomized into the respective treatment arm
    End point type
    Secondary
    End point timeframe
    The relevant time point was reached upon completion of surgery
    End point values
    		 Arm A - FLOT Arm B - FLOT/Ramucirumab mITT Arm A mITT Arm B
    Number of subjects analysed
    91
    89
    79
    73
    Units: Subjects
        Yes
    75
    86
    65
    70
        No
    16
    3
    14
    3
    Statistical analysis title
    		 Fisher Exact Test
    Comparison groups
    mITT Arm A v mITT Arm B
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.009
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Disease-free survival

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    End point title
    		 Disease-free survival
    End point description
    End point type
    Secondary
    End point timeframe
    defined as time from randomization to disease progression, relapse or death
    End point values
    		 Arm A - FLOT Arm B - FLOT/Ramucirumab mITT Arm A mITT Arm B
    Number of subjects analysed
    91
    89
    79
    73
    Units: month
        median (confidence interval 95%)
    20.5 (15.0 to 38.7)
    31.3 (22.4 to 46)
    20.5 (12.7 to 42.7)
    31.9 (23.9 to 999999999)
    Attachments
    		 DFS mITT
    Statistical analysis title
    		 Log Rank Test
    Comparison groups
    mITT Arm B v mITT Arm A
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.248
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.765
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.21

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    OS defined as time from randomization to death;
    End point values
    		 Arm A - FLOT Arm B - FLOT/Ramucirumab mITT Arm A mITT Arm B
    Number of subjects analysed
    91
    89
    79
    73
    Units: month
        median (confidence interval 95%)
    45.2 (24.9 to 9999999)
    45.8 (26.8 to 9999999)
    45.2 (24.9 to 9999999)
    45.8 (26.7 to 999999999)
    Attachments
    		 OS mITT
    Statistical analysis title
    		 Log Rank Test
    Comparison groups
    mITT Arm A v mITT Arm B
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.749
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.923
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.565
         upper limit
    		 1.509

    Secondary: Surigcal morbidity

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    End point title
    		 Surigcal morbidity
    End point description
    End point type
    Secondary
    End point timeframe
    upto 60 days from surgery
    End point values
    		 Arm A - FLOT Arm B - FLOT/Ramucirumab mITT Arm A mITT Arm B
    Number of subjects analysed
    85
    87
    74
    71
    Units: subjects
        Any surgical or medical complication
    30
    39
    24
    29
    No statistical analyses for this end point

    Secondary: Surgical mortality

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    End point title
    		 Surgical mortality
    End point description
    End point type
    Secondary
    End point timeframe
    upto 60 days from surgery
    End point values
    		 Arm A - FLOT Arm B - FLOT/Ramucirumab mITT Arm A mITT Arm B
    Number of subjects analysed
    85
    87
    74
    71
    Units: Subjects
        Mortality at 30 days post OP
    1
    3
    1
    2
        Mortality at 60 dyas post OP
    3
    4
    3
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    after patient has given written informed consent until at least 30 days after the last dose of study treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Arm A safety population
    Reporting group description
    		 include all patients in Arm A who received at least one dose of study treatment

    Reporting group title
    Arm B safety population
    Reporting group description
    		 included all patients in Arm B who received at least one dose of study treatment

    Reporting group title
    Arm A safety population excluding GEJ I
    Reporting group description
    		 includes all patients in Arm A who received at least one dose of study treatment except for those with GEJ type I or in whom transthoracic esophagectomy was planned at study entry.

    Reporting group title
    Arm B safety population excluding GEJ I
    Reporting group description
    		 includes all patients in Arm B who were randomized except for those with GEJ type I or in whom transthoracic esophagectomy was planned at study entry.

    Serious adverse events
    		 Arm A safety population Arm B safety population Arm A safety population excluding GEJ I Arm B safety population excluding GEJ I
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 90 (50.00%)
    67 / 88 (76.14%)
    40 / 79 (50.63%)
    54 / 72 (75.00%)
         number of deaths (all causes)
    40
    39
    34
    30
         number of deaths resulting from adverse events
    4
    12
    4
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leptomeningeal spread
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 88 (2.27%)
    1 / 79 (1.27%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 88 (2.27%)
    0 / 79 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Visceral arterial ischemia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abcess after surgery
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prolonged hospitalisation after surgery
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 88 (0.00%)
    2 / 79 (2.53%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 88 (2.27%)
    1 / 79 (1.27%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    6 / 90 (6.67%)
    7 / 88 (7.95%)
    6 / 79 (7.59%)
    7 / 72 (9.72%)
         occurrences causally related to treatment / all
    3 / 6
    3 / 7
    3 / 6
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flu like symptoms
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess on the pancreatic upper margin
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Collaps event
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    obstruction of implanted port
    Additional description: haematoma, fever
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain exacerbation
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Port obstruction
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 88 (2.27%)
    2 / 79 (2.53%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ disorder
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pain
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 88 (1.14%)
    1 / 79 (1.27%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial fistula
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Chylothorax
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural haemorrhage
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 88 (1.14%)
    2 / 79 (2.53%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic empyema
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 88 (1.14%)
    1 / 79 (1.27%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight loss
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 88 (0.00%)
    2 / 79 (2.53%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    6 / 90 (6.67%)
    10 / 88 (11.36%)
    5 / 79 (6.33%)
    6 / 72 (8.33%)
         occurrences causally related to treatment / all
    0 / 7
    3 / 10
    0 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 1
    Postoperative lymphatic fistula
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    postoperative haemorrhage
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 88 (2.27%)
    0 / 79 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Circulatory dysregulation
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    malignant cardiac arrhythmias
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epileptical attack
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal epilepsy
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 88 (2.27%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Extraocular muscle paresis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 88 (2.27%)
    2 / 79 (2.53%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 90 (3.33%)
    4 / 88 (4.55%)
    3 / 79 (3.80%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 4
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 90 (2.22%)
    5 / 88 (5.68%)
    2 / 79 (2.53%)
    5 / 72 (6.94%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 88 (0.00%)
    2 / 79 (2.53%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 88 (2.27%)
    1 / 79 (1.27%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 88 (1.14%)
    2 / 79 (2.53%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jejunal stenosis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucositis oral
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 90 (3.33%)
    2 / 88 (2.27%)
    3 / 79 (3.80%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 2
    4 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal mucositis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 90 (1.11%)
    5 / 88 (5.68%)
    0 / 79 (0.00%)
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 6
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abcess left hepatic lobe
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 88 (3.41%)
    0 / 79 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Bladder stone
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spondylolisthesis cervical
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 88 (1.14%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    2 / 90 (2.22%)
    4 / 88 (4.55%)
    1 / 79 (1.27%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 88 (2.27%)
    0 / 79 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 88 (0.00%)
    2 / 79 (2.53%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising pancreatitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Port infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis transient
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 88 (2.27%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    infection unknown origin
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 88 (2.27%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 90 (3.33%)
    3 / 88 (3.41%)
    2 / 79 (2.53%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Mucosal infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 88 (3.41%)
    1 / 79 (1.27%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 88 (1.14%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 90 (1.11%)
    5 / 88 (5.68%)
    1 / 79 (1.27%)
    3 / 72 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 6
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 88 (0.00%)
    1 / 79 (1.27%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A safety population Arm B safety population Arm A safety population excluding GEJ I Arm B safety population excluding GEJ I
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    88 / 90 (97.78%)
    88 / 88 (100.00%)
    77 / 79 (97.47%)
    72 / 72 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 90 (4.44%)
    11 / 88 (12.50%)
    4 / 79 (5.06%)
    11 / 72 (15.28%)
         occurrences all number
    4
    16
    4
    16
    Thromboembolic event
         subjects affected / exposed
    6 / 90 (6.67%)
    6 / 88 (6.82%)
    5 / 79 (6.33%)
    6 / 72 (8.33%)
         occurrences all number
    6
    8
    5
    8
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    5 / 90 (5.56%)
    8 / 88 (9.09%)
    5 / 79 (6.33%)
    8 / 72 (11.11%)
         occurrences all number
    5
    8
    5
    8
    Edema limbs
         subjects affected / exposed
    6 / 90 (6.67%)
    16 / 88 (18.18%)
    4 / 79 (5.06%)
    15 / 72 (20.83%)
         occurrences all number
    6
    25
    4
    24
    Fatigue
         subjects affected / exposed
    52 / 90 (57.78%)
    48 / 88 (54.55%)
    44 / 79 (55.70%)
    42 / 72 (58.33%)
         occurrences all number
    111
    109
    87
    96
    Fever
         subjects affected / exposed
    23 / 90 (25.56%)
    24 / 88 (27.27%)
    19 / 79 (24.05%)
    20 / 72 (27.78%)
         occurrences all number
    28
    29
    24
    25
    Pain
         subjects affected / exposed
    21 / 90 (23.33%)
    30 / 88 (34.09%)
    15 / 79 (18.99%)
    27 / 72 (37.50%)
         occurrences all number
    34
    52
    26
    46
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    4 / 90 (4.44%)
    7 / 88 (7.95%)
    4 / 79 (5.06%)
    5 / 72 (6.94%)
         occurrences all number
    4
    9
    4
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 90 (8.89%)
    7 / 88 (7.95%)
    4 / 79 (5.06%)
    5 / 72 (6.94%)
         occurrences all number
    8
    8
    4
    6
    Dyspnoea
         subjects affected / exposed
    4 / 90 (4.44%)
    8 / 88 (9.09%)
    2 / 79 (2.53%)
    6 / 72 (8.33%)
         occurrences all number
    6
    14
    2
    6
    Epistaxis
         subjects affected / exposed
    8 / 90 (8.89%)
    20 / 88 (22.73%)
    5 / 79 (6.33%)
    15 / 72 (20.83%)
         occurrences all number
    9
    24
    5
    19
    Pleural effusion
         subjects affected / exposed
    6 / 90 (6.67%)
    18 / 88 (20.45%)
    2 / 79 (2.53%)
    13 / 72 (18.06%)
         occurrences all number
    7
    24
    2
    20
    Pneumonitis
         subjects affected / exposed
    3 / 90 (3.33%)
    2 / 88 (2.27%)
    3 / 79 (3.80%)
    1 / 72 (1.39%)
         occurrences all number
    3
    2
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 90 (4.44%)
    5 / 88 (5.68%)
    2 / 79 (2.53%)
    2 / 72 (2.78%)
         occurrences all number
    5
    7
    2
    4
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    36 / 90 (40.00%)
    44 / 88 (50.00%)
    28 / 79 (35.44%)
    34 / 72 (47.22%)
         occurrences all number
    72
    84
    57
    61
    Platelet count decreased
         subjects affected / exposed
    6 / 90 (6.67%)
    9 / 88 (10.23%)
    4 / 79 (5.06%)
    7 / 72 (9.72%)
         occurrences all number
    9
    13
    7
    12
    Weight loss
         subjects affected / exposed
    16 / 90 (17.78%)
    17 / 88 (19.32%)
    15 / 79 (18.99%)
    14 / 72 (19.44%)
         occurrences all number
    18
    23
    17
    20
    White blood cell count decreased
         subjects affected / exposed
    36 / 90 (40.00%)
    33 / 88 (37.50%)
    29 / 79 (36.71%)
    25 / 72 (34.72%)
         occurrences all number
    87
    53
    74
    40
    Injury, poisoning and procedural complications
    Wound complication
         subjects affected / exposed
    1 / 90 (1.11%)
    5 / 88 (5.68%)
    1 / 79 (1.27%)
    5 / 72 (6.94%)
         occurrences all number
    1
    7
    1
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 90 (4.44%)
    10 / 88 (11.36%)
    4 / 79 (5.06%)
    9 / 72 (12.50%)
         occurrences all number
    5
    12
    5
    12
    Dysgeusia
         subjects affected / exposed
    14 / 90 (15.56%)
    12 / 88 (13.64%)
    11 / 79 (13.92%)
    12 / 72 (16.67%)
         occurrences all number
    15
    15
    12
    15
    Headache
         subjects affected / exposed
    5 / 90 (5.56%)
    8 / 88 (9.09%)
    3 / 79 (3.80%)
    7 / 72 (9.72%)
         occurrences all number
    5
    10
    3
    8
    Paraesthesia
         subjects affected / exposed
    21 / 90 (23.33%)
    22 / 88 (25.00%)
    18 / 79 (22.78%)
    15 / 72 (20.83%)
         occurrences all number
    40
    46
    34
    38
    Peripheral sensory neuropathy
         subjects affected / exposed
    36 / 90 (40.00%)
    37 / 88 (42.05%)
    29 / 79 (36.71%)
    29 / 72 (40.28%)
         occurrences all number
    71
    74
    55
    66
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 90 (22.22%)
    10 / 88 (11.36%)
    19 / 79 (24.05%)
    10 / 72 (13.89%)
         occurrences all number
    25
    11
    19
    10
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    5 / 90 (5.56%)
    3 / 88 (3.41%)
    4 / 79 (5.06%)
    2 / 72 (2.78%)
         occurrences all number
    9
    4
    7
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    17 / 90 (18.89%)
    16 / 88 (18.18%)
    14 / 79 (17.72%)
    15 / 72 (20.83%)
         occurrences all number
    23
    24
    22
    24
    Ascites
         subjects affected / exposed
    0 / 90 (0.00%)
    5 / 88 (5.68%)
    0 / 79 (0.00%)
    4 / 72 (5.56%)
         occurrences all number
    0
    5
    0
    0
    Constipation
         subjects affected / exposed
    19 / 90 (21.11%)
    19 / 88 (21.59%)
    15 / 79 (18.99%)
    14 / 72 (19.44%)
         occurrences all number
    20
    22
    16
    17
    Diarrhoea
         subjects affected / exposed
    58 / 90 (64.44%)
    52 / 88 (59.09%)
    52 / 79 (65.82%)
    42 / 72 (58.33%)
         occurrences all number
    121
    152
    99
    128
    Dyspepsia
         subjects affected / exposed
    5 / 90 (5.56%)
    3 / 88 (3.41%)
    4 / 79 (5.06%)
    2 / 72 (2.78%)
         occurrences all number
    5
    3
    4
    2
    Dysphagia
         subjects affected / exposed
    9 / 90 (10.00%)
    7 / 88 (7.95%)
    10 / 79 (12.66%)
    8 / 72 (11.11%)
         occurrences all number
    11
    10
    10
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 90 (5.56%)
    6 / 88 (6.82%)
    5 / 79 (6.33%)
    5 / 72 (6.94%)
         occurrences all number
    8
    7
    7
    6
    Mucositis oral
         subjects affected / exposed
    27 / 90 (30.00%)
    29 / 88 (32.95%)
    25 / 79 (31.65%)
    25 / 72 (34.72%)
         occurrences all number
    45
    50
    36
    47
    Nausea
         subjects affected / exposed
    55 / 90 (61.11%)
    56 / 88 (63.64%)
    46 / 79 (58.23%)
    51 / 72 (70.83%)
         occurrences all number
    128
    142
    107
    132
    Vomiting
         subjects affected / exposed
    22 / 90 (24.44%)
    33 / 88 (37.50%)
    15 / 79 (18.99%)
    34 / 72 (47.22%)
         occurrences all number
    39
    65
    28
    61
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    47 / 90 (52.22%)
    39 / 88 (44.32%)
    36 / 79 (45.57%)
    33 / 72 (45.83%)
         occurrences all number
    57
    49
    43
    43
    Dry skin
         subjects affected / exposed
    5 / 90 (5.56%)
    4 / 88 (4.55%)
    5 / 79 (6.33%)
    2 / 72 (2.78%)
         occurrences all number
    5
    4
    5
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    18 / 90 (20.00%)
    14 / 88 (15.91%)
    13 / 79 (16.46%)
    12 / 72 (16.67%)
         occurrences all number
    24
    24
    17
    22
    Rash acneiform
         subjects affected / exposed
    4 / 90 (4.44%)
    6 / 88 (6.82%)
    4 / 79 (5.06%)
    5 / 72 (6.94%)
         occurrences all number
    4
    6
    4
    5
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 90 (0.00%)
    8 / 88 (9.09%)
    0 / 79 (0.00%)
    8 / 72 (11.11%)
         occurrences all number
    0
    16
    0
    16
    Infections and infestations
    Catheter related infection
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 88 (2.27%)
    0 / 79 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    1
    2
    0
    1
    Device related infection
         subjects affected / exposed
    1 / 90 (1.11%)
    4 / 88 (4.55%)
    1 / 79 (1.27%)
    4 / 72 (5.56%)
         occurrences all number
    1
    4
    1
    4
    Lung infection
         subjects affected / exposed
    3 / 90 (3.33%)
    2 / 88 (2.27%)
    2 / 79 (2.53%)
    0 / 72 (0.00%)
         occurrences all number
    3
    2
    2
    0
    Sepsis
         subjects affected / exposed
    2 / 90 (2.22%)
    3 / 88 (3.41%)
    2 / 79 (2.53%)
    1 / 72 (1.39%)
         occurrences all number
    2
    3
    2
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 90 (2.22%)
    7 / 88 (7.95%)
    0 / 79 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    2
    8
    0
    2
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    21 / 90 (23.33%)
    13 / 88 (14.77%)
    19 / 79 (24.05%)
    12 / 72 (16.67%)
         occurrences all number
    27
    28
    19
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2017
    - Patients with esophageal cancer and those with adenocarcinoma of GEJ type I and all patients who are planned to have transthoracic esophagectomy must no longer be included - Patients with severe, especially vascular, concomitant diseases (e.g., pAVK, chronic nicotine and/or previous alcohol abuse) are no longer included - Handling instructions for patients with GEJ type I and II who were already enrolled have been added
    08 Mar 2018
    1) After exclusion of AEG/GEJ type I tumors in the 1st amendment of the study, it was decided to replace the 28 affected patients with an enrollment of 30 additional patients, increasing the total sample size to 180 patients 2) Extension of the study to Italy

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    27 Oct 2017
    An interim safety analysis, examining six deaths which occurred during the study after nearly 40 patients in each arm underwent surgery, revealed that almost all of these died from anastomotic leakage (in some cases months after surgery), received FLOT/ramucirumab, had GEJ type I adenocarcinomas undergoing transthoracic esophagectomy and had in mean three relevant comorbidities predominantly cardiovascular disease like peripheral arterial occlusive disease (PAOD) and chronic heart failure as well as diabetes mellitus, chronic nicotine and/or previous alcohol abuse. Based on these findings, the study protocol was amended in November 2017 to exclude patients with potential increased risk including patients with GEJ type I and planned transthoracic esophagectomy from further enrolment
    30 Nov 2017

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36883420
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