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    Clinical Trial Results:
    A Multicenter, Phase 2, Single Arm, Two Cohort Study Evaluating the Efficacy, Safety, and Pharmacokinetics of AMG 337 in Subjects with MET Amplified Gastric/Gastroesophageal Junction/Esophageal Adenocarcinoma or Other MET Amplified Solid Tumors

    Summary
    EudraCT number
    		 2013-001277-24
    Trial protocol
    		 CZ   GR   DE   BE   GB   IT   AT   HU   PL   ES  
    Global end of trial date
    10 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Oct 2017
    First version publication date
    22 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20130111
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02016534
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to determine antitumor activity of AMG 337 in subjects with mesenchymal epithelial transition factor (MET)-amplified gastric (G), gastroesophageal junction (GEJ), or esophageal (E) adenocarcinoma.
    Protection of trial subjects
    This study was conducted in accordance with the principles of the applicable country, Food and Drug Administration and International Conference on Harmonization (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    60
    EEA total number of subjects
    29
    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
    21
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 34 centers across 12 countries in Asia, Australia, Europe, and North America. Adults with mesenchymal epithelial transition factor (MET)-amplified gastric (G), gastroesophageal junction (GEJ), or esophageal (E) adenocarcinoma or other MET-amplified solid tumors were enrolled.

    Pre-assignment
    Screening details
    		 Participants were enrolled in the following 2 cohorts: - Cohort 1: MET-amplified G/GEJ/E adenocarcinoma with measurable tumor per RECIST version 1.1 - Cohort 2: Non-measurable G/GEJ/E adenocarcinoma (2A), measurable G/GEJ/E adenocarcinoma with prior MET antibody therapy (2B), or MET-amplified mixed solid tumors with measurable tumor (2C).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Measurable G/GEJ/E
    Arm description
    		 Participants with measurable G/GEJ/E adenocarcinoma were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 337
    Investigational medicinal product code
    AMG 337
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects self-administered AMG 337 300 mg orally daily on an empty stomach.

    Arm title
    		 Non-measurable G/GEJ/E
    Arm description
    		 Participants with non-measurable G/GEJ/E adenocarcinoma were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 337
    Investigational medicinal product code
    AMG 337
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects self-administered AMG 337 300 mg orally daily on an empty stomach.

    Arm title
    		 Measurable G/GEJ/E + Prior MET Antibody Therapy
    Arm description
    		 Participants with measurable G/GEJ/E adenocarcinoma who received prior MET antibody therapy were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 337
    Investigational medicinal product code
    AMG 337
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects self-administered AMG 337 300 mg orally daily on an empty stomach.

    Arm title
    		 NSCLC
    Arm description
    		 Participants with non-small cell lung cancer (NSCLC) were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 337
    Investigational medicinal product code
    AMG 337
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects self-administered AMG 337 300 mg orally daily on an empty stomach.

    Number of subjects in period 1
    		Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Started
    45
    10
    1
    4
    Received AMG 337
    45
    9
    1
    3
    Completed
    1
    0
    0
    0
    Not completed
    44
    10
    1
    4
         Consent withdrawn by subject
    4
    2
    -
    -
         Death
    29
    7
    1
    4
         Lost to follow-up
    2
    -
    -
    -
         Decision by sponsor
    9
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Measurable G/GEJ/E
    Reporting group description
    		 Participants with measurable G/GEJ/E adenocarcinoma were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    Non-measurable G/GEJ/E
    Reporting group description
    		 Participants with non-measurable G/GEJ/E adenocarcinoma were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    Measurable G/GEJ/E + Prior MET Antibody Therapy
    Reporting group description
    		 Participants with measurable G/GEJ/E adenocarcinoma who received prior MET antibody therapy were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    NSCLC
    Reporting group description
    		 Participants with non-small cell lung cancer (NSCLC) were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group values
    		 Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC Total
    Number of subjects
    		 45 10 1 4 60
    Age Categorical
    Units: Subjects
        18 - 64 years
    		 28 6 1 3 38
        65 - 84 years
    		 16 4 0 1 21
        85 years and over
    		 1 0 0 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60 ± 13.4 59.6 ± 17.3 59 ± 99999 62.5 ± 3.87 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 11 4 1 2 18
        Male
    		 34 6 0 2 42
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 17 4 0 1 22
        Other
    		 1 0 0 0 1
        White
    		 27 6 1 3 37
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 0 1
        Not Hispanic or Latino
    		 45 9 1 4 59
        Unknown or Not Reported
    		 0 0 0 0 0
    Region
    Units: Subjects
        Asia
    		 17 3 0 0 20
        Australia
    		 3 0 1 2 6
        Europe
    		 23 4 0 2 29
        North America
    		 2 3 0 0 5
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Eastern Cooperative Oncology Group (ECOG) Performance Status is used by doctors and researchers to assess how a participants disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active; 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self- Care; 4 = Completely Disabled, no self-care, confined to bed or chair; 5 = Dead.
    Units: Subjects
        0 (Fully active)
    		 15 3 1 0 19
        1 (Restrictive but ambulatory)
    		 30 7 0 4 41
    Disease Stage at Screening
    Units: Subjects
        Locally advanced
    		 2 0 0 0 2
        Metastatic
    		 43 10 1 4 58

    End points

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    End points reporting groups
    Reporting group title
    Measurable G/GEJ/E
    Reporting group description
    		 Participants with measurable G/GEJ/E adenocarcinoma were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    Non-measurable G/GEJ/E
    Reporting group description
    		 Participants with non-measurable G/GEJ/E adenocarcinoma were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    Measurable G/GEJ/E + Prior MET Antibody Therapy
    Reporting group description
    		 Participants with measurable G/GEJ/E adenocarcinoma who received prior MET antibody therapy were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    NSCLC
    Reporting group description
    		 Participants with non-small cell lung cancer (NSCLC) were assigned to receive 300 mg AMG 337 orally once a day for up to 12 months.

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with MET-amplified gastric/gastroesophageal junction/esophageal adenocarcinoma

    Subject analysis set title
    Cohort 2A, 2B and 2C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with non-measurable G/GEJ/E, measurable G/GEJ/E with prior MET antibody therapy.

    Primary: Objective Response Rate in Participants with MET-amplified Measurable G/GEJ/E Adenocarcinoma (Cohort 1)

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    End point title
    		 Objective Response Rate in Participants with MET-amplified Measurable G/GEJ/E Adenocarcinoma (Cohort 1) [1] [2]
    End point description
    Tumor assessments were based on Investigator assessment of disease progression as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Objective response rate was defined as the percentage of subjects who achieved either a complete response (CR) or a partial response (PR) per RECIST v1.1. Subjects who did not meet the criteria for response by the data cutoff date were considered non-responders. The Response Analysis Set was defined as all enrolled subjects with measurable tumor per RECIST v1.1 at baseline who received at least one dose of AMG 337.
    End point type
    Primary
    End point timeframe
    Tumor assessment scans were performed every 8 weeks during study treatment until week 32, thereafter tumor assessment scans were taken every 12 weeks during study treatment. Median follow-up time was 5.5 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: A formal hypothesis was not tested in this study.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary endpoint was analyzed in cohort 1 subjects only
    End point values
    		 Measurable G/GEJ/E
    Number of subjects analysed
    45
    Units: percentage of participants
        number (confidence interval 95%)
    17.8 (8 to 32.1)
    No statistical analyses for this end point

    Secondary: Objective Response Rate in Participants in Cohort 2

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    End point title
    		 Objective Response Rate in Participants in Cohort 2 [3]
    End point description
    Tumor assessments were based on Investigator assessment of disease progression as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Objective response rate was defined as the percentage of subjects who achieved either a complete response (CR) or a partial response (PR) per RECIST v1.1. Subjects who did not meet the criteria for response by the data cutoff date were considered non-responders. The Response Analysis Set was defined as all enrolled subjects with measurable tumor per RECIST v1.1 at baseline who received at least one dose of AMG 337.
    End point type
    Secondary
    End point timeframe
    Tumor assessment scans were performed every 8 weeks during study treatment until week 32, and thereafter every 12 weeks during study treatment. Median follow-up time was 11.4, 20.3, and 2.2 months in each group respectively.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analyzed in cohort 2 subjects only
    End point values
    		 Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Number of subjects analysed
    0 [4]
    0 [5]
    0 [6]
    Units: percentage of participants
        number (not applicable)
    Notes
    [4] - Response analysis set (only includes subjects with measurable tumor at baseline)
    [5] - Not analyzed due to small number of subjects
    [6] - Not analyzed due to small number of subjects
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response was calculated for responders only and defined as the time from the first observation of a response to the first observation of a disease progression per RECIST v1.1 or death due to any cause. If a responding subject had not progressed or died by the data cutoff date, duration of response was censored at the time of the last evaluable tumor assessment.
    End point type
    Secondary
    End point timeframe
    Tumor assessment scans were performed every 8 weeks during study treatment until week 32, and thereafter every 12 weeks during study treatment. Median follow-up time was 5.5, 11.4, 20.3, and 2.2 months in each group respectively.
    End point values
    		 Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Number of subjects analysed
    8 [7]
    0 [8]
    0 [9]
    0 [10]
    Units: months
        median (confidence interval 95%)
    6 (3.7 to 16.7)
    ( to )
    ( to )
    ( to )
    Notes
    [7] - Response analysis set with an objective response
    [8] - Not analyzed due to small number of subjects
    [9] - Not analyzed due to small number of subjects
    [10] - Not analyzed due to small number of subjects
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    		 Time to Response
    End point description
    Time to response was calculated for those subjects with an objective response and defined as the time from the first dose date to the first observation of a response (CR or PR) per RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Tumor assessment scans were performed every 8 weeks during study treatment until week 32, and thereafter every 12 weeks during study treatment. Median follow-up time was 5.5, 11.4, 20.3, and 2.2 months in each group respectively.
    End point values
    		 Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Number of subjects analysed
    8 [11]
    0 [12]
    0 [13]
    0 [14]
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    7.64 (7.14 to 11.86)
    ( to )
    ( to )
    ( to )
    Notes
    [11] - Response analysis set with an objective response
    [12] - Not analyzed due to small number of subjects
    [13] - Not analyzed due to small number of subjects
    [14] - Not analyzed due to small number of subjects
    No statistical analyses for this end point

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Progression-free survival (PFS) was defined as the time from the first dose date to the first observation of a disease progression per RECIST v1.1 or death due to any cause. If a subject had not progressed or died by the data cutoff date, progression-free survival was censored at the time of the last evaluable tumor assessment. The analysis of PFS was conducted on the Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Tumor assessment scans were performed every 8 weeks during study treatment until week 32, and thereafter every 12 weeks during study treatment. Median follow-up time was 5.5, 11.4, 20.3, and 2.2 months in each group respectively.
    End point values
    		 Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Number of subjects analysed
    45
    9
    0 [15]
    0 [16]
    Units: months
        median (confidence interval 95%)
    3.4 (2.1 to 5)
    3.6 (2.2 to 10.3)
    ( to )
    ( to )
    Notes
    [15] - Measurable G/GEJ/E subjects with prior MET therapy were excluded
    [16] - NSCLC subjects were excluded
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time from the first dose date to the date of death due to any cause. If a subject was lost to follow-up before the data cutoff date or still alive at the data cutoff date, overall survival was censored at the last contact date. This analysis was conducted in the full analysis set.
    End point type
    Secondary
    End point timeframe
    Median follow-up time was 5.5, 11.4, 20.3, and 2.2 months in each group respectively.
    End point values
    		 Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Number of subjects analysed
    45
    9
    0 [17]
    0 [18]
    Units: months
        median (confidence interval 95%)
    7 (4.4 to 10.9)
    11.4 (4.9 to 18.5)
    ( to )
    ( to )
    Notes
    [17] - Measurable G/GEJ/E subjects with prior MET therapy were excluded
    [18] - NSCLC subjects were excluded
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events

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    End point title
    		 Number of Participants with Adverse Events
    End point description
    The adverse event grading scale used was the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. A serious adverse event was defined as an adverse event that meets at least 1 of the following serious criteria: • fatal • life threatening (places the subject at immediate risk of death) • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event The Safety Analysis Set included all enrolled subjects who received at least one dose of AMG 337.
    End point type
    Secondary
    End point timeframe
    From the first dose of study drug up to 30 days after the last dose; median duration of treatment was 2.3, 2.4, 2.1, and 1.6 months in each group respectively.
    End point values
    		 Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Number of subjects analysed
    45 [19]
    9 [20]
    1 [21]
    3 [22]
    Units: participants
        All adverse events
    44
    9
    1
    3
        Adverse events ≥ grade 2
    41
    9
    1
    2
        Adverse events ≥ grade 3
    34
    4
    1
    2
        Adverse events ≥ grade 4
    9
    1
    0
    2
        Serious adverse events
    26
    5
    1
    2
        Leading to discontinuation of study drug
    7
    1
    1
    1
        Fatal adverse events
    7
    0
    0
    2
    Notes
    [19] - Safety analysis set
    [20] - Safety analysis set
    [21] - Safety analysis set
    [22] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Duration of Treatment

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    End point title
    		 Duration of Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    From first dose until last dose
    End point values
    		 Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Number of subjects analysed
    45 [23]
    9 [24]
    1 [25]
    3 [26]
    Units: months
        median (inter-quartile range (Q1-Q3))
    2.3 (0.9 to 5.4)
    2.4 (1.2 to 5.7)
    2.1 (2.1 to 2.1)
    1.6 (1 to 3.9)
    Notes
    [23] - Safety analysis set
    [24] - Safety analysis set
    [25] - Safety analysis set
    [26] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Actual Dose Intensity

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    End point title
    		 Actual Dose Intensity
    End point description
    Actual dose intensity is defined as the average amount of drug delivered per day.
    End point type
    Secondary
    End point timeframe
    From first dose to last dose of study drug
    End point values
    		 Measurable G/GEJ/E Non-measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC
    Number of subjects analysed
    45
    9
    1
    3
    Units: mg/day
        median (inter-quartile range (Q1-Q3))
    288.5 (208.2 to 300)
    300 (300 to 301.9)
    300 (300 to 300)
    265 (104.1 to 300)
    No statistical analyses for this end point

    Secondary: Maximum Observed Drug Concentration of AMG 337

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    End point title
    		 Maximum Observed Drug Concentration of AMG 337
    End point description
    Intensive pharmacokinetic sampling was conducted at selected sites. Plasma concentrations below the lower limit of quantification (5.0 ng/mL) were set to 0 before the analysis. The PK Analysis Set includes all subjects in the Safety Analysis Set who underwent blood sampling during the study and had measurable concentrations above the assay’s limit of quantification. In addition, the non-compartmental analyses excluded subjects for whom non-compartmental parameters could not be derived.
    End point type
    Secondary
    End point timeframe
    Day 1 and day 28, predose up to 24 hours post-dose
    End point values
    		 Cohort 1 Cohort 2A, 2B and 2C
    Number of subjects analysed
    12 [27]
    4 [28]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (N = 12, 4)
    4110 ± 1850
    3080 ± 535
        Day 28 (N = 8, 3)
    3260 ± 832
    3100 ± 448
    Notes
    [27] - PK analysis set exclude subjects for whom non-compartmental parameters could be derived
    [28] - PK analysis set exclude subjects for whom non-compartmental parameters could be derived
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Concentration of AMG 337

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    End point title
    		 Time to Maximum Observed Concentration of AMG 337
    End point description
    Intensive pharmacokinetic sampling was conducted at selected sites. Plasma concentrations below the lower limit of quantification (5.0 ng/mL) were set to 0 before the analysis. The PK Analysis Set includes all subjects in the Safety Analysis Set who underwent blood sampling during the study and had measurable concentrations above the assay’s limit of quantification. In addition, the non-compartmental analyses excluded subjects for whom non-compartmental parameters could not be derived.
    End point type
    Secondary
    End point timeframe
    Day 1 and day 28, predose up to 24 hours post-dose
    End point values
    		 Cohort 1 Cohort 2A, 2B and 2C
    Number of subjects analysed
    12 [29]
    4 [30]
    Units: hours
    median (full range (min-max))
        Day 1 (N = 12, 4)
    3 (1.5 to 6.1)
    2.3 (1.5 to 6)
        Day 28 (N = 8, 3)
    3 (1.5 to 6)
    1.9 (0.48 to 3)
    Notes
    [29] - PK analysis set exclude subjects for whom non-compartmental parameters could be derived
    [30] - PK analysis set exclude subjects for whom non-compartmental parameters could be derived
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve From time 0 to 24 hours

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    End point title
    		 Area Under the Plasma Concentration-time Curve From time 0 to 24 hours
    End point description
    Intensive pharmacokinetic sampling was conducted at selected sites. Plasma concentrations below the lower limit of quantification (5.0 ng/mL) were set to 0 before the analysis. The PK Analysis Set includes all subjects in the Safety Analysis Set who underwent blood sampling during the study and had measurable concentrations above the assay’s limit of quantification. In addition, the non-compartmental analyses excluded subjects for whom non-compartmental parameters could not be derived.
    End point type
    Secondary
    End point timeframe
    Day 1 and day 28, predose up to 24 hours post-dose
    End point values
    		 Cohort 1 Cohort 2A, 2B and 2C
    Number of subjects analysed
    12 [31]
    3 [32]
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Day 1 (N = 12, 3)
    48200 ± 22900
    36000 ± 7530
        Day 28 (N = 7, 3)
    36800 ± 11800
    32800 ± 9020
    Notes
    [31] - PK analysis set exclude subjects for whom non-compartmental parameters could be derived
    [32] - PK analysis set exclude subjects for whom non-compartmental parameters could be derived
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug up to 30 days after the last dose; median duration of treatment was 2.3, 2.4, 2.1, and 1.6 months in each group respectively.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Measurable G/GEJ/E
    Reporting group description
    		 Participants with measurable G/GEJ/E adenocarcinoma received 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    Measurable G/GEJ/E + Prior MET Antibody Therapy
    Reporting group description
    		 Participants with measurable G/GEJ/E adenocarcinoma who received prior MET antibody therapy received 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    NSCLC
    Reporting group description
    		 Participants with NSCLC received 300 mg AMG 337 orally once a day for up to 12 months.

    Reporting group title
    Non-measurable G/GEJ/E
    Reporting group description
    		 Participants with non-measurable G/GEJ/E adenocarcinoma received 300 mg AMG 337 orally once a day for up to 12 months.

    Serious adverse events
    		 Measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC Non-measurable G/GEJ/E
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 45 (57.78%)
    1 / 1 (100.00%)
    2 / 3 (66.67%)
    5 / 9 (55.56%)
         number of deaths (all causes)
    7
    0
    2
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Measurable G/GEJ/E Measurable G/GEJ/E + Prior MET Antibody Therapy NSCLC Non-measurable G/GEJ/E
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 45 (97.78%)
    1 / 1 (100.00%)
    3 / 3 (100.00%)
    9 / 9 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    5 / 9 (55.56%)
         occurrences all number
    1
    0
    0
    5
    Lymphoedema
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    2
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Thrombosis
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 45 (22.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    18
    0
    0
    1
    Chills
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    2
    0
    0
    2
    Face oedema
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    1
    Fatigue
         subjects affected / exposed
    8 / 45 (17.78%)
    1 / 1 (100.00%)
    2 / 3 (66.67%)
    2 / 9 (22.22%)
         occurrences all number
    10
    2
    2
    2
    General physical health deterioration
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Localised oedema
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    3
    0
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema
         subjects affected / exposed
    24 / 45 (53.33%)
    0 / 1 (0.00%)
    2 / 3 (66.67%)
    4 / 9 (44.44%)
         occurrences all number
    81
    0
    6
    31
    Oedema peripheral
         subjects affected / exposed
    14 / 45 (31.11%)
    0 / 1 (0.00%)
    3 / 3 (100.00%)
    2 / 9 (22.22%)
         occurrences all number
    22
    0
    3
    5
    Pain
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    5 / 45 (11.11%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    7
    0
    0
    2
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    1
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    1
    Insomnia
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    4
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    2 / 9 (22.22%)
         occurrences all number
    7
    0
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
         occurrences all number
    6
    0
    1
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 45 (11.11%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    6
    0
    0
    2
    Headache
         subjects affected / exposed
    24 / 45 (53.33%)
    1 / 1 (100.00%)
    2 / 3 (66.67%)
    7 / 9 (77.78%)
         occurrences all number
    41
    1
    3
    10
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    2
    Presyncope
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    3
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    15 / 45 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    18
    0
    0
    4
    Abdominal pain upper
         subjects affected / exposed
    5 / 45 (11.11%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
         occurrences all number
    5
    0
    1
    1
    Ascites
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    3
    0
    0
    2
    Constipation
         subjects affected / exposed
    8 / 45 (17.78%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
         occurrences all number
    8
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    8 / 45 (17.78%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    8
    0
    0
    3
    Dry mouth
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    7 / 45 (15.56%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    9
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    Melaena
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    15 / 45 (33.33%)
    1 / 1 (100.00%)
    1 / 3 (33.33%)
    4 / 9 (44.44%)
         occurrences all number
    17
    1
    1
    5
    Oesophagitis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Proctalgia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    1
    Vomiting
         subjects affected / exposed
    16 / 45 (35.56%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    4 / 9 (44.44%)
         occurrences all number
    21
    0
    1
    6
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    5 / 45 (11.11%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    6
    1
    0
    5
    Pruritus
         subjects affected / exposed
    6 / 45 (13.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    6
    0
    0
    2
    Rash
         subjects affected / exposed
    5 / 45 (11.11%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    7
    0
    0
    4
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 45 (15.56%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    8
    0
    0
    2
    Flank pain
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    1
    Myalgia
         subjects affected / exposed
    4 / 45 (8.89%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    6
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 45 (35.56%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    2 / 9 (22.22%)
         occurrences all number
    21
    0
    1
    2
    Dehydration
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    0
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    9 / 45 (20.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    10
    0
    0
    3
    Hypokalaemia
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2014
    The protocol was amended for the following reasons: 1. Allow ECOG Performance Status 2 subjects to participate in the study 2. Reduce the time interval when no food or liquids can be consumed relative to administration of AMG 337 3. Add dose modifications for when subjects experience ≥ grade 3 headache for which AMG 337 is considered as a cause 4. Add information about management of headaches 5. Add collection of lymphocyte results 6. Add an collection of cell pellet, circulating tumor cells, and optional tumor biopsy at the time of disease progression 7. Include details and clarification of planned efficacy and safety reviews 8. Clarification of minor inconsistencies and correction of minor errors

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

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