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    Clinical Trial Results:
    A Randomized Phase II Multicenter, Open-label Study Evaluating the Efficacy and Safety of IMAB362 in Combination with the EOX (Epirubicin, Oxaliplatin, Capecitabine) Regimen as First-line Treatment of Patients with CLDN18.2-positive Advanced Adenocarcinomas of the Stomach, the Esophagus or the Gastroesophageal Junction (FAST)

    Summary
    EudraCT number
    2011-005285-38
    Trial protocol
    DE   CZ   LV   BG  
    Global end of trial date
    31 Jan 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jan 2020
    First version publication date
    04 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GM-IMAB-001-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01630083
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Acronym: FAST, Other study number: 8951-CL-0202
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc.
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., astellas.resultsdisclosure@astellas.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
    31 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of zolbetuximab in combination with EOX as determined by progression-free survival (PFS) and to determine the safety and tolerability of zolbetuximab in combination with EOX.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Jul 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Czech Republic: 4
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Latvia: 25
    Country: Number of subjects enrolled
    Russian Federation: 105
    Country: Number of subjects enrolled
    Ukraine: 77
    Worldwide total number of subjects
    252
    EEA total number of subjects
    70
    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)
    199
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Male & female participants with CLDN18.2-positive advanced adenocarcinomas of the stomach, esophagus or gastroesophageal junction were enrolled in this multinational, multicenter study. Participants who had a tumor with 2+ or 3+ CLDN18.2 staining intensity in at least 40% of the tumor cells based on immunohistochemical testing were eligible.

    Pre-assignment
    Screening details
    Participants were randomized in two arms in a 1:1 ratio which was later adjusted to 1:1:7 to allow recruitment in Arm 3 which was added at a later date, to catch up with arms 1 & 2. Randomization was later adjusted to 1:1:1 and stratified by CLDN18.2 positivity and presence of nonmeasurable vs measurable disease at baseline.

    Pre-assignment period milestones
    Number of subjects started
    730 [1]
    Intermediate milestone: Number of subjects
    Screen failed: 478
    Number of subjects completed
    252

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Claudin-18 splice variant 2 (CLDN18.2) negative: 352
    Reason: Number of subjects
    CLDN18.2 positive but other criteria not fulfilled: 82
    Reason: Number of subjects
    CLDN18.2 not assessable: 44
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number includes all randomized participants, the pre-assignment period includes participants in the screening period.
    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    EOX Treatment
    Arm description
    Participants received up to 8 cycles of epirubicin, oxaliplatin and capecitabine (EOX) chemotherapy treatment alone (50 mg/m^2 epirubicin intravenously on day 1 of each cycle, 130 mg/m^2 oxaliplatin intravenously on day 1 of each cycle, 625 mg/m^2 capecitabine orally twice daily on days 1 to 21 of each cycle). The first dose of capecitabine taken in the evening of day 1.
    Arm type
    Experimental

    Investigational medicinal product name
    epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin was administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle.

    Investigational medicinal product name
    capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The daily dose of capecitabine was 1250 mg/m^2. Capecitabine tablets were given once daily at a dose of 625 mg/m^2 orally in the evening of day 1 of each cycle and twice daily at a dose of 625 mg/m^2 orally on days 2 to 21 of each cycle; the morning dose of capecitabine on day 1 of each cycle was omitted due to administration of zolbetuximab, epirubicin and oxaliplatin.

    Investigational medicinal product name
    oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin was administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle.

    Arm title
    EOX+zolbetuximab 800/600 mg/m^2
    Arm description
    Participants received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab administered as loading dose of 800 mg/m^2 intravenously on day 1 of cycle 1 followed by 600 mg/m^2 intravenously on day 1 of each subsequent cycle. Zolbetuximab was administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants were permitted to continue zolbetuximab monotherapy (600 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion) until progressive disease (PD), withdrawal of consent or unacceptable toxicity. PD per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5mm must also be demonstrated, unequivocal progression of existing non-target lesions and appearance of one or more new lesions was considered progression.
    Arm type
    Experimental

    Investigational medicinal product name
    epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin was administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle.

    Investigational medicinal product name
    capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The daily dose of capecitabine was 1250 mg/m^2. Capecitabine tablets were given once daily at a dose of 625 mg/m^2 orally in the evening of day 1 of each cycle and twice daily at a dose of 625 mg/m^2 orally on days 2 to 21 of each cycle; the morning dose of capecitabine on day 1 of each cycle was omitted due to administration of zolbetuximab, epirubicin and oxaliplatin.

    Investigational medicinal product name
    zolbetuximab
    Investigational medicinal product code
    IMAB362
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Two different formats of zolbetuximab, comprising different strengths, were provided. Vials contained 22 mg or 105 mg of zolbetuximab. Prior to administration, zolbetuximab was reconstituted with 1.1 mL (22 mg zolbetuximab vials) or 5.0 mL (105 mg zolbetuximab vials) water for injection, which resulted in a concentration of 20 mg/mL zolbetuximab. The extractable volume per vial was 1 mL (for 22 mg zolbetuximab vials) or 5 mL (for 105 mg zolbetuximab vials). The reconstituted solution was further diluted with sodium chloride 0.9% to a final concentration of 2 mg/mL zolbetuximab. Zolbetuximab was administered as an intravenous infusion over 2 to 3 hours.

    Investigational medicinal product name
    oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin was administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle.

    Arm title
    EOX+zolbetuximab 1000 mg/m^2
    Arm description
    Participants received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab 1000 mg/m^2 intravenously on day 1 of each cycle. Zolbetuximab was administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants were permitted to continue zolbetuximab monotherapy (1000 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion ) until PD, withdrawal of consent or unacceptable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin was administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle.

    Investigational medicinal product name
    zolbetuximab
    Investigational medicinal product code
    IMAB362
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Two different formats of zolbetuximab, comprising different strengths, were provided. Vials contained 22 mg or 105 mg of zolbetuximab. Prior to administration, zolbetuximab was reconstituted with 1.1 mL (22 mg zolbetuximab vials) or 5.0 mL (105 mg zolbetuximab vials) water for injection, which resulted in a concentration of 20 mg/mL zolbetuximab. The extractable volume per vial was 1 mL (for 22 mg zolbetuximab vials) or 5 mL (for 105 mg zolbetuximab vials). The reconstituted solution was further diluted with sodium chloride 0.9% to a final concentration of 2 mg/mL zolbetuximab. Zolbetuximab was administered as an intravenous infusion over 2 to 3 hours.

    Investigational medicinal product name
    capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The daily dose of capecitabine was 1250 mg/m^2. Capecitabine tablets were given once daily at a dose of 625 mg/m^2 orally in the evening of day 1 of each cycle and twice daily at a dose of 625 mg/m^2 orally on days 2 to 21 of each cycle; the morning dose of capecitabine on day 1 of each cycle was omitted due to administration of zolbetuximab, epirubicin and oxaliplatin.

    Investigational medicinal product name
    oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin was administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle.

    Number of subjects in period 1
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Started
    85
    79
    88
    Treated
    84
    77
    85
    Discontinued within 8 cycles
    52
    42
    45
    Continued zolbetuximab monotherapy
    0 [2]
    32 [3]
    27 [4]
    Completed
    32
    34
    38
    Not completed
    53
    45
    50
         Randomized but not treated
    1
    2
    3
         Miscellaneous
    4
    4
    1
         Withdrawal of consent
    8
    10
    11
         Significant protocol violation
    2
    -
    1
         Clinical progression
    8
    1
    2
         Change in patient’s condition
    6
    3
    6
         Adverse event (AE)/Serious Adverse Event (SAE)
    3
    4
    3
         EOX not completed cont. zolbetuximab
    -
    1
    2
         Confirmed progression per RECIST v1.1
    21
    19
    21
         Lost to follow-up
    -
    1
    -
    Notes
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: No participants in Arm 1 continued on to receive zolbetuximab as a single-agent maintenance treatment after the EOX phase.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 32 participants in Arm 2 continued to receive zolbetuximab as a single-agent maintenance treatment after the EOX phase.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: A total of 27 participants in Arm 3 continued to receive zolbetuximab as a single-agent maintenance treatment after the EOX phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EOX Treatment
    Reporting group description
    Participants received up to 8 cycles of epirubicin, oxaliplatin and capecitabine (EOX) chemotherapy treatment alone (50 mg/m^2 epirubicin intravenously on day 1 of each cycle, 130 mg/m^2 oxaliplatin intravenously on day 1 of each cycle, 625 mg/m^2 capecitabine orally twice daily on days 1 to 21 of each cycle). The first dose of capecitabine taken in the evening of day 1.

    Reporting group title
    EOX+zolbetuximab 800/600 mg/m^2
    Reporting group description
    Participants received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab administered as loading dose of 800 mg/m^2 intravenously on day 1 of cycle 1 followed by 600 mg/m^2 intravenously on day 1 of each subsequent cycle. Zolbetuximab was administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants were permitted to continue zolbetuximab monotherapy (600 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion) until progressive disease (PD), withdrawal of consent or unacceptable toxicity. PD per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5mm must also be demonstrated, unequivocal progression of existing non-target lesions and appearance of one or more new lesions was considered progression.

    Reporting group title
    EOX+zolbetuximab 1000 mg/m^2
    Reporting group description
    Participants received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab 1000 mg/m^2 intravenously on day 1 of each cycle. Zolbetuximab was administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants were permitted to continue zolbetuximab monotherapy (1000 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion ) until PD, withdrawal of consent or unacceptable toxicity.

    Reporting group values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2 Total
    Number of subjects
    85 79 88
    Age categorical
    Units: Subjects
    Age continuous
    The baseline characteristics consisted of the all randomized population.
    Units: years
        arithmetic mean (standard deviation)
    55.9 ± 10.5 56.8 ± 11.8 57.4 ± 9.8 -
    Gender categorical
    Units: Subjects
        M
    57 48 59 164
        F
    28 31 29 88
    Location of Tumor at First Diagnosis
    Units: Subjects
        ESOPHAGUS
    4 2 0 6
        GASTROESOPHAGEAL JUNCTION
    12 14 8 34
        STOMACH
    69 63 80 212
    Measurable Disease
    Units: Subjects
        MEASURABLE
    67 66 61 194
        NON-MEASURABLE
    18 13 27 58
    Race
    Units: Subjects
        WHITE
    81 75 86 242
        OTHER
    4 4 2 10
    Result of CLDN18.2 IHC Test
    Units: Subjects
        2+
    35 26 43 104
        3+
    50 53 45 148
    Time since First Diagnosis (months)
    Units: Year
        arithmetic mean (standard deviation)
    4.3 ± 6.4 8.2 ± 16.3 6.4 ± 11.8 -

    End points

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    End points reporting groups
    Reporting group title
    EOX Treatment
    Reporting group description
    Participants received up to 8 cycles of epirubicin, oxaliplatin and capecitabine (EOX) chemotherapy treatment alone (50 mg/m^2 epirubicin intravenously on day 1 of each cycle, 130 mg/m^2 oxaliplatin intravenously on day 1 of each cycle, 625 mg/m^2 capecitabine orally twice daily on days 1 to 21 of each cycle). The first dose of capecitabine taken in the evening of day 1.

    Reporting group title
    EOX+zolbetuximab 800/600 mg/m^2
    Reporting group description
    Participants received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab administered as loading dose of 800 mg/m^2 intravenously on day 1 of cycle 1 followed by 600 mg/m^2 intravenously on day 1 of each subsequent cycle. Zolbetuximab was administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants were permitted to continue zolbetuximab monotherapy (600 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion) until progressive disease (PD), withdrawal of consent or unacceptable toxicity. PD per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5mm must also be demonstrated, unequivocal progression of existing non-target lesions and appearance of one or more new lesions was considered progression.

    Reporting group title
    EOX+zolbetuximab 1000 mg/m^2
    Reporting group description
    Participants received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab 1000 mg/m^2 intravenously on day 1 of each cycle. Zolbetuximab was administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants were permitted to continue zolbetuximab monotherapy (1000 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion ) until PD, withdrawal of consent or unacceptable toxicity.

    Primary: Progression-free Survival (PFS)

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    End point title
    Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from randomization to the first observation of disease progression (based on central reading) or death from any cause (as assessed by the independent reviewer). Participants without documented progression or death were censored as of the last tumor evaluation determining lack of progression. The analysis population consisted of the full analysis set (FAS) which consisted of all participants who were randomized and received at least 1 dose of any study medication.
    End point type
    Primary
    End point timeframe
    From randomization to the data cut-off date of 31JAN2019; maximum time on follow-up was, 68.2, 47.2 & 59.6 months in the EOX, EOX+Zolbetuximab 600 mg, and EOX+Zolbetuximab 1000 mg treatment groups respectively.
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    84
    77
    85
    Units: months
        median (confidence interval 95%)
    5.3 (4.1 to 7.1)
    7.5 (5.6 to 11.3)
    7.1 (5.6 to 8.0)
    Statistical analysis title
    PFS Treatment Comparison (Arm 1 versus Arm 2)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0005 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.67
    Notes
    [1] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [2] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    PFS Treatment Comparison (Arm 1 versus Arm 3)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.0114 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    0.85
    Notes
    [3] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [4] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    PFS Treatment Comparison (Arm 3 versus Arm 2)
    Comparison groups
    EOX+zolbetuximab 800/600 mg/m^2 v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.2842 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.18
    Notes
    [5] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [6] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

    Primary: Number of Participants with Adverse Events (AEs)

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    End point title
    Number of Participants with Adverse Events (AEs) [7]
    End point description
    An AE was defined as any unintended or undesirable, noxious or pathological change, compared to pre-existing conditions, experienced by a participant during a clinical study or the follow-up period, regardless of relationship to study medication. Treatment-emergent adverse event (TEAE) were those AEs that started or worsened after the first dose of study medication. The analysis population consisted of the safety analysis set (SAF) which consisted of all participants who received at least 1 dose of any study medication.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug administration up to 30 days after the last study medication administration (up to 1791 days).
    Notes
    [7] - 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 not applicable, only descriptive statistics data applicable for this endpoint.
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    84
    77
    85
    Units: participants
        Any TEAE
    84
    74
    85
        Grade ≥ 3 TEAEs
    54
    54
    58
        Serious TEAEs
    27
    19
    17
        Study drug-related TEAEs
    80
    74
    83
        Study drug-related TEAEs - zolbetuximab
    0
    64
    73
        Study drug-related TEAEs - epirubicin
    76
    70
    77
        Study drug-related TEAEs - oxaliplatin
    76
    71
    74
        Study drug-related TEAEs - capecitabine
    78
    70
    75
        Study drug-related serious TEAEs
    5
    8
    5
        Study drug-related serious TEAEs - zolbetuximab
    0
    1
    0
        Study drug-related serious TEAEs - epirubicin
    4
    6
    3
        Study drug-related serious TEAEs - oxaliplatin
    4
    7
    3
        Study drug-related serious TEAEs - capecitabine
    5
    8
    5
        TEAEs leading to withdrawal of zolbetuximab
    0
    10
    11
        Fatal TEAEs
    15
    8
    9
    No statistical analyses for this end point

    Secondary: Clinical PFS

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    End point title
    Clinical PFS
    End point description
    Clinical PFS (CPFS) was defined as the time from randomization to the first observation of disease progression, either confirmed by CT scans or by clinical evaluation, or death from any cause (as assessed by the independent reviewer with clinical PD considered as an event). Participants without documented progression or death were censored as of the last tumor evaluation determining lack of progression. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization to the data cut-off date of 31JAN2019; maximum time on follow-up was, 68.2, 47.2 & 59.6 months in the EOX, EOX+Zolbetuximab 600 mg, and EOX+Zolbetuximab 1000 mg treatment groups respectively.
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    84
    77
    85
    Units: months
        median (confidence interval 95%)
    4.6 (4.0 to 7.1)
    7.5 (5.6 to 11.3)
    7.1 (5.6 to 8.0)
    Statistical analysis title
    CPFS Treatment Comparison (Arm 1 versus Arm 2)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    < 0.0005 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.65
    Notes
    [8] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [9] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    CPFS Treatment Comparison (Arm 1 versus Arm 3)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.0085 [11]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    0.83
    Notes
    [10] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [11] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    CPFS Treatment Comparison (Arm 3 versus Arm 2)
    Comparison groups
    EOX+zolbetuximab 800/600 mg/m^2 v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2904 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    1.18
    Notes
    [12] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

    Secondary: Overall Survival Rate at 12 Months

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    End point title
    Overall Survival Rate at 12 Months
    End point description
    Overall survival rate at 12 months after therapy initiation was defined as a proportion of participants alive after 12 months from first dose of any study drug. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    Up to 12 months
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    84
    77
    85
    Units: percentage of participants
        number (confidence interval 95%)
    27.4 (18.2 to 37.4)
    52.9 (40.8 to 63.6)
    37.4 (27.0 to 47.8)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death from any cause or last contact (if alive). The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization to the data cut-off date of 31JAN2019; maximum time on follow-up was, 68.2, 47.2 & 59.6 months in the EOX, EOX+Zolbetuximab 600 mg, and EOX+Zolbetuximab 1000 mg treatment groups respectively.
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    84
    77
    85
    Units: months
        median (confidence interval 95%)
    8.3 (6.9 to 10.2)
    13.0 (9.7 to 18.7)
    9.6 (8.3 to 11.4)
    Statistical analysis title
    OS Treatment Comparison (Arm 1 versus Arm 2)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    < 0.0005 [14]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    0.77
    Notes
    [13] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [14] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    OS Treatment Comparison (Arm 1 versus Arm )
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.1292 [16]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.04
    Notes
    [15] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [16] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    OS Treatment Comparison (Arm 3 versus Arm 2)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    P-value
    = 0.128 [18]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.02
    Notes
    [17] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [18] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    TTP was defined as the time from randomization to the first observation of disease progression (based on central reading as assessed by the investigator reviewer). Participants without documented progression were censored as of the last tumor evaluation determining lack of progression. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization to the data cut-off date of 31JAN2019; maximum time on follow-up was, 68.2, 47.2 & 59.6 months in the EOX, EOX+Zolbetuximab 600 mg, and EOX+Zolbetuximab 1000 mg treatment groups respectively.
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    84
    77
    85
    Units: months
        median (confidence interval 95%)
    7.0 (5.7 to 7.7)
    9.0 (6.1 to 11.6)
    6.9 (5.6 to 8.4)
    Statistical analysis title
    TTP Treatment Comparison (Arm 1 versus Arm 2)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    = 0.0076 [20]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    0.83
    Notes
    [19] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [20] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    TTP Treatment Comparison (Arm 3 versus Arm 2)
    Comparison groups
    EOX+zolbetuximab 800/600 mg/m^2 v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.0997 [22]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.06
    Notes
    [21] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [22] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.
    Statistical analysis title
    TTP Treatment Comparison (Arm 1 versus Arm 3)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.183 [24]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.15
    Notes
    [23] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [24] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.

    Secondary: Objective Tumor Response Rate (ORR)

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    End point title
    Objective Tumor Response Rate (ORR)
    End point description
    ORR was defined as the fraction of participants with a complete response (CR) or partial response (PR), according to RECIST v1.1 (as assessed by the investigator reviewer). CR according to RECIST v1.1 was defined as the disappearance of all target lesions, any pathological lymph node must have had reduction in short axis to < 10 mm, disappearance of all non-target lesions and normalization of tumor marker level should have occurred as well as no simultaneous appearance of new lesions. PR according to RECIST v1.1 was defined as at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the screening sum longest diameter and no simultaneous increase in the size of any lesion or the appearance of new lesions should have occurred. The analysis population consisted of the FAS. N is the number of participants with available data.
    End point type
    Secondary
    End point timeframe
    Up to week 94
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    21 [25]
    30 [26]
    26 [27]
    Units: percentage of participants
    number (not applicable)
        Based on best response (confirmed)
    25.0
    39.0
    30.6
        Based on best response (confirmed and unconfirmed)
    33.3
    49.4
    41.2
    Notes
    [25] - N=28 for confirmed and unconfirmed
    [26] - N=38 for confirmed and unconfirmed
    [27] - N=35 for confirmed and unconfirmed
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    Disease Control Rate (DCR)
    End point description
    DCR was defined as the fraction of participants with CR or PR or stable disease (SD) according to RECIST v1.1 (as assessed by the investigator reviewer). SD according to RECIST v1.1 was defined as neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter recorded since treatment started, measurements must have met the SD criteria at least once after study entry at a minimum interval not less than 6 weeks, no simultaneous increase in the size of any lesion or the appearance of new lesions should have occurred, evaluable lesions must have remained stable or regressed for this category. The analysis population consisted of the FAS. N is the number of participants with available data.
    End point type
    Secondary
    End point timeframe
    Up to week 94
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    64
    64
    67 [28]
    Units: percentage of participants
    number (not applicable)
        Based on best response (confirmed)
    76.2
    83.1
    78.8
        Based on best response (confirmed and unconfirmed)
    76.2
    83.1
    80.0
    Notes
    [28] - N=68 for confirmed and unconfirmed
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    Duration of Response (DOR)
    End point description
    DOR was determined as the time when criteria for CR or PR were first met until the first date that recurrent or progressive disease or death occurred (as assessed by the independent reviewer). The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From randomization to the data cut-off date of 31JAN2019; maximum time on follow-up was, 68.2, 47.2 & 59.6 months in the EOX, EOX+Zolbetuximab 600 mg, and EOX+Zolbetuximab 1000 mg treatment groups respectively.
    End point values
    EOX Treatment EOX+zolbetuximab 800/600 mg/m^2 EOX+zolbetuximab 1000 mg/m^2
    Number of subjects analysed
    84
    77
    85
    Units: months
        median (confidence interval 95%)
    5.0 (3.2 to 6.7)
    7.5 (4.8 to 10.9)
    7.6 (4.5 to 11.7)
    Statistical analysis title
    OS Treatment Comparison (Arm 1 versus Arm 2)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 800/600 mg/m^2
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    = 0.0234 [30]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    0.93
    Notes
    [29] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [30] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    OS Treatment Comparison (Arm 1 versus Arm 3)
    Comparison groups
    EOX Treatment v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    169
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    = 0.0854 [32]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    1.09
    Notes
    [31] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [32] - The analyses were performed using 1-sided tests at the 2.5% significance level for comparisons vs Arm 1.
    Statistical analysis title
    OS Treatment Comparison (Arm 3 versus Arm 2)
    Comparison groups
    EOX+zolbetuximab 800/600 mg/m^2 v EOX+zolbetuximab 1000 mg/m^2
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    = 0.5781 [34]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.57
    Notes
    [33] - Hazard ratios were based on a Cox proportional hazard model stratified by presence of measurable vs nonmeasurable disease at baseline and by the number of CLDN18.2 stained cells categorized as < 70% vs ≥ 70%.
    [34] - The analyses were performed using a 2-sided test at the 5% significance level for the comparison of Arm 3 vs Arm 2.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug administration up to 30 days after the last study medication administration (up to 1791 days).
    Adverse event reporting additional description
    The total number of deaths (all causes) includes deaths reported after the time frame above.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    EOX Treatment
    Reporting group description
    Reporting group 1 description

    Reporting group title
    EOX+zolbetuximab 1000 mg/m^2
    Reporting group description
    Reporting group 3 description

    Reporting group title
    EOX+zolbetuximab 800/600 mg/m^2
    Reporting group description
    Reporting group 2 description

    Serious adverse events
    EOX Treatment EOX+zolbetuximab 1000 mg/m^2 EOX+zolbetuximab 800/600 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 84 (32.14%)
    17 / 85 (20.00%)
    19 / 77 (24.68%)
         number of deaths (all causes)
    79
    77
    63
         number of deaths resulting from adverse events
    15
    9
    8
    Vascular disorders
    Arterial thrombosis limb
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Remnant gastritis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer recurrent
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    7 / 84 (8.33%)
    4 / 85 (4.71%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 7
    0 / 4
    0 / 3
    Neoplasm progression
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 85 (2.35%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 85 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    3 / 84 (3.57%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Infections and infestations
    Abscess soft tissue
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 85 (0.00%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 85 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 85 (1.18%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    EOX Treatment EOX+zolbetuximab 1000 mg/m^2 EOX+zolbetuximab 800/600 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 84 (97.62%)
    83 / 85 (97.65%)
    74 / 77 (96.10%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 84 (7.14%)
    5 / 85 (5.88%)
    6 / 77 (7.79%)
         occurrences all number
    7
    5
    18
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 84 (13.10%)
    6 / 85 (7.06%)
    7 / 77 (9.09%)
         occurrences all number
    14
    6
    14
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 84 (10.71%)
    1 / 85 (1.18%)
    6 / 77 (7.79%)
         occurrences all number
    11
    1
    13
    Body temperature increased
         subjects affected / exposed
    7 / 84 (8.33%)
    4 / 85 (4.71%)
    3 / 77 (3.90%)
         occurrences all number
    12
    10
    14
    C-reactive protein increased
         subjects affected / exposed
    3 / 84 (3.57%)
    5 / 85 (5.88%)
    3 / 77 (3.90%)
         occurrences all number
    3
    6
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 84 (7.14%)
    8 / 85 (9.41%)
    9 / 77 (11.69%)
         occurrences all number
    7
    12
    11
    Lipase increased
         subjects affected / exposed
    3 / 84 (3.57%)
    3 / 85 (3.53%)
    4 / 77 (5.19%)
         occurrences all number
    3
    3
    4
    Weight decreased
         subjects affected / exposed
    26 / 84 (30.95%)
    25 / 85 (29.41%)
    25 / 77 (32.47%)
         occurrences all number
    27
    28
    25
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 84 (2.38%)
    4 / 85 (4.71%)
    5 / 77 (6.49%)
         occurrences all number
    4
    8
    5
    Epistaxis
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 85 (1.18%)
    2 / 77 (2.60%)
         occurrences all number
    7
    1
    3
    Dyspnoea
         subjects affected / exposed
    4 / 84 (4.76%)
    4 / 85 (4.71%)
    4 / 77 (5.19%)
         occurrences all number
    6
    7
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    30 / 84 (35.71%)
    40 / 85 (47.06%)
    35 / 77 (45.45%)
         occurrences all number
    35
    59
    59
    Leukopenia
         subjects affected / exposed
    14 / 84 (16.67%)
    14 / 85 (16.47%)
    12 / 77 (15.58%)
         occurrences all number
    19
    28
    23
    Neutropenia
         subjects affected / exposed
    28 / 84 (33.33%)
    40 / 85 (47.06%)
    33 / 77 (42.86%)
         occurrences all number
    48
    85
    70
    Lymphopenia
         subjects affected / exposed
    5 / 84 (5.95%)
    8 / 85 (9.41%)
    3 / 77 (3.90%)
         occurrences all number
    8
    15
    6
    Thrombocytopenia
         subjects affected / exposed
    9 / 84 (10.71%)
    8 / 85 (9.41%)
    11 / 77 (14.29%)
         occurrences all number
    11
    8
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 84 (9.52%)
    4 / 85 (4.71%)
    4 / 77 (5.19%)
         occurrences all number
    30
    4
    15
    Headache
         subjects affected / exposed
    18 / 84 (21.43%)
    13 / 85 (15.29%)
    12 / 77 (15.58%)
         occurrences all number
    56
    31
    68
    Neuropathy peripheral
         subjects affected / exposed
    6 / 84 (7.14%)
    0 / 85 (0.00%)
    6 / 77 (7.79%)
         occurrences all number
    8
    0
    10
    Paraesthesia
         subjects affected / exposed
    9 / 84 (10.71%)
    12 / 85 (14.12%)
    10 / 77 (12.99%)
         occurrences all number
    26
    15
    18
    Peripheral sensory neuropathy
         subjects affected / exposed
    5 / 84 (5.95%)
    10 / 85 (11.76%)
    5 / 77 (6.49%)
         occurrences all number
    16
    13
    10
    Polyneuropathy
         subjects affected / exposed
    4 / 84 (4.76%)
    0 / 85 (0.00%)
    4 / 77 (5.19%)
         occurrences all number
    4
    0
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 84 (22.62%)
    17 / 85 (20.00%)
    18 / 77 (23.38%)
         occurrences all number
    36
    37
    34
    Fatigue
         subjects affected / exposed
    17 / 84 (20.24%)
    21 / 85 (24.71%)
    24 / 77 (31.17%)
         occurrences all number
    31
    32
    47
    Chills
         subjects affected / exposed
    2 / 84 (2.38%)
    3 / 85 (3.53%)
    4 / 77 (5.19%)
         occurrences all number
    3
    3
    5
    Pyrexia
         subjects affected / exposed
    16 / 84 (19.05%)
    9 / 85 (10.59%)
    9 / 77 (11.69%)
         occurrences all number
    28
    12
    12
    Oedema peripheral
         subjects affected / exposed
    6 / 84 (7.14%)
    12 / 85 (14.12%)
    10 / 77 (12.99%)
         occurrences all number
    11
    14
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 84 (3.57%)
    5 / 85 (5.88%)
    3 / 77 (3.90%)
         occurrences all number
    6
    7
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 84 (11.90%)
    9 / 85 (10.59%)
    14 / 77 (18.18%)
         occurrences all number
    17
    17
    24
    Abdominal pain upper
         subjects affected / exposed
    18 / 84 (21.43%)
    8 / 85 (9.41%)
    7 / 77 (9.09%)
         occurrences all number
    26
    10
    9
    Ascites
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 85 (4.71%)
    2 / 77 (2.60%)
         occurrences all number
    14
    5
    5
    Constipation
         subjects affected / exposed
    6 / 84 (7.14%)
    3 / 85 (3.53%)
    4 / 77 (5.19%)
         occurrences all number
    15
    7
    6
    Diarrhoea
         subjects affected / exposed
    31 / 84 (36.90%)
    16 / 85 (18.82%)
    13 / 77 (16.88%)
         occurrences all number
    100
    30
    32
    Dyspepsia
         subjects affected / exposed
    3 / 84 (3.57%)
    4 / 85 (4.71%)
    4 / 77 (5.19%)
         occurrences all number
    9
    4
    5
    Dysphagia
         subjects affected / exposed
    6 / 84 (7.14%)
    2 / 85 (2.35%)
    4 / 77 (5.19%)
         occurrences all number
    7
    2
    6
    Nausea
         subjects affected / exposed
    64 / 84 (76.19%)
    70 / 85 (82.35%)
    63 / 77 (81.82%)
         occurrences all number
    301
    389
    305
    Salivary hypersecretion
         subjects affected / exposed
    2 / 84 (2.38%)
    8 / 85 (9.41%)
    5 / 77 (6.49%)
         occurrences all number
    3
    20
    8
    Vomiting
         subjects affected / exposed
    46 / 84 (54.76%)
    66 / 85 (77.65%)
    52 / 77 (67.53%)
         occurrences all number
    159
    348
    292
    Stomatitis
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 85 (1.18%)
    3 / 77 (3.90%)
         occurrences all number
    5
    1
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    17 / 84 (20.24%)
    22 / 85 (25.88%)
    22 / 77 (28.57%)
         occurrences all number
    18
    22
    23
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    6 / 84 (7.14%)
    3 / 85 (3.53%)
    10 / 77 (12.99%)
         occurrences all number
    6
    3
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 84 (7.14%)
    1 / 85 (1.18%)
    2 / 77 (2.60%)
         occurrences all number
    7
    1
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 84 (22.62%)
    16 / 85 (18.82%)
    15 / 77 (19.48%)
         occurrences all number
    26
    31
    19
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 84 (5.95%)
    8 / 85 (9.41%)
    5 / 77 (6.49%)
         occurrences all number
    5
    9
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2012
    The changes included: Amendment 1 was issued before the first patient was enrolled into the study. The amendment revised the inclusion criterion related to CLDN18.2 expression in tumor cells.
    12 Jun 2013
    The changes included: Amendment 2 was issued after approximately 60 patients had been enrolled into each of Arms 1 and 2. This amendment specified the addition of Arm 3
    26 May 2014
    The changes included: Amendment 3 was issued after 248 patients had been enrolled into the study. The amendment clarified the analysis parameters.
    04 Nov 2014
    The changes included: Amendment 4 was issued after 252 patients had been enrolled into the study. The amendment specified the addition of the interim analysis.
    28 Jul 2015
    The changes included: Amendment 5 added a single additional blood draw for patients receiving zolbetuximab for > 12 months to allow for an assessment of adaptive immunity.
    26 Jan 2016
    The changes included: Amendment 6 condensed the schedule of procedures to facilitate the longer-term follow-up of patients including prolonging the imaging intervals from 6 to 12 weeks and simplifying the follow-up procedures.
    11 Sep 2017
    The changes included: Amendment 7 changed the study sponsor from Ganymed Pharmaceuticals, Ag to Astellas Pharma Global Development, Inc.

    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.
    The study was conducted by Ganymed AG, a company that was acquired by Astellas in Dec 2016.
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