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    Clinical Trial Results:
    International, Multicenter, Open-label, Phase II Study to Investigate the Efficacy and Safety of Multiple Doses of IMAB362 in Patients With Advanced Adenocarcinoma of the Stomach or the Lower Esophagus

    Summary
    EudraCT number
    		 2009-017365-36
    Trial protocol
    		 DE   LV   CZ   LT   AT   BG  
    Global end of trial date
    13 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2019
    First version publication date
    10 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8951-CL-0201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01197885
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Protocol Number: GM-IMAB-001-02, Acronym: MONO
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, 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
    13 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine antitumoral activity of zolbetuximab as monotherapy in patients with metastatic, refractory or recurrent disease of advanced adenocarcinoma of the stomach or the lower esophagus proven by histology.
    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
    03 Sep 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Latvia: 10
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Switzerland: 5
    Worldwide total number of subjects
    54
    EEA total number of subjects
    49
    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)
    38
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multinational, multicenter study was conducted at 21 contracted sites in 5 countries including Germany (13 sites), Bulgaria (3 sites), Latvia (3 sites), Lithuania (1 site) and Switzerland (1 site).

    Pre-assignment
    Screening details
    		 Prior to any screening procedures, all participants provided written informed consent to participate in the study. Screening evaluations were performed from 15 days to 1 day before (day -15 to day -1) administration of the study drug on visit 2. Eligible participants who met inclusion criteria and none of the exclusion criteria were enrolled.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Zolbetuximab 300 mg/m^2
    Arm description
    		 Participants received repeated doses of zolbetuximab at a lower dose level (300 mg/m^2 Body Surface Area (BSA)) every 2 weeks on visits 2, 5, 6, 7 and 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zolbetuximab
    Investigational medicinal product code
    IMAB362
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Zolbetuximab was administered to cohorts 1, 2 and 3 with the applicable dosage (antibody/body surface area) and in a sequential manner, i.e, the last participant in a prior cohort had to complete the 5 infusions before starting the infusion of the first participant in the next cohort. Zolbetuximab was administered as a 2-hour intravenous infusion, using an infusion system.

    Arm title
    		 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Arm description
    		 Cohort 2 participants received repeated doses of zolbetuximab at a higher dose level (600 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8. Cohort 3 participants received repeated doses of zolbetuximab (600 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zolbetuximab
    Investigational medicinal product code
    IMAB362
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Zolbetuximab was administered to cohorts 1, 2 and 3 with the applicable dosage (antibody/body surface area) and in a sequential manner, i.e, the last participant in a prior cohort had to complete the 5 infusions before starting the infusion of the first participant in the next cohort. Zolbetuximab was administered as a 2-hour intravenous infusion, using an infusion system.

    Number of subjects in period 1
    		Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Started
    4
    50
    Treated
    4
    50
    Completed
    1
    4
    Not completed
    3
    46
         Death
    1
    5
         Miscellaneous
    1
    26
         Adverse event
    1
    6
         Withdrawal of consent
    -
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Zolbetuximab 300 mg/m^2
    Reporting group description
    		 Participants received repeated doses of zolbetuximab at a lower dose level (300 mg/m^2 Body Surface Area (BSA)) every 2 weeks on visits 2, 5, 6, 7 and 8.

    Reporting group title
    Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Reporting group description
    		 Cohort 2 participants received repeated doses of zolbetuximab at a higher dose level (600 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8. Cohort 3 participants received repeated doses of zolbetuximab (600 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8.

    Reporting group values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2 Total
    Number of subjects
    		 4 50
    Age categorical
    Units: Subjects
    Age continuous
    The analysis population for the baseline characteristics consisted of the All-patients-treated set (APT), comprised of all participants who received at least 1 administration of study drug at any dose level and for any period of time.
    Units: years
        arithmetic mean (standard deviation)
    		 58.8 ( 9.5 ) 59.1 ( 10.6 ) -
    Gender categorical
    Units:
        Male
    		 1 36 37
        Female
    		 3 14 17
    Race
    Units: Subjects
        White
    		 4 50 54

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Zolbetuximab 300 mg/m^2
    Reporting group description
    		 Participants received repeated doses of zolbetuximab at a lower dose level (300 mg/m^2 Body Surface Area (BSA)) every 2 weeks on visits 2, 5, 6, 7 and 8.

    Reporting group title
    Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Reporting group description
    		 Cohort 2 participants received repeated doses of zolbetuximab at a higher dose level (600 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8. Cohort 3 participants received repeated doses of zolbetuximab (600 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8.

    Subject analysis set title
    Cohort 1: KI 80 at baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with a KI of 80% at baseline, defined as normal activity with effort; some signs or symptoms of disease.

    Subject analysis set title
    Cohort 2+3: KI 70 at baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with a KI of 70% at baseline, defined as cares for self; unable to carry on normal activity or to do active work.

    Subject analysis set title
    Cohort 2+3: KI 80 at baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with a KI of 80% at baseline, defined as normal activity with effort; some signs or symptoms of disease.

    Subject analysis set title
    Cohort 2+3: KI 90 at baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with a KI of 90% at baseline, defined as able to carry on normal activity; minor signs or symptoms of disease.

    Subject analysis set title
    Cohort 2+3: KI 100 at baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with a KI of 100% at baseline, defined as normal, no complaints; no evidence of disease.

    Subject analysis set title
    Cohort 1: ECOG Grade 1 at baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with a score of grade 1 at baseline, defined as restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.

    Subject analysis set title
    Cohort 2+3: ECOG Grade 0 at baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with a score of grade 0 at baseline, defined as fully active, able to carry on all pre-disease performance without restriction.

    Subject analysis set title
    Cohort 2+3: ECOG Grade 1 at baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with a score of grade 1 at baseline, defined as restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.

    Primary: Percentage of Participants with at Least 30% Decrease in Size of Lesions

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    End point title
    		 Percentage of Participants with at Least 30% Decrease in Size of Lesions [1]
    End point description
    Decrease of 30% size of lesions was defined as a 30% decrease from baseline of one-dimensional measure of tumor size without significant increasing of nontarget lesion and no new lesion, based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria determined by computed tomography (CT) or magnetic resonance imaging (MRI), i.e., the sum of the 5 longest tumor diameters at the target lesions. The sum of the longest diameters at visit 9 was used if available, if not available, the sum at visit 10 was used. Nontarget lesions with status “unequivocal progression” or “unknown” were regarded to be significant increasing. RECIST version 1.0 was used [Eisenhauer et al, 2000] and new version 1.1 [Eisenhauer et al, 2009] was accepted, if used for all examinations for a single participant. The analysis population consisted of the full analysis set (FAS), comprised of all participants who received at least 1 dose of study drug and for whom efficacy data upon treatment was available.
    End point type
    Primary
    End point timeframe
    From first infusion until the end of study, maximum time on study was 36.4 months.
    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 analysis is not applicable for this endpoint.
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    3
    36
    Units: percentage of participants
        number (not applicable)
    0.0
    5.0
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a participant administered a study drug and which does not necessarily have to have a causal relationship with this treatment, and includes an abnormal laboratory finding or test. A treatment-emergent adverse event (TEAE) was defined as any adverse event with a start date on or after the date of the first infusion and until 28 days after the last infusion. A serious adverse event (SAE) was defined as any untoward medical occurrence that: ●Resulted in death ●Was life-threatening ●Required hospitalization or prolongation of an existing hospitalization ●Resulted in disability/incapacity or ●Was a congenital anomaly/birth defect in the offspring of a study participant ●Was another medically important condition. The analysis population consisted of the APT.
    End point type
    Secondary
    End point timeframe
    From start of first infusion up to until 28 days after the last infusion; Up to 35.71 months.
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    50
    Units: participants
        Any TEAE
    4
    48
        Adverse reactions (ARs) or Drug-related TEAEs
    3
    41
        Deaths
    0
    10
        Serious TEAEs
    1
    24
        Serious ARs (SARs) or Drug-related Serious TEAEs
    1
    4
        TEAEs Leading to Study Drug Discontinuation
    1
    10
        ARs or Drug-related TEAEs Leading to Drug Disc.
    0
    4
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time between start of first infusion and date of first observed disease progression according to the overall response or death due to any cause. PFS was calculated and plotted using Kaplan-Meier estimation with 95% confidence interval (CI). Participants with no baseline and postbaseline tumor assessments, no progression or death reported, discontinued study other than death or progressive disease and progression or death after 2 or more consecutive missed CT scans were censored. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From first infusion until the end of study, maximum time on study was 36.4 months.
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    3
    35
    Units: weeks
        median (confidence interval 95%)
    10.00 (10.000 to 11.000)
    10.00 (8.600 to 10.100)
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-Zolbetuximab (IMAB362) Antibodies

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    End point title
    		 Number of Participants with Anti-Zolbetuximab (IMAB362) Antibodies
    End point description
    The analysis population consisted of the APT.
    End point type
    Secondary
    End point timeframe
    From first infusion until the end of study, maximum time on study was 36.4 months.
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    50
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Quality of Life (QoL) per European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30)

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    End point title
    		 Change from Baseline in Quality of Life (QoL) per European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30)
    End point description
    The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients. It is supplemented by a disease-specific module (QLQ-STO22). EORTC QLQ-C30 (version 3) was analyzed according to the scoring manual. All of the scales and single-item measures range from 0 to 100 by applying a linear transformation to standardize the raw score. A high scale score represents a higher response level: A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL scale represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. The analysis population consisted of the FAS with data available at baseline and visit 10. N is the number of participants with available data. Data not available/applicable is denoted as "99999."
    End point type
    Secondary
    End point timeframe
    Baseline and X (where X is a time point 7-9 weeks after last treatment)
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    1
    24
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Global health status [N=0, 24]
    99999 ( 99999 )
    -3.7 ( 19.6 )
        Physical functioning [N=1, 12]
    0.0 ( 99999 )
    -15.8 ( 23.5 )
        Role functioning [N=1, 12]
    0.0 ( 99999 )
    -16.7 ( 27.4 )
        Emotional functioning [N=0, 11]
    99999 ( 99999 )
    -8.5 ( 15.8 )
        Cognitive functioning [N=0, 11]
    99999 ( 99999 )
    -10.6 ( 13.5 )
        Social functioning [N=0, 11]
    99999 ( 99999 )
    -13.5 ( 24.7 )
        Fatigue [N=1, 12]
    34.0 ( 99999 )
    9.2 ( 29.2 )
        Nausea and vomiting [N=1, 12]
    50.0 ( 99999 )
    29.1 ( 37.7 )
        Pain [N=1, 12]
    0.0 ( 99999 )
    11.3 ( 25.9 )
        Dyspnoea [N=0, 11]
    99999 ( 99999 )
    6.0 ( 25.0 )
        Insomnia [N=1, 12]
    34.0 ( 99999 )
    16.8 ( 22.5 )
        Appetite loss [N=1, 12]
    33.0 ( 99999 )
    27.9 ( 37.2 )
        Constipation [N=1, 12]
    -100.0 ( 99999 )
    13.9 ( 33.2 )
        Diarrhoea [N=0, 11]
    99999 ( 99999 )
    3.1 ( 18.0 )
        Financial difficulties [N=0, 11]
    99999 ( 99999 )
    -3.2 ( 31.7 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in QoL per Quality of Life Questionnaire Gastric Cancer Module (QLQ-STO22)

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    End point title
    		 Change from Baseline in QoL per Quality of Life Questionnaire Gastric Cancer Module (QLQ-STO22)
    End point description
    The QLQ-STO22 is a disease-specific module. All of the scales and single-item measures range from 0 to 100 by applying a linear transformation to standardize the raw score. A high scale score represents a higher response level: A high score for a functional scale represents a high/healthy level of functioning but a high score for a symptom scale/item represents a high level of symptomatology/problems. The analysis population consisted of the FAS with data available at baseline and visit 10. N is the number of participants with available data. Data not available/applicable is denoted as "99999."
    End point type
    Secondary
    End point timeframe
    Baseline and X (where X is a time point 7-9 weeks after last treatment)
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    1
    12
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Dysphagia [N=1, 12]
    -6.0 ( 99999 )
    13.0 ( 33.1 )
        Pain [N=1, 12]
    25.0 ( 99999 )
    7.0 ( 26.8 )
        Reflux symptoms [N=1, 12]
    27.0 ( 99999 )
    11.0 ( 34.4 )
        Eating restrictions [N=1, 12]
    17.0 ( 99999 )
    11.9 ( 32.9 )
        Anxiety [N=1, 12]
    0.0 ( 99999 )
    5.9 ( 26.0 )
        Dry Mouth [N=1, 12]
    -34.0 ( 99999 )
    8.5 ( 29.1 )
        Taste [N=1, 12]
    34.0 ( 99999 )
    11.1 ( 25.8 )
        Body image [N=1, 12]
    0.0 ( 99999 )
    -5.7 ( 23.9 )
        Hair loss [N=1, 12]
    -33.0 ( 99999 )
    -18.1 ( 38 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Change from Baseline in Karnofsky Index (KI)

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    End point title
    		 Percentage of Participants with Change from Baseline in Karnofsky Index (KI)
    End point description
    Karnofsky Index: 100 Normal, no complaints; no evidence of disease. 90 Able to carry on normal activity; minor signs or symptoms of disease. 80 Normal activity with effort; some signs or symptoms of disease. 70 Cares for self; unable to carry on normal activity or to do active work. 60 Requires occasional assistance, but is able to care for most of his personal needs. 50 Requires considerable assistance and frequent medical care. 40 Disabled; requires special care and assistance. 30 Severely disabled; hospital admission is indicated although death not imminent. 20 Very sick; hospital admission necessary; active supportive treatment necessary. 10 Moribund; fatal processes progressing rapidly. 0 Dead. The analysis population consisted of the FAS participants with KI of 80% at baseline for cohort 1 and 70-100% at baseline for cohort 2 and 3.
    End point type
    Secondary
    End point timeframe
    Baseline and X (where X is a time point 7-9 weeks after last treatment)
    End point values
    		 Cohort 1: KI 80 at baseline Cohort 2+3: KI 70 at baseline Cohort 2+3: KI 80 at baseline Cohort 2+3: KI 90 at baseline Cohort 2+3: KI 100 at baseline
    Number of subjects analysed
    1
    1
    5
    7
    2
    Units: percentage of participants
    number (not applicable)
        KI 60 at Visit 10
    0
    0
    13.3
    6.7
    0
        KI 70 at Visit 10
    100.0
    6.7
    6.7
    0
    0
        KI 80 at Visit 10
    0
    0
    0
    13.3
    0
        KI 90 at Visit 10
    0
    0
    6.7
    13.3
    13.3
        KI 100 at Visit 10
    0
    0
    6.7
    13.3
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

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    End point title
    		 Percentage of Participants with Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
    End point description
    ECOG Performance Status Grades: 0 Fully active, able to carry on all pre-disease performance without restriction. 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work. 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 Dead. The analysis population consisted of the FAS participants with a score of 1 at baseline for cohort 1 and a score of 0 or 1 at baseline for cohort 2 and 3.
    End point type
    Secondary
    End point timeframe
    Baseline and X (where X is a time point 7-9 weeks after last treatment)
    End point values
    		 Cohort 1: ECOG Grade 1 at baseline Cohort 2+3: ECOG Grade 0 at baseline Cohort 2+3: ECOG Grade 1 at baseline
    Number of subjects analysed
    1
    7
    8
    Units: percentage of participants
    number (not applicable)
        Grade 0 at Visit 10
    0
    26.7
    6.7
        Grade 1 at Visit 10
    100.0
    13.3
    26.7
        Grade 2 at Visit 10
    0
    6.7
    20.0
    No statistical analyses for this end point

    Secondary: Overall Clinical Benefit According to RECIST

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    End point title
    		 Overall Clinical Benefit According to RECIST
    End point description
    Clinical benefit was defined as a participant's response of complete remission (CR), partial remission (PR), and stable disease (SD) according to RECIST. Clinical benefit was determined at visit 9. The analysis population consisted of the FAS. Data not calculated is denoted as "99999." There were no participants for cohort 1 who achieved CR, PR or SD and is also denoted as "99999."
    End point type
    Secondary
    End point timeframe
    From first infusion until the end of study, maximum time on study was 36.4 months.
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    3
    26
    Units: percentage of participants
        number (confidence interval 95%)
    99999 (99999 to 99999)
    34.6 (17.21 to 55.67)
    No statistical analyses for this end point

    Secondary: Best Overall Response According to RECIST

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    End point title
    		 Best Overall Response According to RECIST
    End point description
    Best overall response was determined as PR, SD and progressive disease (PD) according to RECIST. Best overall response was determined based on visit 9 and/or end-of study visit 10. The analysis population consisted of the FAS.
    End point type
    Secondary
    End point timeframe
    From first infusion until the end of study, maximum time on study was 36.4 months.
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    3
    40
    Units: percentage of participants
    number (not applicable)
        PR
    0
    10.0
        SD
    0
    15.0
        PD
    100.0
    70.0
        Not evaluable
    0
    5.0
    No statistical analyses for this end point

    Secondary: Overall Objective Response According to RECIST

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    End point title
    		 Overall Objective Response According to RECIST
    End point description
    Objective response was defined as a participant's response of CR or PR according to RECIST. Objective response was determined at visit 9. The analysis population consisted of the FAS. Data not calculated is denoted as "99999." There were no participants for cohort 1 who achieved CR or PR, and is also denoted as "99999."
    End point type
    Secondary
    End point timeframe
    From first infusion until the end of study, maximum time on study was 36.4 months.
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    3
    26
    Units: percentage of participants
        number (confidence interval 95%)
    99999 (99999 to 99999)
    7.7 (0.95 to 25.13)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve from the Time of Dosing to Day 14 After End of Infusion (AUC0-14day)

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    End point title
    		 Area Under the Concentration-Time Curve from the Time of Dosing to Day 14 After End of Infusion (AUC0-14day)
    End point description
    The analysis population consisted of the pharmacokinetic analysis set (PKAS; comprised of all participants who received study drug at least once and for whom at least 1 pharmacokinetic measurement upon treatment was available) with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    38
    Units: day*μg/mL
        arithmetic mean (standard deviation)
    776 ( 83.0 )
    1450 ( 408 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast)

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    End point title
    		 Area Under the Concentration-Time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast)
    End point description
    The analysis population consisted of the PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    40
    Units: day*ug/mL
        arithmetic mean (standard deviation)
    795 ( 117 )
    1230 ( 533 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)

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    End point title
    		 Area Under the Concentration-Time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)
    End point description
    The analysis population consisted of the PKAS with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    33
    Units: day*ug/mL
        arithmetic mean (standard deviation)
    1030 ( 256 )
    1930 ( 922 )
    No statistical analyses for this end point

    Secondary: Percentage of the Area Under the Concentration-Time Curve from the Time of Dosing to Time Infinity Due to Extrapolation from the Last Measurable Concentration to Time Infinity (AUCinf_%Extrap)

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    End point title
    		 Percentage of the Area Under the Concentration-Time Curve from the Time of Dosing to Time Infinity Due to Extrapolation from the Last Measurable Concentration to Time Infinity (AUCinf_%Extrap)
    End point description
    The analysis population consisted of the PKAS with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    33
    Units: percentage extrapolated
        arithmetic mean (standard deviation)
    21.4 ( 8.16 )
    26.6 ( 15.1 )
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax)

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    End point title
    		 Maximum Concentration (Cmax)
    End point description
    The analysis population consisted of the PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    40
    Units: μg/mL
        arithmetic mean (standard deviation)
    288 ( 68.6 )
    355 ( 69.1 )
    No statistical analyses for this end point

    Secondary: Last Measurable Concentration (Clast)

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    End point title
    		 Last Measurable Concentration (Clast)
    End point description
    The analysis population consisted of the PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    40
    Units: μg/mL
        arithmetic mean (standard deviation)
    28.3 ( 8.48 )
    94.7 ( 79.4 )
    No statistical analyses for this end point

    Secondary: Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough)

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    End point title
    		 Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough)
    End point description
    The analysis population consisted of the PKAS. N is the number of participants with available data.
    End point type
    Secondary
    End point timeframe
    Days 15, 29, 43, 57, and 71
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    34
    Units: μg/mL
    arithmetic mean (standard deviation)
        Day 15 [N= 4, 34]
    22.5 ( 10.5 )
    47.3 ( 28.8 )
        Day 29 [N= 4, 29]
    34.9 ( 15.8 )
    90.4 ( 57.9 )
        Day 43 [N= 3, 24]
    44.9 ( 14.5 )
    123 ( 76.2 )
        Day 57 [N= 3, 19]
    46.1 ( 18.5 )
    143 ( 90.4 )
        Day 71 [N= 3, 18]
    34.5 ( 12.2 )
    164 ( 98.7 )
    No statistical analyses for this end point

    Secondary: Time of the Maximum Concentration (Tmax)

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    End point title
    		 Time of the Maximum Concentration (Tmax)
    End point description
    The analysis population consisted of the PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    40
    Units: days
        median (full range (min-max))
    0.205 (0.153 to 0.378)
    0.148 (0.0833 to 0.340)
    No statistical analyses for this end point

    Secondary: Time of the Last Measurable Concentration (Tlast)

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    End point title
    		 Time of the Last Measurable Concentration (Tlast)
    End point description
    The analysis population consisted of the PKAS.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    40
    Units: days
        arithmetic mean (standard deviation)
    12.0 ( 3.86 )
    9.62 ( 4.80 )
    No statistical analyses for this end point

    Secondary: Terminal Elimination Half-Life (T1/2)

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    End point title
    		 Terminal Elimination Half-Life (T1/2)
    End point description
    The analysis population consisted of the PKAS with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    33
    Units: days
        arithmetic mean (standard deviation)
    5.83 ( 2.70 )
    5.38 ( 2.56 )
    No statistical analyses for this end point

    Secondary: Total Clearance After Intravenous Dosing (CL)

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    End point title
    		 Total Clearance After Intravenous Dosing (CL)
    End point description
    The analysis population consisted of the PKAS with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    33
    Units: L/day
        arithmetic mean (standard deviation)
    0.496 ( 0.153 )
    0.718 ( 0.366 )
    No statistical analyses for this end point

    Secondary: Volume of Distribution (Vd)

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    End point title
    		 Volume of Distribution (Vd)
    End point description
    The analysis population consisted of the PKAS with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    End point values
    		 Cohort 1: Zolbetuximab 300 mg/m^2 Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Number of subjects analysed
    4
    33
    Units: liters
        arithmetic mean (standard deviation)
    3.77 ( 1.33 )
    4.61 ( 1.30 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of first infusion up to until 28 days after the last infusion; Up to 35.71 months.
    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
    20.0
    Reporting groups
    Reporting group title
    Cohorts 2+3: Zolbetuximab 600 mg/m^2
    Reporting group description
    		 Cohort 2 participants received repeated doses of zolbetuximab at a higher dose level (600 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8. Cohort 3 participants received repeated doses of zolbetuximab (600 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8.

    Reporting group title
    Cohort 1: Zolbetuximab 300 mg/m^2
    Reporting group description
    		 Participants received repeated doses of zolbetuximab at a lower dose level (300 mg/m^2 BSA) every 2 weeks on visits 2, 5, 6, 7 and 8.

    Serious adverse events
    		 Cohorts 2+3: Zolbetuximab 600 mg/m^2 Cohort 1: Zolbetuximab 300 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 50 (48.00%)
    1 / 4 (25.00%)
         number of deaths (all causes)
    23
    3
         number of deaths resulting from adverse events
    10
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohorts 2+3: Zolbetuximab 600 mg/m^2 Cohort 1: Zolbetuximab 300 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 50 (94.00%)
    4 / 4 (100.00%)
    Investigations
    Weight decreased
         subjects affected / exposed
    8 / 50 (16.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Tumour pain
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 4 (75.00%)
         occurrences all number
    3
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 50 (10.00%)
    1 / 4 (25.00%)
         occurrences all number
    7
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    12 / 50 (24.00%)
    0 / 4 (0.00%)
         occurrences all number
    15
    0
    Chills
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Fatigue
         subjects affected / exposed
    22 / 50 (44.00%)
    1 / 4 (25.00%)
         occurrences all number
    39
    1
    Feeling hot
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    General physical health deterioration
         subjects affected / exposed
    7 / 50 (14.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    0
    Oedema peripheral
         subjects affected / exposed
    12 / 50 (24.00%)
    0 / 4 (0.00%)
         occurrences all number
    16
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 50 (14.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    0
    Abdominal pain upper
         subjects affected / exposed
    8 / 50 (16.00%)
    0 / 4 (0.00%)
         occurrences all number
    10
    0
    Ascites
         subjects affected / exposed
    5 / 50 (10.00%)
    1 / 4 (25.00%)
         occurrences all number
    7
    1
    Constipation
         subjects affected / exposed
    13 / 50 (26.00%)
    1 / 4 (25.00%)
         occurrences all number
    21
    1
    Diarrhoea
         subjects affected / exposed
    11 / 50 (22.00%)
    0 / 4 (0.00%)
         occurrences all number
    12
    0
    Dyspepsia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Dysphagia
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Flatulence
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    32 / 50 (64.00%)
    2 / 4 (50.00%)
         occurrences all number
    91
    4
    Retching
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Salivary hypersecretion
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Vomiting
         subjects affected / exposed
    29 / 50 (58.00%)
    2 / 4 (50.00%)
         occurrences all number
    80
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    Dyspnoea
         subjects affected / exposed
    8 / 50 (16.00%)
    0 / 4 (0.00%)
         occurrences all number
    9
    0
    Pleural effusion
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Anxiety
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Sleep disorder
         subjects affected / exposed
    7 / 50 (14.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Back pain
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 50 (32.00%)
    0 / 4 (0.00%)
         occurrences all number
    23
    0
    Dehydration
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 4 (0.00%)
         occurrences all number
    5
    0
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2010
    Amendment 1 (Protocol version 2.0) was issued to implement the Data Safety Monitoring Board (DSMB) Working Procedure. The infusion interval was changed from once weekly to once every 2 weeks due to the availability of new human pharmacokinetic data. The study duration was increased as a consequence, with infusions taking place on days 1, 15, 29, 43 and 57 as opposed to the previously proposed days 1, 8, 15, 22 and 29.
    02 Mar 2011
    Amendment 2 (Protocol version 3.0) was issued to add language to the introduction section as per the recommendations of German Competent Authority (Paul-Ehrlich-Institute) after the sponsor presented results from a mouse study, which showed acute severe allergic reactions in some animals following administration of a murinized variant of chimeric zolbetuximab, obtained by a different purification process with different pharmacokinetic properties. Changes were also made to update screening procedures, blood sample collection and to analyze more laboratory parameters for better patient monitoring.
    09 Jun 2011
    Amendment 3 (Protocol version 4.0) was issued to provide continued access to treatment after a patient showed no tumor remission but showed stable disease conditions. The preconditions for continued treatment were changed to enable patients with stable disease to enter the continued treatment phase.
    27 Jul 2011
    Amendment 4 (Protocol version 5.0) was issued since new batches of study drug were manufactured using a different manufacturing process to meet the increased demand from the high rate of patient drop-out and continued treatment of patients with stable disease. Furthermore, the first 3 patients dosed with the newly produced study drug in cohort 3 were to be monitored after receiving all 5 infusions, followed by DSMB review and pharmacokinetic analysis, and a decision was to be made for continuation of treatment.
    13 Sep 2011
    Amendment 5 (Protocol version 6.0) was issued to improve the observation of tumor status and quality of life (QoL) of patients included in the continued treatment phase by measuring body weight, conducting computed tomography (CT)/magnetic resonance imaging (MRI), requesting European Organisation for Research and Treatment of Cancer (EORTC) questionnaires and taking blood samples for analysis of tumor markers. Additional blood sampling was added before and after each infusion during the continued treatment phase for pharmacokinetic analysis.
    08 Nov 2011
    Amendment 6 (Protocol version 7.0) was issued to obtain more pharmacokinetic data. Pharmacokinetic evaluation was to be performed for all patients during the study treatment phase to account for inter-individual differences.
    11 Jan 2012
    Amendment 7 (Protocol version 8.0) was issued to clarify that safety of the study drug manufactured by the new process was considered assessable after the first 3 patients of cohort 3 received at least 4 infusions (as opposed to all 5 infusions as previously proposed), before more patients could be treated in cohort 3.
    12 Nov 2012
    Amendment 8 (Protocol version 9.0) was issued to change the duration of treatment for responders in the continued treatment phase from about 6 months (12 further infusions) to more than 6 months, until the time of disease progression, unacceptable toxicity or withdrawal of consent.
    30 Oct 2013
    Amendment 9 (Protocol version 10.0) was issued to introduce additional antidrug antibody (ADA) measurements on samples initially collected for pharmacokinetic analysis in order to increase patient safety. Administrative changes were also made (contract research organization [CRO] was changed and safety reporting was to be covered by the sponsor), and 20R size vials were introduced as drug product containers in addition to the previously used 6R vials.

    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.
    This study was conducted by Ganymed AG, a company that was acquired by Astellas in December of 2016.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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