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    Clinical Trial Results:
    A Phase 1b/2 Study Assessing Safety and Anti-tumor Activity of AMG 820 in Combination With Pembrolizumab in Select Advanced Solid Tumors

    Summary
    EudraCT number
    2016-001080-36
    Trial protocol
    BE   DE   ES  
    Global end of trial date
    17 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    30 May 2020
    First version publication date
    30 May 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20150195
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02713529
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320-1799
    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
    17 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - Evaluate the safety and tolerability of AMG 820 administered in combination with pembrolizumab in subjects with select advanced solid tumors - Evaluate the objective response rate (ORR) of AMG 820 and pembrolizumab combination as per irRECIST in subjects with select advanced solid tumors
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. 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 Apr 2016
    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
    United States: 57
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Germany: 5
    Worldwide total number of subjects
    117
    EEA total number of subjects
    33
    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)
    64
    From 65 to 84 years
    52
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 15 centers in Australia, Canada, United States of America, and Europe.

    Pre-assignment
    Screening details
    Part 1 was a phase Ib safety study comprised of two cohorts. Part 2 was a phase 2 safety and efficacy study comprised of 5 groups.

    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
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg
    Arm description
    Part 1 Cohort 2 includes participants with advanced solid tumors who were treated with 1100 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed.
    Arm type
    Experimental

    Investigational medicinal product name
    AMG 820
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1100 mg administered intravenously (IV) every third week.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

    Arm title
    Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg
    Arm description
    Part 1 Cohort 1 includes participants with advanced solid tumors who were treated with 1400 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed. If >= 3 participants had dose limiting toxicities (DLTs), a second cohort was created with a lower AMG 820 dose + Pem 200 mg.
    Arm type
    Experimental

    Investigational medicinal product name
    AMG 820
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1400 mg administered intravenously (IV) every third week.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

    Arm title
    Part 2, Group 1: CRC MMR-proficient
    Arm description
    Group 1 is comprised of participants with colorectal cancer (CRC) who are proficient in mismatch repair genes (MMR). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.
    Arm type
    Experimental

    Investigational medicinal product name
    AMG 820
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1100 mg administered intravenously (IV) every third week.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

    Arm title
    Part 2, Group 2: Pancreatic Cancer
    Arm description
    Group 2 is comprised of participants with advanced pancreatic cancer who are naïve to anti programmed-death 1 (PD-1), anti PD-ligand 1 (PD-L1), colony stimulating factor 1 (CSF-1) and colony stimulating factor 1 receptor (CSF-1R) therapies. AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.
    Arm type
    Experimental

    Investigational medicinal product name
    AMG 820
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1100 mg administered intravenously (IV) every third week.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

    Arm title
    Part 2, Group 3: NSCLC PD-L1 Low, Naïve
    Arm description
    Group 3 is comprised of participants with non-small cell lung cancer (NSCLC) who have low (< 50%) tumor PD-L1- expression and are naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R agents. AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.
    Arm type
    Experimental

    Investigational medicinal product name
    AMG 820
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1100 mg administered intravenously (IV) every third week.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

    Arm title
    Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low
    Arm description
    Group 4a is comprised of participants who did not respond to or who relapsed during monotherapy with anti-PD-1/PD-L1 agents and are anti-CSF-1/CSF-1R naïve. These participants have low PD-L1 tumor expression (<50%). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.
    Arm type
    Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

    Investigational medicinal product name
    AMG 820
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1100 mg administered intravenously (IV) every third week.

    Arm title
    Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
    Arm description
    Group 4b is comprised of participants who did not respond to or who relapsed during monotherapy with anti-PD-1/PD-L1 agents and are anti-CSF-1/CSF-1R naïve. These participants have high PD-L1 tumor expression (>=50%). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.
    Arm type
    Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Keytruda
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab was administered at a dose of 200 mg intravenously every third week following the administration of AMG 820.

    Investigational medicinal product name
    AMG 820
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1100 mg administered intravenously (IV) every third week.

    Number of subjects in period 1
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
    Started
    8
    7
    42
    31
    4
    19
    6
    Completed
    1
    3
    11
    2
    1
    5
    2
    Not completed
    7
    4
    31
    29
    3
    14
    4
         Adverse event, serious fatal
    3
    3
    26
    27
    3
    13
    3
         Consent withdrawn by subject
    3
    1
    4
    2
    -
    1
    1
         Lost to follow-up
    1
    -
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg
    Reporting group description
    Part 1 Cohort 2 includes participants with advanced solid tumors who were treated with 1100 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed.

    Reporting group title
    Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg
    Reporting group description
    Part 1 Cohort 1 includes participants with advanced solid tumors who were treated with 1400 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed. If >= 3 participants had dose limiting toxicities (DLTs), a second cohort was created with a lower AMG 820 dose + Pem 200 mg.

    Reporting group title
    Part 2, Group 1: CRC MMR-proficient
    Reporting group description
    Group 1 is comprised of participants with colorectal cancer (CRC) who are proficient in mismatch repair genes (MMR). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group title
    Part 2, Group 2: Pancreatic Cancer
    Reporting group description
    Group 2 is comprised of participants with advanced pancreatic cancer who are naïve to anti programmed-death 1 (PD-1), anti PD-ligand 1 (PD-L1), colony stimulating factor 1 (CSF-1) and colony stimulating factor 1 receptor (CSF-1R) therapies. AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group title
    Part 2, Group 3: NSCLC PD-L1 Low, Naïve
    Reporting group description
    Group 3 is comprised of participants with non-small cell lung cancer (NSCLC) who have low (< 50%) tumor PD-L1- expression and are naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R agents. AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group title
    Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low
    Reporting group description
    Group 4a is comprised of participants who did not respond to or who relapsed during monotherapy with anti-PD-1/PD-L1 agents and are anti-CSF-1/CSF-1R naïve. These participants have low PD-L1 tumor expression (<50%). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group title
    Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
    Reporting group description
    Group 4b is comprised of participants who did not respond to or who relapsed during monotherapy with anti-PD-1/PD-L1 agents and are anti-CSF-1/CSF-1R naïve. These participants have high PD-L1 tumor expression (>=50%). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group values
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High Total
    Number of subjects
    8 7 42 31 4 19 6 117
    Age Categorical
    Units: participants
        18-64 years
    2 6 24 18 3 7 4 64
        65-74 years
    6 1 15 10 1 6 2 41
        75-84 years
    0 0 3 3 0 5 0 11
        >=85 years
    0 0 0 0 0 1 0 1
    Sex: Female, Male
    Units: participants
        Female
    5 3 16 14 1 1 3 43
        Male
    3 4 26 17 3 18 3 74
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 1 3 1 0 0 0 5
        Not Hispanic or Latino
    8 6 36 29 4 19 6 108
        Unknown or Not Reported
    0 0 3 1 0 0 0 4
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0 0 0 0
        Asian
    0 1 1 3 0 0 0 5
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0 0 0
        Black or African American
    0 0 0 1 0 2 1 4
        White
    8 5 39 26 4 17 5 104
        More than one race
    0 0 0 0 0 0 0 0
        Unknown or Not Reported
    0 1 2 1 0 0 0 4
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
    Units: Subjects
        Grade 0
    6 4 19 7 1 4 2 43
        Grade 1
    2 3 23 24 3 15 4 74
        Grade 2
    0 0 0 0 0 0 0 0
        Grade 3
    0 0 0 0 0 0 0 0
        Grade 4
    0 0 0 0 0 0 0 0
        Grade 5
    0 0 0 0 0 0 0 0
    Number of Prior Line of Therapy
    Units: Subjects
        0 therapies
    0 0 0 0 0 0 0 0
        1 therapy
    0 0 2 3 3 1 0 9
        2 therapies
    1 1 9 13 1 7 3 35
        3 therapies
    4 3 11 8 0 7 3 36
        4 therapies
    1 1 10 5 0 1 0 18
        5 therapies
    2 2 10 2 0 3 0 19
        >5 therapies
    0 0 0 0 0 0 0 0
    Disease Stage at Screening
    There are five stages of cancer: stage 0 (or, carcinoma in situ), stage I, stage II, stage III, and stage IV. Lower stages indicate that the disease is more localized, or contained, whereas higher stages refer to cancers that have spread into other areas of the body.
    Units: Subjects
        Stage I
    1 1 0 0 0 0 0 2
        Stage II
    1 0 3 3 1 1 0 9
        Stage III
    0 0 4 2 0 2 1 9
        Stage IV
    6 6 35 26 3 16 5 97

    End points

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    End points reporting groups
    Reporting group title
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg
    Reporting group description
    Part 1 Cohort 2 includes participants with advanced solid tumors who were treated with 1100 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed.

    Reporting group title
    Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg
    Reporting group description
    Part 1 Cohort 1 includes participants with advanced solid tumors who were treated with 1400 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed. If >= 3 participants had dose limiting toxicities (DLTs), a second cohort was created with a lower AMG 820 dose + Pem 200 mg.

    Reporting group title
    Part 2, Group 1: CRC MMR-proficient
    Reporting group description
    Group 1 is comprised of participants with colorectal cancer (CRC) who are proficient in mismatch repair genes (MMR). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group title
    Part 2, Group 2: Pancreatic Cancer
    Reporting group description
    Group 2 is comprised of participants with advanced pancreatic cancer who are naïve to anti programmed-death 1 (PD-1), anti PD-ligand 1 (PD-L1), colony stimulating factor 1 (CSF-1) and colony stimulating factor 1 receptor (CSF-1R) therapies. AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group title
    Part 2, Group 3: NSCLC PD-L1 Low, Naïve
    Reporting group description
    Group 3 is comprised of participants with non-small cell lung cancer (NSCLC) who have low (< 50%) tumor PD-L1- expression and are naïve to anti-PD-1/PD-L1/CSF-1/CSF-1R agents. AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group title
    Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low
    Reporting group description
    Group 4a is comprised of participants who did not respond to or who relapsed during monotherapy with anti-PD-1/PD-L1 agents and are anti-CSF-1/CSF-1R naïve. These participants have low PD-L1 tumor expression (<50%). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Reporting group title
    Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
    Reporting group description
    Group 4b is comprised of participants who did not respond to or who relapsed during monotherapy with anti-PD-1/PD-L1 agents and are anti-CSF-1/CSF-1R naïve. These participants have high PD-L1 tumor expression (>=50%). AMG 820 was administered at the recommended dose of 1100 mg intravenously in combination with pembrolizumab 200 mg every 3 weeks (± 3 days). Each group in Part 2 was evaluated separately using a Simon 2-stage design. Treatment continued until confirmed disease progression per modified irRECIST, or intolerance of study treatment, or clinically significant deterioration of health status requiring discontinuation, whichever occurred first, or the subject withdrew consent.

    Subject analysis set title
    Part 1: AMG 820 + Pem 200 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Part 1 Cohorts 1 + 2 combined. Participants with advanced solid tumors were treated with 1400 mg or 1100 mg AMG 820 plus 200 mg pembrolizumab (Pem) every three weeks (Q3W) to determine safety. Participants could be treated up to 24 months if treatment was tolerable and clinical benefit was observed.

    Subject analysis set title
    AMG 820 1100 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Includes participants from all treatment arms that were administered AMG 820 1100 mg.

    Subject analysis set title
    AMG 820 1400 mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Includes participants from all treatment arms who were administered AMG 820 1400 mg

    Primary: Participants with Dose Limiting Toxicities (DLT)

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    End point title
    Participants with Dose Limiting Toxicities (DLT) [1]
    End point description
    DLTs were evaluated by the Dose Level Review Team (DLRT). A DLT was defined as any grade >=3 adverse event occurring during a DLT time window (21 day period from the initial administration of AMG 820 and pembrolizumab in combination), and if judged by the investigator to be related to the administration of AMG 820 and/or pembrolizumab.
    End point type
    Primary
    End point timeframe
    The DLT evaluation period was Day 1 to Day 21
    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: The statistical reporting of the safety outcomes was entirely descriptive, with no formal statistical testing performed.
    End point values
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
    Number of subjects analysed
    8
    7
    41
    31
    4
    19
    6
    Units: participants
        Participants with treatment emergent DLTs
    0
    1
    3
    2
    0
    1
    0
        DLT: Autoimmune pancreatitis
    0
    1
    0
    0
    0
    0
    0
        DLT: Autoimmune hepatitis
    0
    1
    0
    0
    0
    0
    0
        DLT: Cholecystitis
    0
    1
    0
    0
    0
    0
    0
        DLT: Electrolyte imbalance
    0
    1
    0
    0
    0
    0
    0
        DLT: Fatigue
    0
    0
    1
    0
    0
    0
    0
        DLT: Aspartate aminotransferase increased
    0
    0
    1
    1
    0
    0
    0
        DLT: Lipase increased
    0
    0
    0
    0
    0
    1
    0
        DLT: Epilepsy
    0
    0
    0
    1
    0
    0
    0
        DLT: Rash generalised
    0
    0
    1
    0
    0
    0
    0
        DLT: Rash maculo-papular
    0
    0
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Participants with Treatment -Emergent Adverse Events (TEAEs)

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    End point title
    Participants with Treatment -Emergent Adverse Events (TEAEs) [2]
    End point description
    TEAEs include any adverse event starting on or after the first dose of AMG 820 or pembrolizumab. Relation to study drugs was determined by the investigator. Adverse events (AEs) were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. Errors in the case report form design resulted in investigators misunderstanding the CTCAE definition for severity grade 5. Therefore, data are not reported for severity grade 5 (9999=not available). Readers are referred to the ‘Fatal TEAE’ line in the table below for counts of participants who died during the TEAE timeframe.
    End point type
    Primary
    End point timeframe
    Day 1 up to 207 days for Part 1 and Day 1 up to 572 days for Part 2
    Notes
    [2] - 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: The statistical reporting of the safety outcomes was entirely descriptive, with no formal statistical testing performed.
    End point values
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
    Number of subjects analysed
    8
    7
    41
    31
    4
    19
    6
    Units: participants
    number (not applicable)
        >=1 TEAE
    8
    7
    41
    31
    4
    19
    6
        Grade >=3
    7
    7
    40
    30
    4
    19
    6
        Grade >=4
    2
    4
    24
    26
    2
    12
    4
        Grade >=5
    9999
    9999
    9999
    9999
    9999
    9999
    9999
        Serious AE
    5
    2
    31
    23
    3
    11
    5
        Leading to interruption of AMG 820
    4
    3
    23
    7
    1
    7
    2
        Leading to discontinuation AMG 820
    0
    0
    6
    5
    2
    1
    3
        ---- SAE leading to d/c AMG 820
    0
    0
    4
    4
    1
    0
    2
        ----Non-serious AE leading to d/c AMG 820
    0
    0
    2
    1
    1
    1
    1
        Leading to discontinuation of PEM
    1
    0
    7
    5
    2
    1
    3
        ---- SAE leading to d/c PEM
    0
    0
    4
    4
    1
    0
    2
        ----Non-serious AE leading to d/c PEM
    1
    0
    3
    1
    1
    1
    1
        Fatal TEAE
    1
    0
    4
    3
    0
    3
    2
        TEAE related to study procedure/activity
    0
    1
    11
    5
    0
    3
    1
    No statistical analyses for this end point

    Primary: Participants with Treatment -Emergent Adverse Events (TEAEs) Related to AMG 820 Treatment

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    End point title
    Participants with Treatment -Emergent Adverse Events (TEAEs) Related to AMG 820 Treatment [3]
    End point description
    TEAEs include any adverse event starting on or after the first dose of AMG 820 or pembrolizumab. Relation to study drugs was determined by the investigator. Adverse events (AEs) were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. Errors in the case report form design resulted in investigators misunderstanding the CTCAE definition for severity grade 5. Therefore, data are not reported for severity grade 5 (9999=not available). Readers are referred to the ‘Fatal TEAE’ line in the table below for counts of participants who died during the TEAE timeframe.
    End point type
    Primary
    End point timeframe
    Day 1 up to 207 days for Part 1; Day 1 up to 572 days for Part 2
    Notes
    [3] - 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: The statistical reporting of the safety outcomes was entirely descriptive, with no formal statistical testing performed.
    End point values
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
    Number of subjects analysed
    8
    7
    41
    31
    4
    19
    6
    Units: participants
        >=1 TEAE
    5
    7
    41
    25
    4
    14
    6
        Grade >=3
    3
    5
    28
    11
    1
    10
    6
        Grade >=4
    1
    1
    5
    5
    0
    2
    2
        Grade >=5
    9999
    9999
    9999
    9999
    9999
    9999
    9999
        Serious AE
    2
    2
    12
    4
    0
    3
    3
        Leading to interruption of AMG 820
    2
    3
    16
    7
    0
    5
    2
        Leading to discontinuation AMG 820
    0
    0
    3
    3
    1
    0
    3
        ---- SAE leading to d/c AMG 820
    0
    0
    3
    2
    0
    0
    2
        ----Non-serious AE leading to d/c AMG 820
    0
    0
    0
    1
    1
    0
    1
        Leading to discontinuation of PEM
    0
    0
    4
    3
    1
    0
    3
        ---- SAE leading to d/c PEM
    0
    0
    3
    2
    0
    0
    2
        ----Non-serious AE leading to d/c PEM
    0
    0
    1
    1
    1
    0
    1
        Fatal TEAE
    0
    0
    1
    0
    0
    0
    1
        TEAE related to study procedure/activity
    0
    0
    8
    2
    0
    3
    1
    No statistical analyses for this end point

    Primary: Participants with Treatment -Emergent Adverse Events (TEAEs) Related to Pembrolizumab Treatment

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    End point title
    Participants with Treatment -Emergent Adverse Events (TEAEs) Related to Pembrolizumab Treatment [4]
    End point description
    TEAEs include any adverse event starting on or after the first dose of AMG 820 or pembrolizumab. Relation to study drugs was determined by the investigator. Adverse events (AEs) were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. Errors in the case report form design resulted in investigators misunderstanding the CTCAE definition for severity grade 5. Therefore, data are not reported for severity grade 5 (9999=not available). Readers are referred to the ‘Fatal TEAE’ line in the table below for counts of participants who died during the TEAE timeframe.
    End point type
    Primary
    End point timeframe
    Day 1 up to 207 days for Part 1 and Day 1 up to 572 days for Part 2
    Notes
    [4] - 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: The statistical reporting of the safety outcomes was entirely descriptive, with no formal statistical testing performed.
    End point values
    Part 1, Cohort 2: AMG 820 1100 mg + Pem 200 mg Part 1, Cohort 1: AMG 820 1400 mg + Pem 200 mg Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High
    Number of subjects analysed
    8
    7
    41
    31
    4
    19
    6
    Units: participants
        >=1 TEAE
    5
    7
    39
    24
    4
    13
    6
        Grade >=3
    2
    5
    29
    9
    1
    10
    4
        Grade >=4
    1
    1
    5
    4
    0
    2
    2
        Grade >=5
    9999
    9999
    9999
    9999
    9999
    9999
    9999
        Serious AE
    2
    2
    16
    5
    0
    3
    4
        Leading to interruption of PEM
    1
    3
    15
    6
    0
    5
    2
        Leading to discontinuation AMG 820
    0
    0
    4
    2
    1
    1
    3
        ---- SAE leading to d/c AMG 820
    0
    0
    3
    1
    0
    0
    2
        ----Non-serious AE leading to d/c AMG 820
    0
    0
    1
    1
    1
    1
    1
        Leading to discontinuation of PEM
    0
    0
    5
    2
    1
    1
    3
        ---- SAE leading to d/c PEM
    0
    0
    3
    1
    0
    0
    2
        ----Non-serious AE leading to d/c PEM
    0
    0
    2
    1
    1
    1
    1
        Fatal TEAE
    0
    0
    1
    0
    0
    0
    1
        TEAE related to study procedure/activity
    0
    0
    9
    3
    0
    2
    1
    No statistical analyses for this end point

    Primary: Objective Response Rate (ORR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST)

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    End point title
    Objective Response Rate (ORR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) [5] [6]
    End point description
    ORR was defined as the percentage of participants with a best overall response of complete response or partial response assessed by the investigator using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Response was based on the size of tumors assessed by computed tomography (CT) or magnetic resonance imaging (MRI). During treatment radiographic imaging was performed at Week 10 and repeated at least every 10 weeks until disease progression. Complete response (iCR): Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (iPR): Decrease in tumor burden ≥ 30% relative to baseline. Confirmation by a consecutive assessment at least 4 weeks after first documentation required.
    End point type
    Primary
    End point timeframe
    Baseline: Day -28; Treatment: up to Month 13.7
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical testing was performed comparing groups of participants with different diagnoses.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part 1 dose finding cohorts were combined when reporting results for this outcome.
    End point values
    Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High Part 1: AMG 820 + Pem 200 mg
    Number of subjects analysed
    41
    31
    4
    19
    6
    15
    Units: percentage of participants
        number (confidence interval 95%)
    4.9 (0.60 to 16.53)
    0.0 (0.0 to 0.0)
    0.0 (0.0 to 0.0)
    5.3 (0.13 to 26.03)
    0.0 (0.0 to 0.0)
    0.0 (0.00 to 0.00)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) For Participants Who Responded

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    End point title
    Time to Response (TTR) per Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST) For Participants Who Responded [7]
    End point description
    Time to response was defined as the time from first dose of AMG 820 until first documented complete or partial response per irRECIST divided by 365.25 days/12.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 16 (max time to censoring)
    Notes
    [7] - 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: Part 1 dose finding cohorts were combined when reporting results for this outcome.
    End point values
    Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High Part 1: AMG 820 + Pem 200 mg
    Number of subjects analysed
    2
    0 [8]
    0 [9]
    1
    0 [10]
    0 [11]
    Units: month
        arithmetic mean (full range (min-max))
    2.1587 (2.004 to 2.168)
    ( to )
    ( to )
    2.0698 (2.0698 to 2.0698)
    ( to )
    ( to )
    Notes
    [8] - No responders
    [9] - No responders
    [10] - No responders
    [11] - No responders
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP) for Participants Who had Progressive Disease

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    End point title
    Time to Progression (TTP) for Participants Who had Progressive Disease [12]
    End point description
    Time to progression was defined as the time from first dose of AMG 820 until first documented progressive disease per irRECIST divided by 365.25 days/12.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 14.4 months (max time to censoring)
    Notes
    [12] - 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: Part 1 dose finding cohorts were combined when reporting results for this outcome.
    End point values
    Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High Part 1: AMG 820 + Pem 200 mg
    Number of subjects analysed
    29
    13
    3
    8
    4
    10
    Units: month
        arithmetic mean (full range (min-max))
    3.0691 (0.559 to 8.411)
    2.3878 (0.296 to 4.698)
    4.6762 (2.070 to 6.604)
    6.0863 (1.150 to 11.992)
    7.7864 (1.938 to 13.667)
    2.1865 (0.460 to 5.552)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimates for Overall Survival (OS) at Month 6 and Month 12

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    End point title
    Kaplan-Meier Estimates for Overall Survival (OS) at Month 6 and Month 12 [13]
    End point description
    Overall survival time was calculated as the number of days from the first administration of AMG 820 to date of death or censoring divided by (365.25/12). Data are reported as the percentage of participants who were alive at Month 6 and Month 12.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 6 or Month 12
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part 1 dose finding cohorts were combined when reporting results for this outcome.
    End point values
    Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High Part 1: AMG 820 + Pem 200 mg
    Number of subjects analysed
    41 [14]
    31 [15]
    4 [16]
    19 [17]
    6 [18]
    15 [19]
    Units: percentage of participants
    number (confidence interval 90%)
        Month 6
    53.915 (40.00 to 63.93)
    16.705 (7.40 to 29.24)
    75.000 (22.34 to 94.63)
    52.105 (31.91 to 68.93)
    41.667 (9.26 to 72.47)
    59.077 (32.25 to 78.28)
        Month 12
    38.963 (25.77 to 51.94)
    8.353 (2.22 to 19.81)
    25.00 (2.08 to 60.89)
    34.737 (17.37 to 52.79)
    41.667 (9.26 to 72.47)
    47.262 (21.19 to 69.63)
    Notes
    [14] - Month 6; 19 subjects at risk Month 12: 10 subjects at risk
    [15] - Month 6; 5 subjects at risk Month 12: 2 subjects at risk
    [16] - Month 6; 3 subjects at risk Month 12: 0 subjects at risk
    [17] - Month 6; 9 subjects at risk Month 12: 6 subjects at risk
    [18] - Month 6; 2 subjects at risk Month 12: 2 subjects at risk
    [19] - Month 6; 5 subjects at risk Month 12: 2 subjects at risk
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimates for Progression-Free Survival (PFS) as per irRECIST at Month 6 and Month 12

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    End point title
    Kaplan-Meier Estimates for Progression-Free Survival (PFS) as per irRECIST at Month 6 and Month 12 [20]
    End point description
    Progression-free survival time was calculated as the number of days from the first administration of AMG 820 to date of progressive disease or death or censoring divided by (365.25/12). Data are reported as the percentage of participants who were alive and progression-free at Month 6 and Month 12.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 6 or Month 12
    Notes
    [20] - 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: Part 1 dose finding cohorts were combined when reporting results for this outcome.
    End point values
    Part 2, Group 1: CRC MMR-proficient Part 2, Group 2: Pancreatic Cancer Part 2, Group 3: NSCLC PD-L1 Low, Naïve Part 2, Group 4a: Refractory / Relapsing NSCLC PD-L1 Low Part 2, Group 4b: Refractory/Relapsing NSCLC PD-L1 High Part 1: AMG 820 + Pem 200 mg
    Number of subjects analysed
    41 [21]
    31 [22]
    4 [23]
    19 [24]
    6 [25]
    15 [26]
    Units: percentage of participants
    number (confidence interval 90%)
        Month 6
    13.490 (5.99 to 24.04)
    0.000 (0.00 to 0.00)
    25.000 (2.08 to 60.89)
    26.471 (10.67 to 45.41)
    33.333 (7.37 to 62.95)
    10.476 (1.23 to 31.40)
        Month 12
    5.396 (1.36 to 13.77)
    0.000 (0.00 to 0.00)
    0.000 (0.00 to 0.00)
    6.618 (0.77 to 21.97)
    33.333 (7.37 to 62.95)
    0.000 (0.00 to 0.00)
    Notes
    [21] - Month 6: 5 subjects at risk Month 12: 1 subject at risk
    [22] - Month 6: 0 subjects at risk Month 12: 0 subject at risk
    [23] - Month 6: 1 subject at risk Month 12: 0 subject at risk
    [24] - Month 6: 4 subjects at risk Month 12: 1 subject at risk
    [25] - Month 6: 2 subjects at risk Month 12: 2 subjects at risk
    [26] - Month 6: 1 subject at risk Month 12: 0 subject at risk
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Time of Maximum Observed Concentration (tmax) During Treatment Cycles 1 + 2

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Time of Maximum Observed Concentration (tmax) During Treatment Cycles 1 + 2
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    97
    18
    Units: hour
    median (full range (min-max))
        Cycle 1 (n=97, 18)
    2.0 (1.0 to 170)
    2.0 (1.0 to 7.0)
        Cycle 2 (n=71, 10)
    3.00 (1.00 to 25.0)
    2.00 (1.00 to 25.0)
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Maximum Observed Drug Concentration (Cmax) During Treatment Cycles 1 + 2

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Maximum Observed Drug Concentration (Cmax) During Treatment Cycles 1 + 2
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    97
    18
    Units: ug/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=97, 18)
    331 ± 27
    485 ± 23
        Cycle 2 (n=71, 10)
    363 ± 32
    536 ± 21
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve last (AUClast) During Treatment Cycles 1 + 2

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve last (AUClast) During Treatment Cycles 1 + 2
    End point description
    AUClast is the area under the serum concentration-time curve from time zero to time of last quantifiable concentration.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    97
    18
    Units: hr*ug/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=97, 18)
    55100 ± 37
    80400 ± 33
        Cycle 2 (n=71, 10)
    55200 ± 38
    73500 ± 45
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve Over the Dose Interval (AUCtau) During Treatment Cycles 1 + 2

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Area Under the Curve Over the Dose Interval (AUCtau) During Treatment Cycles 1 + 2
    End point description
    AUCtau is the area under the serum concentration-time curve over the dose interval tau, with tau equal to 21 days.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    97
    18
    Units: hr*ug/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=97, 18)
    59300 ± 33
    90000 ± 29
        Cycle 2 (n=68, 9)
    75400 ± 35
    114000 ± 31
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Minimum Observed Drug Concentration (Cmin) During Treatment Cycles 1 + 2

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Minimum Observed Drug Concentration (Cmin) During Treatment Cycles 1 + 2
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    70
    10
    Units: ug/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=70, 10)
    49.9 ± 51
    90.9 ± 35
        Cycle 2 (n=48, 3)
    78.7 ± 66
    199 ± 34
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Terminal Elimination Half-life (t1/2z) During Treatment Cycles 1 + 2

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Terminal Elimination Half-life (t1/2z) During Treatment Cycles 1 + 2
    End point description
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    46
    7
    Units: hour
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=46, 7)
    217 ± 26
    214 ± 24
        Cycle 2 (n=7, not reported)
    170 ± 16
    9999 ± 9999
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Volume of Distribution (Vz) During Treatment Cycles 1 + 2

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Volume of Distribution (Vz) During Treatment Cycles 1 + 2
    End point description
    Volume of distribution observed at terminal phase after intravenous dosing.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    46
    7
    Units: liter
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=46, 7)
    5200 ± 35
    4110 ± 25
        Cycle 2 (n=7, not reported)
    4560 ± 21
    9999 ± 9999
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Drug Clearance (CL) During Treatment Cycles 1 + 2

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Drug Clearance (CL) During Treatment Cycles 1 + 2
    End point description
    Drug clearance observed after intravenous dosing.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    46
    7
    Units: liter/hour
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n=46, 7)
    16.6 ± 37
    13.3 ± 33
        Cycle 2 (n=7, not reported)
    18.6 ± 30
    9999 ± 9999
    No statistical analyses for this end point

    Secondary: AMG 820 Pharmacokinetic Parameter by Dose Group: Accumulation Ratio (AR)

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    End point title
    AMG 820 Pharmacokinetic Parameter by Dose Group: Accumulation Ratio (AR)
    End point description
    Accumulation ratio is AUCtau following administration in Cycle 2 / AUCtau after administration in Cycle 1
    End point type
    Secondary
    End point timeframe
    Cycle 1, Study Day 1: pre-infusion, at end of infusion, hours 1, 6 and 24 post infusion, Days 5, 8 and 15. Cycle 2, Study Day 22: pre-infusion, at end of infusion, hours 1, 6, 24 post infusion, Days 26, 29 and 36
    End point values
    AMG 820 1100 mg AMG 820 1400 mg
    Number of subjects analysed
    68
    9
    Units: ratio
        geometric mean (geometric coefficient of variation)
    1.23 ± 18
    1.25 ± 16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The TEAE timeframe was Day 1 up to 207 days for Part 1 and Day 1 up to 572 days for Part 2. The median time frame is 122 days..
    Adverse event reporting additional description
    All adverse events (AEs) and disease related events (DREs) are integrated in the summaries.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    AMG 820 1400 MG
    Reporting group description
    Includes participants from all treatment arms that were administered AMG 820 1400 mg.

    Reporting group title
    AMG 820 1100 MG
    Reporting group description
    Includes participants from all treatment arms that were administered AMG 820 1100 mg.

    Serious adverse events
    AMG 820 1400 MG AMG 820 1100 MG
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 18 (55.56%)
    70 / 98 (71.43%)
         number of deaths (all causes)
    1
    12
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Colorectal cancer metastatic
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour flare
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Tumour haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 18 (0.00%)
    8 / 98 (8.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 18 (0.00%)
    4 / 98 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar infarction
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune pancreatitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enterovesical fistula
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal haemorrhage
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema nodosum
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis staphylococcal
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 98 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 98 (3.06%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AMG 820 1400 MG AMG 820 1100 MG
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 18 (100.00%)
    97 / 98 (98.98%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Embolism
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Hypertension
         subjects affected / exposed
    4 / 18 (22.22%)
    16 / 98 (16.33%)
         occurrences all number
    4
    25
    Hypotension
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    5
    Venous thrombosis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer metastatic
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 98 (1.02%)
         occurrences all number
    3
    1
    Colorectal cancer metastatic
         subjects affected / exposed
    1 / 18 (5.56%)
    4 / 98 (4.08%)
         occurrences all number
    1
    4
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    4 / 18 (22.22%)
    9 / 98 (9.18%)
         occurrences all number
    4
    9
    Pancreatic carcinoma
         subjects affected / exposed
    2 / 18 (11.11%)
    6 / 98 (6.12%)
         occurrences all number
    2
    6
    Rectal cancer
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Tumour haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 18 (0.00%)
    8 / 98 (8.16%)
         occurrences all number
    0
    9
    Chills
         subjects affected / exposed
    3 / 18 (16.67%)
    11 / 98 (11.22%)
         occurrences all number
    3
    12
    Fatigue
         subjects affected / exposed
    10 / 18 (55.56%)
    52 / 98 (53.06%)
         occurrences all number
    12
    78
    Face oedema
         subjects affected / exposed
    5 / 18 (27.78%)
    14 / 98 (14.29%)
         occurrences all number
    10
    20
    Hyperthermia malignant
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    1 / 18 (5.56%)
    4 / 98 (4.08%)
         occurrences all number
    1
    4
    Pain
         subjects affected / exposed
    0 / 18 (0.00%)
    6 / 98 (6.12%)
         occurrences all number
    0
    6
    Oedema peripheral
         subjects affected / exposed
    2 / 18 (11.11%)
    10 / 98 (10.20%)
         occurrences all number
    2
    12
    Pyrexia
         subjects affected / exposed
    3 / 18 (16.67%)
    25 / 98 (25.51%)
         occurrences all number
    4
    34
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 18 (5.56%)
    6 / 98 (6.12%)
         occurrences all number
    1
    6
    Anxiety
         subjects affected / exposed
    2 / 18 (11.11%)
    5 / 98 (5.10%)
         occurrences all number
    2
    5
    Insomnia
         subjects affected / exposed
    4 / 18 (22.22%)
    4 / 98 (4.08%)
         occurrences all number
    4
    4
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 18 (0.00%)
    6 / 98 (6.12%)
         occurrences all number
    0
    12
    Alanine aminotransferase
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 18 (22.22%)
    21 / 98 (21.43%)
         occurrences all number
    4
    28
    Amylase increased
         subjects affected / exposed
    5 / 18 (27.78%)
    19 / 98 (19.39%)
         occurrences all number
    5
    35
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 18 (66.67%)
    58 / 98 (59.18%)
         occurrences all number
    20
    110
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 18 (27.78%)
    13 / 98 (13.27%)
         occurrences all number
    13
    18
    Blood bilirubin increased
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    11
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 98 (1.02%)
         occurrences all number
    2
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    8
    Liver function test abnormal
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Lipase increased
         subjects affected / exposed
    5 / 18 (27.78%)
    18 / 98 (18.37%)
         occurrences all number
    5
    37
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Transaminases increased
         subjects affected / exposed
    0 / 18 (0.00%)
    7 / 98 (7.14%)
         occurrences all number
    0
    10
    Weight decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    6 / 98 (6.12%)
         occurrences all number
    1
    7
    Troponin increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 18 (5.56%)
    19 / 98 (19.39%)
         occurrences all number
    1
    23
    Hiccups
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Dyspnoea
         subjects affected / exposed
    3 / 18 (16.67%)
    22 / 98 (22.45%)
         occurrences all number
    3
    26
    Nasal congestion
         subjects affected / exposed
    1 / 18 (5.56%)
    5 / 98 (5.10%)
         occurrences all number
    1
    7
    Oropharyngeal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 98 (3.06%)
         occurrences all number
    1
    3
    Pleural effusion
         subjects affected / exposed
    0 / 18 (0.00%)
    9 / 98 (9.18%)
         occurrences all number
    0
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 18 (22.22%)
    35 / 98 (35.71%)
         occurrences all number
    8
    70
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Aphasia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Dysgeusia
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    5
    Dizziness
         subjects affected / exposed
    1 / 18 (5.56%)
    6 / 98 (6.12%)
         occurrences all number
    1
    7
    Facial paresis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    2 / 18 (11.11%)
    11 / 98 (11.22%)
         occurrences all number
    2
    15
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    10 / 18 (55.56%)
    38 / 98 (38.78%)
         occurrences all number
    13
    46
    Periorbital swelling
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    4
    Photophobia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Uveitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 98 (2.04%)
         occurrences all number
    2
    2
    Visual impairment
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 18 (5.56%)
    6 / 98 (6.12%)
         occurrences all number
    1
    6
    Abdominal pain
         subjects affected / exposed
    6 / 18 (33.33%)
    20 / 98 (20.41%)
         occurrences all number
    7
    29
    Ascites
         subjects affected / exposed
    0 / 18 (0.00%)
    6 / 98 (6.12%)
         occurrences all number
    0
    7
    Constipation
         subjects affected / exposed
    9 / 18 (50.00%)
    22 / 98 (22.45%)
         occurrences all number
    10
    27
    Diarrhoea
         subjects affected / exposed
    5 / 18 (27.78%)
    23 / 98 (23.47%)
         occurrences all number
    7
    36
    Dry mouth
         subjects affected / exposed
    3 / 18 (16.67%)
    8 / 98 (8.16%)
         occurrences all number
    3
    8
    Duodenal obstruction
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    6
    Dysphagia
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 98 (3.06%)
         occurrences all number
    1
    3
    Flatulence
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Nausea
         subjects affected / exposed
    7 / 18 (38.89%)
    26 / 98 (26.53%)
         occurrences all number
    8
    32
    Oral pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Proctalgia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Stomatitis
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 98 (3.06%)
         occurrences all number
    1
    3
    Vomiting
         subjects affected / exposed
    5 / 18 (27.78%)
    12 / 98 (12.24%)
         occurrences all number
    8
    15
    Renal and urinary disorders
    Bladder spasm
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Haematuria
         subjects affected / exposed
    1 / 18 (5.56%)
    7 / 98 (7.14%)
         occurrences all number
    1
    10
    Nephrotic syndrome
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    Urinary retention
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Proteinuria
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    6
    Photosensitivity reaction
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    4 / 18 (22.22%)
    19 / 98 (19.39%)
         occurrences all number
    7
    26
    Rash
         subjects affected / exposed
    2 / 18 (11.11%)
    25 / 98 (25.51%)
         occurrences all number
    3
    46
    Rash maculo-papular
         subjects affected / exposed
    5 / 18 (27.78%)
    14 / 98 (14.29%)
         occurrences all number
    8
    26
    Skin lesion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 18 (11.11%)
    9 / 98 (9.18%)
         occurrences all number
    2
    9
    Muscular weakness
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    7
    Back pain
         subjects affected / exposed
    1 / 18 (5.56%)
    10 / 98 (10.20%)
         occurrences all number
    3
    10
    Musculoskeletal pain
         subjects affected / exposed
    0 / 18 (0.00%)
    7 / 98 (7.14%)
         occurrences all number
    0
    7
    Myalgia
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 98 (2.04%)
         occurrences all number
    2
    2
    Myopathy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 18 (0.00%)
    6 / 98 (6.12%)
         occurrences all number
    0
    6
    Parathyroid disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 18 (5.56%)
    6 / 98 (6.12%)
         occurrences all number
    1
    6
    Decreased appetite
         subjects affected / exposed
    9 / 18 (50.00%)
    22 / 98 (22.45%)
         occurrences all number
    11
    29
    Hyperglycaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    4 / 98 (4.08%)
         occurrences all number
    1
    7
    Hyperlipasaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    12
    Hyperuricaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    2
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 18 (11.11%)
    11 / 98 (11.22%)
         occurrences all number
    2
    12
    Hypokalaemia
         subjects affected / exposed
    3 / 18 (16.67%)
    9 / 98 (9.18%)
         occurrences all number
    3
    14
    Hypocalcaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    6 / 98 (6.12%)
         occurrences all number
    3
    11
    Hypomagnesaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    10 / 98 (10.20%)
         occurrences all number
    0
    11
    Hypophosphataemia
         subjects affected / exposed
    8 / 18 (44.44%)
    18 / 98 (18.37%)
         occurrences all number
    17
    30
    Hyponatraemia
         subjects affected / exposed
    2 / 18 (11.11%)
    12 / 98 (12.24%)
         occurrences all number
    6
    21
    Ketoacidosis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Candida infection
         subjects affected / exposed
    0 / 18 (0.00%)
    8 / 98 (8.16%)
         occurrences all number
    0
    9
    Conjunctivitis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    Mucosal infection
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    Lung infection
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 98 (3.06%)
         occurrences all number
    1
    5
    Oral candidiasis
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    6
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    5 / 98 (5.10%)
         occurrences all number
    0
    7
    Skin infection
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    6 / 98 (6.12%)
         occurrences all number
    0
    6
    Viral infection
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 98 (1.02%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Oct 2016
    • Updated Safety Follow Up period from 30 days to 135 days after last study treatment throughout the protocol. • Added a Dose Rationale section for AMG 820 (Section 2.2.4) and corresponding Table of Contents entry. • Clarified important identified risks, important potential risks, and referred to most current IB for AMG 820 in Risk Assessment Section 2.3. • Added new exclusion criterion to exclude subjects with active infection within 2 weeks prior to study enrollment. • Added new exclusion criterion to exclude subjects who have received systemic immunostimulatory agents within 6 weeks or five half-lives, whichever is shorter, prior to first dose of study treatment (except anti PD-1/PD-L1 treatment if recruited into Group 4a or 4b). • Modified existing exclusion criteria to also exclude subjects with prior stem cell transplantation. • Modified existing exclusion criteria to also exclude subjects who have other signs or symptoms of clinical immune system suppression. • Part of an existing exclusion criterion was updated to be a stand-alone criterion (previously part of Exclusion 205, the following is now Exclusion 206: receiving systemic immunosuppressive therapy (> 2 weeks) within 7 days prior to the first dose of study treatment, including oral steroid doses > 10 mg/day of prednisone or equivalent except for management of adverse events during the course of the study. Subjects that require intermittent use of bronchodilators or local steroid injection will not be excluded from the study). • Updated exclusion criteria to include only highly effective methods of birth control which are in accordance with CTFG’s recommendations (removed statements regarding barrier methods of contraception as being acceptable). - Others
    15 Jun 2018
     Updated Section 2.4 and Section 2.5 with Merck-provided language for pembrolizumab product background.  Updated Section 3.4 to clarify that all subjects who are not DLT evaluable can be replaced.  Updated Section 3.5.1 to clarify the data collected for subjects who continue past 12 months and up to 24 months on treatment.  Updated Section 4 to clarify that all windows in Inclusion and Exclusion criteria are relative to first day of study treatment.  Modified Exclusion Criterion to exclude subjects with history of or active pneumonitis.  Updated relevant sections to require safety labs to be reviewed within 2 days prior to dosing.  Updated Table 2 to indicate that pembrolizumab should be permanently discontinued for Recurrent Grade 2 pneumonitis.  Updated Table 2 with footnote to indicate that treatment may possibly continue under certain circumstances of isolated elevated AST attributed to AMG 820 with agreement from Medical Monitor.  Updated Table 3 to indicate that pembrolizumab should be permanently discontinued for Recurrent Grade 2 pneumonitis or ILD.  Provided language for corticosteroid treatment of Hepatic Toxicity (Section 6.2.4.6) or Renal Failure or Nephritis (Section 6.2.4.7): Grade 2 events should be treated with IV or oral corticosteroids while grade 3-4 events should be treated with IV corticosteroids.  Updated the reporting period of Pembrolizumab Events of Clinical Interest to be after the first dose of pembrolizumab through 135 (+7) days after the last dose of pembrolizumab, or 135 (+7) days after initiation of a new cancer therapy. - Updated Section 6.2.4.10 through Section 6.2.4.10.4 to include AMG 820 as well as pembrolizumab in diet and other considerations while taking treatment. - As Amgen has decided to discontinue investigating the combination of AMG 820 and pembrolizumab, removed non-essential biomarker and tissue sample collection from Schedule of Assessments. - others

    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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