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    Clinical Trial Results:
    FIGHT: A Phase 2 Randomized, Double-Blind, Controlled Study Evaluating FPA144 and Modified FOLFOX6 in Patients with Previously Untreated Advanced Gastric and Gastroesophageal Cancer: Phase 2 Preceded by Dose-Finding in Phase 1

    Summary
    EudraCT number
    		 2017-003507-22
    Trial protocol
    		 HU   GB   DE   PT   FR   ES   RO   PL   IT  
    Global end of trial date
    13 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2022
    First version publication date
    31 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FPA144-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03694522
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov (Phase 1): NCT03343301
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the Phase 1 portion of this study was to determine the recommended dose of bemarituzumab (FPA144), a targeted antibody, in combination with 5-fluorouracil, leucovorin and oxaliplatin (modified FOLFOX6) to use in the Phase 2 portion of the trial. The main objective of the Phase 2 part of the study was to evaluate the efficacy of bemarituzumab in combination with modified FOLFOX6 compared to placebo in combination with modified FOLFOX6 in participants with advanced gastrointestinal cancer.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonization (ICH) Good Clinical Practice (GCP) and applicable national or regional regulations/guidelines. The study protocol and all amendments, the informed consent form (ICF), and any accompanying materials provided to the subjects were reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) at each study center. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Dec 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    China: 27
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 54
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Turkey: 15
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    167
    EEA total number of subjects
    38
    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)
    117
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study FPA144-004 was a Phase 1/2 study. Phase 1 was a safety run-in to determine the recommended dose of bemarituzumab to be administered in combination with a fixed dose of modified FOLFOX6 (mFOLFOX6) chemotherapy regimen in the Phase 2 part of the study.

    Pre-assignment
    Screening details
    		 In Phase 1, dose cohorts began at bemarituzumab 6 mg/kg per dose, with enrollment into subsequent dose cohorts depending on safety and tolerability. In Phase 2 participants were randomized equally, stratified based on geographic region, prior treatment status, and administration of a single dose of mFOLFOX6 prior to enrollment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The Phase 1 safety run-in was an open-label dose escalation study. The Phase 2 part was a randomized, controlled, double-blind study design.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6
    Arm description
    		 Participants received 6 mg/kg bemarituzumab administered every 2 weeks (Q2W) and modified FOLFOX6 (mFOLFOX6) chemotherapy administered Q2W until unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bemarituzumab
    Investigational medicinal product code
    FPA144
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion over approximately 30 minutes.

    Investigational medicinal product name
    Modified FOLFOX6
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Modified FOLFOX6 regimen consists of the following: - Oxaliplatin 85 mg/m² IV infusion over 120 minutes; - Leucovorin 400 mg/m² IV infusion over 120 minutes, or 200 mg/m² levo-leucovorin if leucovorin is unavailable; - 5-fluorouracil (5-FU) 400 mg/m² bolus over approximately 5 minutes then 5-FU 2400 mg/m² as a continuous IV infusion over approximately 48 hours.

    Arm title
    		 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Arm description
    		 Participants received 15 mg/kg bemarituzumab administered Q2W with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bemarituzumab
    Investigational medicinal product code
    FPA144
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion over approximately 30 minutes.

    Investigational medicinal product name
    Modified FOLFOX6
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Modified FOLFOX6 regimen consists of the following: - Oxaliplatin 85 mg/m² IV infusion over 120 minutes; - Leucovorin 400 mg/m² IV infusion over 120 minutes, or 200 mg/m² levo-leucovorin if leucovorin is unavailable; - 5-fluorouracil (5-FU) 400 mg/m² bolus over approximately 5 minutes then 5-FU 2400 mg/m² as a continuous IV infusion over approximately 48 hours.

    Arm title
    		 Phase 2: Bemarituzumab + mFOLFOX6
    Arm description
    		 Participants received 15 mg/kg bemarituzumab administered Q2W with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bemarituzumab
    Investigational medicinal product code
    FPA144
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion over approximately 30 minutes.

    Investigational medicinal product name
    Modified FOLFOX6
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Modified FOLFOX6 regimen consists of the following: - Oxaliplatin 85 mg/m² IV infusion over 120 minutes; - Leucovorin 400 mg/m² IV infusion over 120 minutes, or 200 mg/m² levo-leucovorin if leucovorin is unavailable; - 5-fluorouracil (5-FU) 400 mg/m² bolus over approximately 5 minutes then 5-FU 2400 mg/m² as a continuous IV infusion over approximately 48 hours.

    Arm title
    		 Phase 2: Placebo + mFOLFOX6
    Arm description
    		 Participants received placebo for bemarituzumab administered Q2W with a single additional placebo dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion over approximately 30 minutes.

    Investigational medicinal product name
    Modified FOLFOX6
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Modified FOLFOX6 regimen consists of the following: - Oxaliplatin 85 mg/m² IV infusion over 120 minutes; - Leucovorin 400 mg/m² IV infusion over 120 minutes, or 200 mg/m² levo-leucovorin if leucovorin is unavailable; - 5-fluorouracil (5-FU) 400 mg/m² bolus over approximately 5 minutes then 5-FU 2400 mg/m² as a continuous IV infusion over approximately 48 hours.

    Number of subjects in period 1
    		Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6 Phase 2: Bemarituzumab + mFOLFOX6 Phase 2: Placebo + mFOLFOX6
    Started
    3
    9
    77
    78
    Received Any Study Treatment
    3
    9
    76
    77
    Completed
    0
    0
    15
    12
    Not completed
    3
    9
    62
    66
         Consent withdrawn by subject
    1
    1
    8
    10
         Death
    -
    2
    53
    54
         Other
    -
    6
    1
    1
         Lost to follow-up
    -
    -
    -
    1
         Missing
    2
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6
    Reporting group description
    		 Participants received 6 mg/kg bemarituzumab administered every 2 weeks (Q2W) and modified FOLFOX6 (mFOLFOX6) chemotherapy administered Q2W until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Reporting group description
    		 Participants received 15 mg/kg bemarituzumab administered Q2W with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 2: Bemarituzumab + mFOLFOX6
    Reporting group description
    		 Participants received 15 mg/kg bemarituzumab administered Q2W with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 2: Placebo + mFOLFOX6
    Reporting group description
    		 Participants received placebo for bemarituzumab administered Q2W with a single additional placebo dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Reporting group values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6 Phase 2: Bemarituzumab + mFOLFOX6 Phase 2: Placebo + mFOLFOX6 Total
    Number of subjects
    		 3 9 77 78 167
    Age categorical
    Units: Subjects
        < 65 years
    		 1 5 58 53 117
        >= 65 years
    		 2 4 19 25 50
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.7 ( 21.46 ) 62.3 ( 16.45 ) 58.0 ( 11.11 ) 59.1 ( 12.04 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 0 25 19 46
        Male
    		 1 9 52 59 121
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2 2 3 9
        Not Hispanic or Latino
    		 1 7 74 75 157
        Missing
    		 0 0 1 0 1
    Race
    Units: Subjects
        Asian
    		 0 1 45 44 90
        Black or African American
    		 1 0 0 1 2
        American Indian or Alaska Native
    		 0 0 0 1 1
        White
    		 2 7 30 31 70
        Other
    		 0 1 2 1 4
    Geographic Region
    Geographic region was a stratification factor in Phase 2. European Union (EU) includes Italy, Turkey, Spain, Portugal, Hungary, Germany, France, Romania, Poland, and the United Kingdom. Rest of Asia includes Japan, Taiwan, and South Korea. Phase 1 was only conducted in the United States.
    Units: Subjects
        United States / European Union
    		 3 9 32 34 78
        China
    		 0 0 14 13 27
        Rest of Asia
    		 0 0 31 31 62
    Prior Treatment Status
    Prior treatment status based on history of prior chemotherapy administered for neo-adjuvant or adjuvant therapy, was a stratification factor in Phase 2.
    Units: Subjects
        Prior adjuvant/ neoadjuvant therapy
    		 0 0 14 13 27
        No prior adjuvant/ neoadjuvant therapy
    		 0 0 63 65 128
        Not Reported
    		 3 9 0 0 12
    Administration of a Single Dose of mFOLFOX6 Prior to Enrollment
    In Phase 2 participants were stratified based on whether they have received a single dose of mFOLFOX6 chemotherapy for advanced stage disease prior to enrollment. Confirmation of positive fibroblast growth factor receptor 2 (FGFR2) overexpression status was required for enrolment in Phase 2. The results of the centralised FGFR2 testing took approximately 2 weeks; therefore, patients were permitted to receive a single dose of mFOLFOX6 during this prescreening period at the discretion of the investigator.
    Units: Subjects
        Yes
    		 0 0 35 36 71
        No
    		 0 0 42 42 84
        Not applicable
    		 3 9 0 0 12
    Phase 1: Clinical Diagnosis of Cancer
    Patients enrolling in Phase 1 of the study must have had histologically or cytologically confirmed gastrointestinal (GI) malignancy for which mFOLFOX6 was considered an appropriate treatment (eg, gastric cancer, colorectal carcinoma, pancreatic adenocarcinoma).
    Units: Subjects
        Colorectal Cancer
    		 3 5 0 0 8
        Gastric Cancer / Esophageal Cancer
    		 0 3 0 0 3
        Pancreatic Cancer
    		 0 1 0 0 1
        Not applicable
    		 0 0 77 78 155
    Phase 2: Clinical Diagnosis of Cancer
    Patients enrolling in Phase 2 of the study must have had histologically documented gastric or gastroesophageal junction (GEJ) adenocarcinoma (not amenable to curative therapy).
    Units: Subjects
        Gastric Adenocarcinoma
    		 0 0 66 71 137
        Gastroesophageal Junction (GEJ) Adenocarcinoma
    		 0 0 11 7 18
        Not applicable
    		 3 9 0 0 12
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
    Units: Subjects
        0 (Fully active)
    		 0 6 25 28 59
        1 (Restricted activity but ambulatory)
    		 3 3 52 50 108

    End points

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    End points reporting groups
    Reporting group title
    Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6
    Reporting group description
    		 Participants received 6 mg/kg bemarituzumab administered every 2 weeks (Q2W) and modified FOLFOX6 (mFOLFOX6) chemotherapy administered Q2W until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Reporting group description
    		 Participants received 15 mg/kg bemarituzumab administered Q2W with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 2: Bemarituzumab + mFOLFOX6
    Reporting group description
    		 Participants received 15 mg/kg bemarituzumab administered Q2W with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 2: Placebo + mFOLFOX6
    Reporting group description
    		 Participants received placebo for bemarituzumab administered Q2W with a single additional placebo dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Primary: Phase 1: Number of Participants With Treatment-related Adverse Events ≥ Grade 2

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    End point title
    		 Phase 1: Number of Participants With Treatment-related Adverse Events ≥ Grade 2 [1] [2]
    End point description
    A treatment-related adverse event (TRAE) is defined as an adverse event (AE) with an onset date on or after the date of first dose of study treatment, or an event present before treatment that worsened after treatment, and with an onset date prior to 28 days after the last date of dose, for which the investigator assessed as related to investigational product The investigator classified the severity of each AE using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0 on a scale from mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), or death due to the AE (Grade 5).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 28 days after last dose; Actual median (min, max) duration of treatment emergent period was 19.3 (12.3, 22.3) weeks in the bemarituzumab 6 mg/kg group and 19.4 (4.0, 35.4) weeks in the bemarituzumab 15 mg/kg group.
    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: Statistical analyses were not conducted in Phase 1.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Number of subjects analysed
    3 [3]
    9 [4]
    Units: participants
    1
    4
    Notes
    [3] - Safety analysis set (participants who received any portion of at least 1 dose of study treatment)
    [4] - Safety analysis set
    No statistical analyses for this end point

    Primary: Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)

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    End point title
    		 Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs) [5] [6]
    End point description
    DLTs were defined as any of the following events considered by the investigator to be related to study drug: -Absolute neutrophil count (ANC) < 0.5 × 10^9/L > 5 days duration or febrile neutropenia. -Platelets < 25 × 10^9/L or < 50 × 10^9/L with bleeding requiring medical intervention or for > 3 days. -Grade 4 anemia. -Any Grade 2-3 ophthalmologic AE not resolving within 7 days. -Any Grade 4 ophthalmologic AE. -Any Grade 4 laboratory value. -Any Grade 3 laboratory values that are not of clinical significance according to investigator and Sponsor agreement if they do not resolve within 72 hours. -Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≥ 3 × upper limit of normal (ULN) and concurrent total bilirubin ≥ 2 × ULN not related to liver involvement with cancer. -Any non-hematological AE ≥ Grade 3 (except nausea, vomiting, and diarrhea). -Grade 3 nausea, vomiting or diarrhea not resolving with supportive care in 72 hours. -Grade 4 nausea, vomiting or diarrhea.
    End point type
    Primary
    End point timeframe
    28 days
    Notes
    [5] - 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: Statistical analyses were not conducted in Phase 1.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Number of subjects analysed
    3 [7]
    8 [8]
    Units: participants
    0
    0
    Notes
    [7] - DLT-evaluable analysis set (participants who completed 2 cycles of treatment or experienced a DLT)
    [8] - DLT-evaluable analysis set
    No statistical analyses for this end point

    Primary: Phase 2: Progression-Free Survival (PFS)

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    End point title
    		 Phase 2: Progression-Free Survival (PFS) [9]
    End point description
    PFS was defined as time from randomization until the date of radiographic disease progression based on investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death from any cause, whichever came first. PFS was analyzed using Kaplan-Meier methods. Participants with no progression or death, or who started new anticancer therapy before documented progression or death without documented progression, or who had ≥ 2 consecutive missing tumor assessments before documented progression or death without documented progression were censored on the date of last adequate tumor assessment. Participants with no baseline tumor assessment, were censored at the date of randomization. The primary efficacy analysis was pre-specified to be conducted after at least 84 PFS events were observed.
    End point type
    Primary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 23 September 2020; median time on follow-up was 10.9 months.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 2: Bemarituzumab + mFOLFOX6 Phase 2: Placebo + mFOLFOX6
    Number of subjects analysed
    77 [10]
    78 [11]
    Units: months
        median (confidence interval 95%)
    9.5 (7.3 to 12.9)
    7.4 (5.8 to 8.4)
    Notes
    [10] - Intent-to-treat population (all participants randomized in Phase 2)
    [11] - Intent-to-treat population
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    A non-parametric stratified log-rank test was used to compare the treatment groups with the stratification factors of geographical region and administration of a single dose of mFOLFOX6. Hazard ratio and 95% CIs were calculated using the Cox proportional hazards model, adjusted for randomization stratification factors.
    Comparison groups
    Phase 2: Bemarituzumab + mFOLFOX6 v Phase 2: Placebo + mFOLFOX6
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0727 [12]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.04
    Notes
    [12] - Stratified log-rank test adjusted for randomization stratification factors of geographic region and administration of mFOLFOX6 single dose prior to randomization.

    Secondary: Phase 1: Number of Participants With Treatment-emergent Adverse Events

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    End point title
    		 Phase 1: Number of Participants With Treatment-emergent Adverse Events [13]
    End point description
    Treatment-emergent adverse events are defined as AEs that started or worsened between the start of study drug and 28 days after permanent discontinuation of study drug. A serious AE is defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, or was a congenital anomaly or birth defect. The investigator assessed the causality/relationship between the study treatment and each AE, and assessed the severity of each AE according to the NCI-CTCAE, version 5.0. Ocular events associated with symptomatic corneal involvement and symptomatic and asymptomatic retinal involvement were events of special interest (TE-AESI) in this study. Cornea and retina AEs were defined by Standardized Medical Dictionary for Regulatory Activities Queries (SMQs) of corneal disorders and retinal disorders (broad).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 28 days after last dose; Actual median (min, max) duration of the treatment emergent period was 19.3 (12.3, 22.3) weeks in the bemarituzumab 6 mg/kg group and 19.4 (4.0, 35.4) weeks in the bemarituzumab 15 mg/kg group.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Number of subjects analysed
    3 [14]
    9 [15]
    Units: participants
        Any treatment-emergent adverse event (TEAE)
    3
    9
        TEAE with Grade ≥ 3
    1
    6
        TEAE related to any study drug
    3
    9
        TEAE related to bemarituzumab (BEMA)
    2
    5
        TEAE related to any agent of mFOLFOX6
    3
    9
        TEAE with Grade ≥ 3 related to any study drug
    1
    4
        Serious adverse event (SAE)
    0
    4
        SAE related to any study drug
    0
    1
        SAE related to bemarituzumab
    0
    0
        SAE related to any agent of mFOLFOX6
    0
    1
        TEAE leading to discontinuation (DC) of BEMA
    0
    4
        TEAE leading to DC of any agent of mFOLFOX6
    0
    4
        TEAE leading to dose reduction of bemarituzumab
    1
    0
        TEAE leading to dose reduction of mFOLFOX6
    1
    5
        TE-AESI: corneal/retina disorders (C/R)
    0
    4
        TE-AESI: C/R disorders related to bemarituzumab
    0
    4
        TE-AESI: C/R disorders leading to DC of BEMA
    0
    2
    Notes
    [14] - Safety analysis set
    [15] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Phase 1: Maximum Observed Serum Concentration (Cmax) of Bemarituzumab

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    End point title
    		 Phase 1: Maximum Observed Serum Concentration (Cmax) of Bemarituzumab [16]
    End point description
    Bemarituzumab serum concentration was measured by a validated enzyme linked immunosorbent assay (ELISA). The lower limit of quantitation (LLOQ) of the assay was 0.125 μg/mL. The pharmacokinetic (PK)-evaluable analysis set included all participants who had sufficient PK data for the reliable calculation of at least 1 PK parameter.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 at predose, 0.25, 4, 48, and 168 hours after end of infusion, and for participants in Cohort 2 day 8 at 0.25 and 4 hours end of infusion; Cycle 2 day 1 at predose, 0.25 and 48 hours after end of infusion.
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Number of subjects analysed
    3 [17]
    8 [18]
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1
    119 ( 8.52 )
    329 ( 60.3 )
        Cycle 2
    123 ( 13.8 )
    377 ( 82.8 )
    Notes
    [17] - PK-evaluable analysis set
    [18] - PK-evaluable analysis set; N=7 for Cycle 2
    No statistical analyses for this end point

    Secondary: Phase 1: Observed Serum Concentration of Bemarituzumab at the End of the Dose Interval (Ctrough)

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    End point title
    		 Phase 1: Observed Serum Concentration of Bemarituzumab at the End of the Dose Interval (Ctrough) [19]
    End point description
    Bemarituzumab serum concentration was measured by a validated enzyme linked immunosorbent assay (ELISA). The lower limit of quantitation (LLOQ) of the assay was 0.125 μg/mL.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 14 predose for cohort 1 and day 8 predose for cohort 2; Cycle 2 day 14 predose
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Number of subjects analysed
    3 [20]
    8 [21]
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1
    16.5 ( 8.80 )
    118 ( 25.1 )
        Cycle 2
    25.6 ( 10.6 )
    131 ( 55.3 )
    Notes
    [20] - PK-evaluable analysis set
    [21] - PK-evaluable analysis set
    No statistical analyses for this end point

    Secondary: Phase 1: Area Under the Observed Concentration-time Curve From the Time of Dosing to Day 14 (AUC0-14)

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    End point title
    		 Phase 1: Area Under the Observed Concentration-time Curve From the Time of Dosing to Day 14 (AUC0-14) [22]
    End point description
    Bemarituzumab serum concentration was measured by a validated enzyme linked immunosorbent assay (ELISA). The lower limit of quantitation (LLOQ) of the assay was 0.125 μg/mL. Area under the observed concentration-time curve from the time of dosing to Day 14 (0-336h) calculated by log-linear trapezoidal approximation.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 at predose, 0.25, 4, 48, and 168 hours after end of infusion, and for participants in Cohort 2 day 8 at 0.25 and 4 hours after the end of infusion.
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Number of subjects analysed
    3 [23]
    7 [24]
    Units: μg*day/mL
        arithmetic mean (standard deviation)
    556 ( 232 )
    2350 ( 394 )
    Notes
    [23] - PK-evaluable analysis set
    [24] - PK-evaluable analysis set with available AUC data
    No statistical analyses for this end point

    Secondary: Phase 1: Terminal Half-life (t1/2) of Bemarituzumab

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    End point title
    		 Phase 1: Terminal Half-life (t1/2) of Bemarituzumab [25]
    End point description
    Bemarituzumab serum concentration was measured by a validated enzyme linked immunosorbent assay (ELISA). The lower limit of quantitation (LLOQ) of the assay was 0.125 μg/mL.
    End point type
    Secondary
    End point timeframe
    Cycle 1 day 1 at predose, 0.25, 4, 48, and 168 hours after end of infusion, and for participants in Cohort 2 day 8 at 0.25 and 4 hours after end of infusion.
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Number of subjects analysed
    3 [26]
    3 [27]
    Units: days
        arithmetic mean (standard deviation)
    8.35 ( 3.36 )
    4.23 ( 0.447 )
    Notes
    [26] - PK-evaluable analysis set
    [27] - PK-evaluable analysis set with available half-life data
    No statistical analyses for this end point

    Secondary: Phase 1 : Number of Participants With Treatment Induced Anti-bemarituzumab Antibodies

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    End point title
    		 Phase 1 : Number of Participants With Treatment Induced Anti-bemarituzumab Antibodies [28]
    End point description
    Postbaseline treatment induced antidrug antibody (ADA) positive is defined as participants who were: • ADA negative at baseline and ADA positive at any postbaseline timepoint, or • ADA positive at baseline and ADA positive with titer of at least 4-fold of the baseline titer at one or more postbaseline timepoint. The ADA-evaluable analysis set includes all enrolled participants who received at least 1 dose of bemarituzumab and had at least 1 ADA sample drawn at any timepoint with available ADA data.
    End point type
    Secondary
    End point timeframe
    Samples were collected for ADA analysis predose on day 1 of Cycles 1, 2, 3, 7, and 10 and at 28 days following the last dose.
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1: Bemarituzumab 15 mg/kg + mFOLFOX6
    Number of subjects analysed
    3 [29]
    9 [30]
    Units: participants
    0
    0
    Notes
    [29] - ADA-evaluable analysis set
    [30] - ADA-evaluable analysis set
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival (OS)

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    End point title
    		 Phase 2: Overall Survival (OS) [31]
    End point description
    OS is defined as time from randomization until death from any cause. Participants who were lost to follow-up or did not have a date of death were censored at the last date that they were known to be alive. Participants with confirmed death or alive status after the data cutoff date were censored at the data cutoff date. Median OS was estimated using a Kaplan-Meier analysis. "99999" indicates values that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From randomization until the primary analysis data cut-off date of 23 September 2020; median time on follow-up was 10.9 months.
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 2: Bemarituzumab + mFOLFOX6 Phase 2: Placebo + mFOLFOX6
    Number of subjects analysed
    77 [32]
    78 [33]
    Units: months
        median (confidence interval 95%)
    99999 (13.8 to 99999)
    12.9 (9.1 to 15.0)
    Notes
    [32] - Intent-to-treat population
    [33] - Intent-to-treat population
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Phase 2: Bemarituzumab + mFOLFOX6 v Phase 2: Placebo + mFOLFOX6
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0268 [34]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.95
    Notes
    [34] - Stratified log-rank test adjusted for randomization stratification factors, including geographic region and administration of mFOLFOX6 single dose prior to randomization.

    Secondary: Phase 2: Overall Response Rate (ORR)

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    End point title
    		 Phase 2: Overall Response Rate (ORR) [35]
    End point description
    Tumor response assessment was performed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines. ORR is defined as the percentage of participants who achieved a best overall response (BOR) of either complete response (CR) or partial response (PR) based on investigator assessment of tumor lesions per RECIST v1.1. CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 8 weeks until 12 months and then every 12 weeks thereafter until disease progression or additional anticancer therapy was initiated; the median duration of follow-up time was 10.9 months.
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 2: Bemarituzumab + mFOLFOX6 Phase 2: Placebo + mFOLFOX6
    Number of subjects analysed
    77 [36]
    78 [37]
    Units: percentage of participants
        number (confidence interval 95%)
    46.8 (35.3 to 58.5)
    33.3 (23.1 to 44.9)
    Notes
    [36] - Intent-to-treat population
    [37] - Intent-to-treat population
    Statistical analysis title
    		 Analysis of ORR
    Comparison groups
    Phase 2: Bemarituzumab + mFOLFOX6 v Phase 2: Placebo + mFOLFOX6
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.106 [38]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    13.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 29
    Notes
    [38] - P-value was calculated based on stratum-adjusted Cochran-Mantel-Haenszel (CMH) proportions

    Secondary: Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) [39]
    End point description
    TEAEs are defined as adverse events (AEs) that started or worsened from the start of study drug to 28 days after permanent discontinuation of study drug. A serious AE is defined as any untoward medical occurrence that: • Resulted in death; • Was life-threatening; • Required inpatient hospitalization or prolongation of existing hospitalization; • Resulted in persistent or significant disability or incapacity; • Was a congenital anomaly or birth defect. The investigator assessed the causality/relationship between study treatment and each AE, and assessed the severity of each AE according to the NCI-CTCAE, version 5.0 on a scale from mild (Grade 1), moderate (Grade 2), severe (Grade 3), life-threatening (Grade 4), or death due to the AE (Grade 5). Cornea and retina AEs were defined by Standardized Medical Dictionary for Regulatory Activities Queries (SMQs) of corneal disorders and retinal disorders (broad).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug to 28 days after last dose of study drug. Actual median (min, max) duration of treatment emergent period was 29 (4.1, 157) weeks in the bemarituzumab + mFOLFOX6 group and 28 (4.3, 133) weeks in the placebo + mFOLFOX6 group.
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 2: Bemarituzumab + mFOLFOX6 Phase 2: Placebo + mFOLFOX6
    Number of subjects analysed
    76 [40]
    77 [41]
    Units: participants
        Any treatment-emergent adverse event (TEAE)
    76
    76
        TEAE with Grade ≥ 3
    63
    58
        TEAE related to any study drug
    72
    73
        TEAE with Grade ≥ 3 related to any study drug
    57
    48
        Serious adverse event (SAE)
    26
    28
        SAE related to any study drug
    11
    15
        TEAE leading to discontinuation of BEMA/placebo
    31
    4
        TEAE leading to DC of any agent of mFOLFOX6
    35
    29
        TEAE leading to dose reduction of BEMA/placebo
    9
    7
        TEAE leading to dose reduction of mFOLFOX6
    48
    44
        TEAE leading to dose delay of BEMA/placebo
    51
    41
        TEAE leading to dose delay of mFOLFOX6
    54
    44
        TE-AESI: Corneal disorders
    51
    8
        TE-AESI: Corneal disorders with Grade ≥ 3
    21
    0
        TE-AESI: Corneal disorders related to BEMA/placebo
    46
    7
        TE-AESI: Corneal disorders leading to DC of BEMA
    24
    0
        TE-AESI: Retinal disorders
    18
    7
        TE-AESI: Retinal disorders with Grade ≥ 3
    1
    0
        TE-AESI: Retinal disorders related to BEMA/placebo
    12
    5
        TE-AESI: Retinol disorders leading to DC of BEMA
    2
    0
        TEAE leading to death (Grade 5)
    5
    4
    Notes
    [40] - Safety analysis set
    [41] - Safety analysis set
    No statistical analyses for this end point

    Post-hoc: Phase 2: Overall Survival - Updated Analysis

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    End point title
    		 Phase 2: Overall Survival - Updated Analysis [42]
    End point description
    OS is defined as time from randomization until death from any cause. Participants who were lost to follow-up or did not have a date of death were censored at the last date that they were known to be alive. Median OS was estimated using a Kaplan-Meier analysis. "99999" indicates values that could not be estimated due to the low number of events.
    End point type
    Post-hoc
    End point timeframe
    From randomization until 28 February 2021; median time on follow-up was 12.5 months.
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 and Phase 2 results are reported separately.
    End point values
    		 Phase 2: Bemarituzumab + mFOLFOX6 Phase 2: Placebo + mFOLFOX6
    Number of subjects analysed
    77 [43]
    78 [44]
    Units: months
        median (confidence interval 95%)
    19.2 (13.6 to 99999)
    13.5 (9.3 to 15.9)
    Notes
    [43] - Intent-to-treat population
    [44] - Intent-to-treat population
    Statistical analysis title
    		 Post-hoc Analysis of Overall Survival
    Statistical analysis description
    Hazard ratio and 95% CIs were calculated using the Cox proportional hazards model, adjusted for randomization stratification factors, including geographic region and administration of mFOLFOX6 single dose prior to randomization.
    Comparison groups
    Phase 2: Bemarituzumab + mFOLFOX6 v Phase 2: Placebo + mFOLFOX6
    Number of subjects included in analysis
    155
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.94

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Deaths: Up to end of study; median (range) time on study was 21 (4-50) weeks in Phase 1, 59 (1-176) weeks in Phase 2. AEs: From first dose to 28 days after last dose; median (range) duration was 19 (4-35) weeks in Phase 1, 29 (4-157) weeks in Phase 2.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6
    Reporting group description
    		 Participants received 6 mg/kg bemarituzumab administered Q2W and mFOLFOX6 chemotherapy administered Q2W until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 1:Bemarituzumab 15 mg/kg + mFOLFOX6
    Reporting group description
    		 Participants received 15 mg/kg bemarituzumab administered Q2W with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 2: Placebo + mFOLFOX6
    Reporting group description
    		 Participants received placebo for bemarituzumab administered Q2W with a single additional placebo dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Reporting group title
    Phase 2: Bemarituzumab + mFOLFOX6
    Reporting group description
    		 Participants received 15 mg/kg bemarituzumab administered Q2W with a single additional bemarituzumab 7.5 mg/kg dose on cycle 1 day 8. Participants also received mFOLFOX6 chemotherapy administered Q2W. Treatment continued until unacceptable toxicity, disease progression, or death.

    Serious adverse events
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1:Bemarituzumab 15 mg/kg + mFOLFOX6 Phase 2: Placebo + mFOLFOX6 Phase 2: Bemarituzumab + mFOLFOX6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 9 (44.44%)
    28 / 77 (36.36%)
    26 / 76 (34.21%)
         number of deaths (all causes)
    0
    2
    55
    53
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    3 / 77 (3.90%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Product issues
    Device issue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (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
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    3 / 77 (3.90%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    Septic shock
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    		 Phase 1: Bemarituzumab 6 mg/kg + mFOLFOX6 Phase 1:Bemarituzumab 15 mg/kg + mFOLFOX6 Phase 2: Placebo + mFOLFOX6 Phase 2: Bemarituzumab + mFOLFOX6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    9 / 9 (100.00%)
    75 / 77 (97.40%)
    76 / 76 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    5 / 77 (6.49%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    12
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    16 / 77 (20.78%)
    20 / 76 (26.32%)
         occurrences all number
    0
    0
    25
    65
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    2
    1
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    8 / 9 (88.89%)
    21 / 77 (27.27%)
    16 / 76 (21.05%)
         occurrences all number
    1
    13
    57
    31
    Feeling cold
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 9 (33.33%)
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences all number
    0
    4
    1
    1
    Infusion site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 9 (33.33%)
    4 / 77 (5.19%)
    8 / 76 (10.53%)
         occurrences all number
    1
    4
    4
    35
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    4 / 77 (5.19%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    4
    5
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    12 / 77 (15.58%)
    10 / 76 (13.16%)
         occurrences all number
    0
    0
    17
    15
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    8 / 77 (10.39%)
    8 / 76 (10.53%)
         occurrences all number
    0
    0
    8
    11
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    3 / 77 (3.90%)
    17 / 76 (22.37%)
         occurrences all number
    1
    1
    5
    24
    Nasal congestion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nasal ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    5 / 77 (6.49%)
    3 / 76 (3.95%)
         occurrences all number
    0
    1
    7
    3
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    5 / 77 (6.49%)
    2 / 76 (2.63%)
         occurrences all number
    1
    1
    6
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    11 / 77 (14.29%)
    23 / 76 (30.26%)
         occurrences all number
    0
    0
    37
    52
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    15 / 77 (19.48%)
    24 / 76 (31.58%)
         occurrences all number
    0
    0
    45
    56
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    5 / 77 (6.49%)
    7 / 76 (9.21%)
         occurrences all number
    0
    0
    6
    13
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    4 / 77 (5.19%)
    7 / 76 (9.21%)
         occurrences all number
    0
    0
    18
    17
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    4 / 77 (5.19%)
    2 / 76 (2.63%)
         occurrences all number
    0
    0
    7
    2
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 9 (33.33%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences all number
    0
    4
    12
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    33 / 77 (42.86%)
    31 / 76 (40.79%)
         occurrences all number
    0
    1
    116
    129
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    21 / 77 (27.27%)
    14 / 76 (18.42%)
         occurrences all number
    0
    3
    72
    37
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    10 / 77 (12.99%)
    16 / 76 (21.05%)
         occurrences all number
    0
    1
    15
    22
    Weight increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    4 / 77 (5.19%)
    0 / 76 (0.00%)
         occurrences all number
    0
    0
    5
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    12 / 77 (15.58%)
    16 / 76 (21.05%)
         occurrences all number
    0
    0
    51
    103
    Injury, poisoning and procedural complications
    Corneal abrasion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    3
    1
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    7 / 77 (9.09%)
    6 / 76 (7.89%)
         occurrences all number
    0
    0
    21
    16
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    4 / 77 (5.19%)
    6 / 76 (7.89%)
         occurrences all number
    0
    0
    4
    9
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    6 / 77 (7.79%)
    5 / 76 (6.58%)
         occurrences all number
    0
    1
    10
    10
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    4 / 77 (5.19%)
    7 / 76 (9.21%)
         occurrences all number
    1
    0
    6
    8
    Neuralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    11 / 77 (14.29%)
    13 / 76 (17.11%)
         occurrences all number
    0
    3
    17
    23
    Neurotoxicity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    5 / 77 (6.49%)
    3 / 76 (3.95%)
         occurrences all number
    0
    0
    8
    5
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    10 / 77 (12.99%)
    13 / 76 (17.11%)
         occurrences all number
    0
    2
    22
    24
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    15 / 77 (19.48%)
    15 / 76 (19.74%)
         occurrences all number
    0
    0
    27
    28
    Taste disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    0
    3
    Tremor
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 9 (33.33%)
    28 / 77 (36.36%)
    25 / 76 (32.89%)
         occurrences all number
    0
    3
    92
    80
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    9 / 77 (11.69%)
    8 / 76 (10.53%)
         occurrences all number
    0
    1
    60
    35
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 9 (33.33%)
    13 / 77 (16.88%)
    15 / 76 (19.74%)
         occurrences all number
    0
    3
    38
    63
    Thrombocytopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 9 (33.33%)
    4 / 77 (5.19%)
    11 / 76 (14.47%)
         occurrences all number
    2
    4
    7
    36
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences all number
    0
    1
    1
    4
    Blepharospasm
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cataract
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 77 (1.30%)
    7 / 76 (9.21%)
         occurrences all number
    0
    1
    1
    9
    Conjunctivochalasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Corneal disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    0
    11
    Corneal epithelium defect
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    7 / 76 (9.21%)
         occurrences all number
    0
    2
    0
    13
    Dry eye
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    5 / 77 (6.49%)
    21 / 76 (27.63%)
         occurrences all number
    0
    3
    5
    32
    Eye pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    3 / 77 (3.90%)
    3 / 76 (3.95%)
         occurrences all number
    1
    0
    5
    3
    Eye pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    1
    0
    0
    1
    Keratitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    11 / 76 (14.47%)
         occurrences all number
    0
    0
    1
    22
    Lacrimation increased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    2
    1
    0
    7
    Limbal stem cell deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    6 / 76 (7.89%)
         occurrences all number
    0
    1
    0
    7
    Myopia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Photophobia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    0 / 77 (0.00%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    0
    2
    Pinguecula
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Punctate keratitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    2 / 77 (2.60%)
    10 / 76 (13.16%)
         occurrences all number
    0
    5
    2
    23
    Ulcerative keratitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    0
    4
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    1 / 77 (1.30%)
    13 / 76 (17.11%)
         occurrences all number
    0
    3
    1
    16
    Vitreous floaters
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 77 (1.30%)
    3 / 76 (3.95%)
         occurrences all number
    0
    1
    1
    3
    Abdominal distension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    6 / 77 (7.79%)
    4 / 76 (5.26%)
         occurrences all number
    1
    0
    8
    4
    Abdominal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 9 (33.33%)
    20 / 77 (25.97%)
    17 / 76 (22.37%)
         occurrences all number
    3
    3
    28
    31
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    5 / 77 (6.49%)
    6 / 76 (7.89%)
         occurrences all number
    0
    0
    8
    7
    Anorectal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    3 / 77 (3.90%)
    2 / 76 (2.63%)
         occurrences all number
    0
    1
    3
    2
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 9 (22.22%)
    24 / 77 (31.17%)
    23 / 76 (30.26%)
         occurrences all number
    1
    2
    30
    37
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 9 (44.44%)
    23 / 77 (29.87%)
    31 / 76 (40.79%)
         occurrences all number
    3
    5
    30
    58
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    1
    4
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    9 / 77 (11.69%)
    7 / 76 (9.21%)
         occurrences all number
    0
    0
    11
    11
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences all number
    0
    0
    6
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Loose tooth
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 9 (44.44%)
    41 / 77 (53.25%)
    37 / 76 (48.68%)
         occurrences all number
    4
    4
    95
    92
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences all number
    0
    2
    1
    2
    Stomatitis
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 9 (33.33%)
    10 / 77 (12.99%)
    26 / 76 (34.21%)
         occurrences all number
    2
    3
    19
    68
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 9 (44.44%)
    23 / 77 (29.87%)
    23 / 76 (30.26%)
         occurrences all number
    1
    5
    41
    51
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    6 / 77 (7.79%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    6
    5
    Dermatitis acneiform
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    2
    1
    Nail discolouration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    0
    1
    Nail disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    6 / 76 (7.89%)
         occurrences all number
    0
    0
    1
    6
    Night sweats
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Onychalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    3 / 76 (3.95%)
         occurrences all number
    0
    1
    0
    4
    Onychoclasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Onycholysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    1
    10
    Onychomadesis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    5 / 76 (6.58%)
         occurrences all number
    0
    0
    1
    5
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 9 (11.11%)
    1 / 77 (1.30%)
    6 / 76 (7.89%)
         occurrences all number
    1
    1
    1
    13
    Photosensitivity reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    8 / 77 (10.39%)
    8 / 76 (10.53%)
         occurrences all number
    0
    0
    11
    14
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    2 / 77 (2.60%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    2
    9
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 9 (33.33%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences all number
    0
    3
    1
    2
    Urticaria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    3 / 77 (3.90%)
    4 / 76 (5.26%)
         occurrences all number
    0
    1
    5
    8
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    3 / 77 (3.90%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 9 (22.22%)
    5 / 77 (6.49%)
    3 / 76 (3.95%)
         occurrences all number
    0
    2
    7
    3
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    3 / 77 (3.90%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    3
    1
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    4 / 77 (5.19%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    5
    5
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    5 / 77 (6.49%)
    1 / 76 (1.32%)
         occurrences all number
    0
    0
    6
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    2 / 77 (2.60%)
    5 / 76 (6.58%)
         occurrences all number
    0
    2
    2
    6
    Dermatophytosis of nail
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Onychomycosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    0 / 77 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    0
    4
    Rhinitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    0
    1
    Stoma site infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 9 (0.00%)
    3 / 77 (3.90%)
    1 / 76 (1.32%)
         occurrences all number
    1
    0
    3
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 9 (44.44%)
    28 / 77 (36.36%)
    23 / 76 (30.26%)
         occurrences all number
    2
    4
    53
    38
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    3 / 77 (3.90%)
    3 / 76 (3.95%)
         occurrences all number
    0
    2
    4
    3
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    10 / 77 (12.99%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    14
    10
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    7 / 77 (9.09%)
    4 / 76 (5.26%)
         occurrences all number
    0
    1
    8
    14
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 9 (0.00%)
    1 / 77 (1.30%)
    4 / 76 (5.26%)
         occurrences all number
    0
    0
    1
    7
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    4 / 77 (5.19%)
    5 / 76 (6.58%)
         occurrences all number
    0
    1
    4
    9
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 9 (11.11%)
    1 / 77 (1.30%)
    3 / 76 (3.95%)
         occurrences all number
    0
    1
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jan 2018
    Major changes included: - Updated phase 3 objectives and endpoints to reflect OS instead of PFS; - Updated method of radiological assessment to investigator assessed instead of blinded independent central review; - Updated statistical methods to support revised endpoint of OS, increase in phase 3 sample size; - Revised adverse event reporting period for ophthalmologic exams; - Updated clinical experience of bemarituzumab based on recent data, clarified the timing for serious adverse event reporting; - Defined adverse events of special interest; - Updated timing of tumor scans.
    19 Nov 2018
    Major changes included: - Removed language involving informed consent requirements in protocol synopsis; - Clarified distinction between prescreening and screening period; - Added phase 3 recommended dose; - Added exception for anemia to exclusion criteria; - Revised window for baseline radiographic imaging to be within 28 days (± 3 days); - Clarified when and how bemarituzumab dose recalculations should be performed; - Removed rounding convention for oxaliplatin and 5-FU; - Addressed explicit dose levels for dose reduction; - Added PI ability to unblind treatment code in case of emergency.
    05 Jun 2020
    Major changes included: - Changed study design to phase 2; - Changed primary endpoint to PFS; - Changed secondary endpoint to OS; - Changed PK/ADA to exploratory endpoints; - Removed circulating tumor DNA (ctDNA) analysis at end of treatment (EOT).
    10 Mar 2021
    Major changes included: - Updated long term follow up (LTFU) survival duration (phase 2) to 24 months; - The planned duration for study completion approximately 43 months.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36244398
    http://www.ncbi.nlm.nih.gov/pubmed/32965540
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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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