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    Clinical Trial Results:
    A Phase 1b Open-label Study to Evaluate the Safety and Tolerability of MEDI4736 in Combination with Tremelimumab in Subjects with Advanced Non-small Cell Lung Cancer

    Summary
    EudraCT number
    		 2015-003715-38
    Trial protocol
    		 BE   ES   DE   GB   FR  
    Global end of trial date
    17 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Sep 2020
    First version publication date
    26 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D4190C00006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02000947
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    MedImmune, LLC
    Sponsor organisation address
    One MedImmune Way, Gaithersburg, United States, CB21 6GH
    Public contact
    Shahram Rahimian, MedImmune, LLC, +1 800-236-9933, information.center@astrazeneca.com
    Scientific contact
    Shahram Rahimian, MedImmune, LLC, +1 800-236-9933, information.center@astrazeneca.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
    19 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives in dose-escalation phase are: 1) to determine maximum tolerated dose (MTD) or highest protocol-defined dose in absence of exceeding MTD and safety profile of MEDI4736 and tremelimumab in participants with advanced non-small cell lung cancer (NSCLC) using every 2 weeks (Q2W) and every 4 weeks (Q4W) schedules. Primary objectives in dose-expansion phase are: 1) To determine safety profile of MEDI4736 and tremelimumab at the recommended dose Q4W in treatment-naïve and immunotherapy-naive participants, and participants with refractory and relapsed disease 2) To determine antitumor activity of MEDI4736 and tremelimumab at the recommended dose Q4W in immunotherapy-naive participants and participants with refractory and relapsed disease 3) To evaluate safety profile of MEDI4736 monotherapy in participants who have experienced immune-mediated treatment-emergent adverse events (imTEAEs) after discontinuing MEDI4736 in combination with tremelimumab
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Oct 2013
    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: 318
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 60
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United Kingdom: 10
    Worldwide total number of subjects
    457
    EEA total number of subjects
    76
    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)
    220
    From 65 to 84 years
    235
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted from 25Oct2013 to 17Sep2019.

    Pre-assignment
    Screening details
    		 A total of 102 participants were enrolled and treated in dose-escalation arms and a total of 355 participants were enrolled and treated in dose-expansion arms.

    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
    		 Total Escalation
    Arm description
    		 Participants received MEDI4736 IV escalation doses (Dose 1 or 2 or 3 or 4) every 4 weeks (Q4W; up to 13 doses) or every two weeks (Q2W; up to 26 doses) and IV tremelimumab dose (Dose 1, 2, or 3) Q4W for 6 doses and then every 12 weeks (Q12W) for 3 doses (up to 9 doses in total) for 12 months or until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDI4736
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 escalation doses (Dose 1 or 2 or 3 or 4 ) were administered intravenously Q4W (up to 13 doses) or Q2W (up to 26 doses) for 12 months.

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab dose (Dose 1 or 2 or 3) was administered intravenously Q4W for 6 doses and then Q12W for 3 doses (up to 9 doses in total) for 12 months.

    Arm title
    		 Expansion Cohort A
    Arm description
    		 Treatment-naïve, non-epidermal growth factor receptor (non-EGFR) mutation positive, and non-anaplastic lymphoma kinase (non-ALK) rearrangement positive participants received IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab Dose 1 Q4W was administered intravenously for 4 doses.

    Investigational medicinal product name
    MEDI4736
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 Dose 4 Q4W was administered intravenously to complete a total of 12 months of therapy.

    Arm title
    		 Expansion Cohort B (Coadmin)
    Arm description
    		 Immunotherapy-naive participants received co-administration of IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab Dose 1 Q4W was administered intravenously for 4 doses.

    Investigational medicinal product name
    MEDI4736
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 Dose 4 Q4W was administered intravenously to complete a total of 12 months of therapy.

    Arm title
    		 Expansion Cohort B (Sequential)
    Arm description
    		 Immunotherapy-naive participants received sequential administration of IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W monotherapy for 9 doses to complete a total of 12 months of therapy or until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDI4736
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intratumoral use, Intravenous use
    Dosage and administration details
    MEDI4736 Dose 4 Q4W was administered intravenously to complete a total of 12 months of therapy.

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab Dose 1 Q4W was administered intravenously for 4 doses.

    Arm title
    		 Expansion Cohort C (Refractory)
    Arm description
    		 Participants who were refractory to previous immunotherapy treatment received IV infusion of MEDI4736 Dose 4 Q4W and tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDI4736
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 Dose 4 Q4W was administered intravenously to complete a total of 12 months of therapy.

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab Dose 1 Q4W was administered intravenously for 4 doses.

    Arm title
    		 Expansion Cohort C (Relapsed)
    Arm description
    		 Participants whom disease was relapsed with the previous immunotherapy treatment received IV infusion of MEDI4736 Dose 4 Q4W and tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MEDI4736
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MEDI4736 Dose 4 Q4W was administered intravenously to complete a total of 12 months of therapy.

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Tremelimumab Dose 1 Q4W was administered intravenously for 4 doses.

    Number of subjects in period 1
    		Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Started
    102
    45
    19
    213
    38
    40
    Completed
    0
    1
    0
    3
    0
    0
    Not completed
    102
    44
    19
    210
    38
    40
         Adverse event, serious fatal
    66
    24
    15
    126
    28
    31
         Consent withdrawn by subject
    21
    15
    3
    26
    6
    6
         Unspecified
    12
    4
    1
    52
    3
    2
         Lost to follow-up
    3
    1
    -
    6
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Total Escalation
    Reporting group description
    		 Participants received MEDI4736 IV escalation doses (Dose 1 or 2 or 3 or 4) every 4 weeks (Q4W; up to 13 doses) or every two weeks (Q2W; up to 26 doses) and IV tremelimumab dose (Dose 1, 2, or 3) Q4W for 6 doses and then every 12 weeks (Q12W) for 3 doses (up to 9 doses in total) for 12 months or until disease progression.

    Reporting group title
    Expansion Cohort A
    Reporting group description
    		 Treatment-naïve, non-epidermal growth factor receptor (non-EGFR) mutation positive, and non-anaplastic lymphoma kinase (non-ALK) rearrangement positive participants received IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort B (Coadmin)
    Reporting group description
    		 Immunotherapy-naive participants received co-administration of IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort B (Sequential)
    Reporting group description
    		 Immunotherapy-naive participants received sequential administration of IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W monotherapy for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort C (Refractory)
    Reporting group description
    		 Participants who were refractory to previous immunotherapy treatment received IV infusion of MEDI4736 Dose 4 Q4W and tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort C (Relapsed)
    Reporting group description
    		 Participants whom disease was relapsed with the previous immunotherapy treatment received IV infusion of MEDI4736 Dose 4 Q4W and tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy.

    Reporting group values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed) Total
    Number of subjects
    		 102 45 19 213 38 40 457
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 34 11 9 126 15 25 220
        From 65-84 years
    		 67 33 10 87 23 15 235
        85 years and over
    		 1 1 0 0 0 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.3 ( 9.6 ) 68.4 ( 8.3 ) 62.8 ( 10.5 ) 61.2 ( 10.4 ) 66.5 ( 8.2 ) 62.3 ( 8.0 ) -
    Sex: Female, Male
    Units:
        Female
    		 47 21 12 80 12 17 189
        Male
    		 55 24 7 133 26 23 268
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaskan Native
    		 0 0 0 0 0 0 0
        Asian
    		 5 2 0 64 2 3 76
        Black or African American
    		 1 1 1 2 1 2 8
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 1 0 1 2
        White
    		 95 42 17 133 34 30 351
        Other
    		 1 0 1 6 1 1 10
        Not reported
    		 0 0 0 7 0 3 10
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 2 1 12 1 1 20
        Not Hispanic or Latino
    		 99 43 17 194 36 37 426
        Unknown or Not Reported
    		 0 0 1 7 1 2 11

    End points

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    End points reporting groups
    Reporting group title
    Total Escalation
    Reporting group description
    		 Participants received MEDI4736 IV escalation doses (Dose 1 or 2 or 3 or 4) every 4 weeks (Q4W; up to 13 doses) or every two weeks (Q2W; up to 26 doses) and IV tremelimumab dose (Dose 1, 2, or 3) Q4W for 6 doses and then every 12 weeks (Q12W) for 3 doses (up to 9 doses in total) for 12 months or until disease progression.

    Reporting group title
    Expansion Cohort A
    Reporting group description
    		 Treatment-naïve, non-epidermal growth factor receptor (non-EGFR) mutation positive, and non-anaplastic lymphoma kinase (non-ALK) rearrangement positive participants received IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort B (Coadmin)
    Reporting group description
    		 Immunotherapy-naive participants received co-administration of IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort B (Sequential)
    Reporting group description
    		 Immunotherapy-naive participants received sequential administration of IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W monotherapy for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort C (Refractory)
    Reporting group description
    		 Participants who were refractory to previous immunotherapy treatment received IV infusion of MEDI4736 Dose 4 Q4W and tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort C (Relapsed)
    Reporting group description
    		 Participants whom disease was relapsed with the previous immunotherapy treatment received IV infusion of MEDI4736 Dose 4 Q4W and tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy.

    Subject analysis set title
    Escalation MEDI4736 Dose 1 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Dose 1 Q4W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation MEDI4736 Dose 2 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Dose 2 Q4W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation MEDI4736 Dose 3 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Dose 3 Q4W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation & Expansion MEDI4736 Dose 4 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In escalation part of the study, participants received IV MEDI4736 Dose 4 Q4W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months. in expansion part of the study, participants received IV MEDI4736 Dose 4 Q4W and IV tremelimumab Q4W for up to 4 doses each, followed by IV MEDI4736 Dose 4 Q4W monotherapy for 9 doses for a total duration of 12 months.

    Subject analysis set title
    Escalation MEDI4736 Dose 2 (Q2W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Dose 2 Q2W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation MEDI4736 Dose 2 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Dose 2 Q4W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation MEDI4736 Dose 3 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Dose 3 Q4W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation Tremelimumab Dose 1 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Q4W/Q2W for 12 months and IV tremelimumab Dose 1 Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation Tremelimumab Dose 2 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Q4W/Q2W for 12 months and IV tremelimumab Dose 2 Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation Tremelimumab Dose 3 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Q4W and IV tremelimumab Dose 3 Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Expansion Tremelimumab Dose 1 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Q4W and IV tremelimumab Dose 1 Q4W for 4 doses, followed IV MEDI4736 Q4W monotherapy for 12 months in expansion part of the study.

    Subject analysis set title
    Escalation & Expansion MEDI4736 Dose 4 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    In escalation part of the study, participants received IV MEDI4736 Dose 4 Q4W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months. in expansion part of the study, participants received IV MEDI4736 Dose 4 Q4W and IV tremelimumab Q4W for up to 4 doses each, followed IV MEDI4736 Dose 4 Q4W monotherapy for 9 doses for a total duration of 12 months.

    Subject analysis set title
    Escalation MEDI4736 Dose 2 (Q2W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Dose 2 Q2W for 12 months and IV tremelimumab Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation Tremelimumab Dose 1 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Q4W/Q2W for 12 months and IV tremelimumab Dose 1 Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Escalation Tremelimumab Dose 2 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Q4W/Q2W for 12 months and IV tremelimumab Dose 2 Q4W for 6 doses and then Q12W for 3 doses (for a total of up to 9 doses) for 12 months in escalation part of the study.

    Subject analysis set title
    Expansion Tremelimumab Dose 1 (Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received IV MEDI4736 Q4W and IV tremelimumab Dose 1 Q4W for 4 doses, followed IV MEDI4736 Q4W monotherapy for 12 months in expansion part of the study.

    Primary: Number of Participants With Dose-limiting Toxicities (DLT) in the Dose-escalation phase

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    End point title
    		 Number of Participants With Dose-limiting Toxicities (DLT) in the Dose-escalation phase [1] [2]
    End point description
    A DLT was defined as any Grade 3 or higher treatment-related toxicity that occurred during DLT-evaluation period including any >=Grade 3 colitis, Grade 4 immune-related adverse event (irAE; AEs of immune nature in absence of a clear alternative etiology), Grade 3 irAE that does not downgrade to <=Grade 2 within 3 days after onset of the event despite maximal supportive care including systemic corticosteroids or downgrade to <=Grade 1 or baseline within 14 days, liver transaminase elevation higher than 8×upper limit of normal (ULN) or total bilirubin higher than 5×ULN, any >=Grade 2 pneumonitis that does not resolve to <=Grade 1 within 3 days of the initiation of maximal supportive care. DLT evaluable population included all participants enrolled in the dose-escalation phase who received the protocol-assigned treatment with MEDI4736 and tremelimumab, and completed the safety follow-up through the DLT evaluation period or experienced a DLT or died during the DLT evaluation period.
    End point type
    Primary
    End point timeframe
    From the first dose of MEDI4736 (Day 1) until third dose of MEDI4736 Dose 1 (Day 57) and until second dose of MEDI4736 for other MEDI4736 doses (Day 29)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Total Escalation
    Number of subjects analysed
    100
    Units: Participants
    2
    No statistical analyses for this end point

    Primary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [3] [4]
    End point description
    An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Primary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    [4] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    102
    45
    19
    38
    40
    Units: Participants
        Any TEAE
    101
    44
    19
    37
    38
        Any TESAE
    68
    20
    11
    26
    22
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs [5] [6]
    End point description
    Number of participants with clinical laboratory abnormalities reported as TEAEs are reported. Clinical laboratory abnormalities are defined as any abnormal findings in analysis of serum chemistry, hematology, coagulation, and urine. The data for TEAEs >=5% frequency in any arm are reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Primary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    [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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    102
    45
    19
    38
    40
    Units: Participants
        Anemia
    20
    5
    2
    2
    7
        international normalized ratio increased
    1
    1
    2
    0
    0
        Activated partial thromboplastin time prolonged
    0
    0
    2
    1
    0
        Blood fibrinogen increased
    0
    0
    1
    0
    0
        Alanine aminotransferase increased
    13
    4
    3
    0
    3
        Aspartate aminotransferase increased
    11
    2
    4
    0
    2
        Gamma glutamyl transferase increased
    11
    1
    1
    2
    1
        Blood alkaline phosphatase increased
    5
    3
    3
    1
    3
        Hypoalbuminemia
    0
    3
    2
    0
    3
        Hyperbilirubinemia
    0
    0
    1
    1
    1
        Transaminases increased
    0
    1
    1
    0
    0
        Acute kidney injury
    4
    3
    1
    0
    1
        Blood creatinine increased
    11
    1
    1
    2
    3
        Proteinuria
    5
    1
    1
    0
    1
        Hematuria
    0
    1
    1
    0
    0
        Pollakiuria
    0
    3
    1
    0
    0
        Chromaturia
    0
    1
    1
    0
    0
        Polyuria
    0
    0
    1
    0
    0
        Amylase increased
    20
    8
    1
    2
    1
        Lipase increased
    15
    6
    3
    1
    4
        Hyperglycemia
    11
    3
    2
    2
    4
        Hypomagnesemia
    8
    2
    0
    5
    2
        Hyponatremia
    7
    5
    3
    5
    4
        Hypokalemia
    5
    5
    1
    3
    7
        Hypercalcemia
    2
    3
    0
    1
    0
        Hyperkalemia
    2
    2
    1
    1
    2
        Hypertriglyceridemia
    2
    0
    2
    1
    2
        Hypocalcemia
    1
    2
    1
    0
    1
        Hypoglycemia
    0
    0
    1
    1
    0
        Blood cholesterol increased
    0
    0
    1
    0
    0
        Lymphocyte count decreased
    1
    1
    0
    0
    2
        Blood triglycerides increased
    1
    0
    0
    0
    3
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs [7] [8]
    End point description
    Number of participants with abnormal vital signs and physical examinations reported as TEAEs are reported. Abnormal vital signs and physical examinations reported as TEAEs included any abnormal findings in body temperature, blood pressure, pulse rate, respiratory rate, and body weight. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Primary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    [8] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    102
    45
    19
    38
    40
    Units: Participants
        Pyrexia
    21
    4
    2
    4
    2
        Hypotension
    7
    1
    3
    1
    3
        Hypoxia
    7
    2
    3
    2
    3
        Hypertension
    6
    1
    0
    2
    1
        Weight decreased
    6
    4
    3
    5
    5
        Heart rate irregular
    1
    0
    0
    0
    0
        Palpitations
    1
    1
    1
    0
    0
        Respiratory distress
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs [9] [10]
    End point description
    Number of participants with abnormal ECG reported as TEAEs are reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Primary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    [10] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    102
    45
    19
    38
    40
    Units: Participants
        Sinus tachycardia
    5
    1
    0
    1
    2
        Atrial fibrillation
    4
    3
    4
    0
    0
        Sinus bradycardia
    2
    0
    0
    0
    0
        Tachycardia
    2
    0
    0
    1
    1
        Bradycardia
    1
    0
    0
    0
    0
        Electrocardiogram QT prolonged
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants With Objective Response (OR) per Blinded Independent Central Review (BICR) in Expansion Cohort B (Sequential Administration) and Cohort C

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    End point title
    		 Percentage of Participants With Objective Response (OR) per Blinded Independent Central Review (BICR) in Expansion Cohort B (Sequential Administration) and Cohort C [11] [12]
    End point description
    The OR is defined as best overall response of confirmed complete response (CR) or confirmed partial response (PR) based on Response Evaluation Criteria in Solid Tumours (RECIST v1.1). The CR is defined as disappearance of all target and non-target lesions and no new lesions. A confirmed CR is defined as two CRs that were separated by at least 28 days with no evidence of progression in-between. The PR is defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days with no evidence of progression in-between. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Primary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    [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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    213
    38
    40
    Units: Percentage of participants
        number (confidence interval 95%)
    16.9 (12.1 to 22.6)
    5.3 (0.6 to 17.7)
    0 (0 to 8.8)
    No statistical analyses for this end point

    Primary: Number of Participants With Immune-mediated Treatment-emergent Adverse Events (imTEAEs) and Immune-mediated Treatment-emergent Serious Adverse Events (imTESAEs) for Dose-expansion Cohorts

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    End point title
    		 Number of Participants With Immune-mediated Treatment-emergent Adverse Events (imTEAEs) and Immune-mediated Treatment-emergent Serious Adverse Events (imTESAEs) for Dose-expansion Cohorts [13] [14]
    End point description
    Immune-mediated AEs are defined as any adverse events of special interest (AESI, excluding AESIs of infusion related/ hypersensitivity/ anaphylactic reactions) that required the use of systemic steroids, endocrine therapy, or other immunosuppressants; were consistent with an immune mediated mechanism of action; and no clear alternate etiology. An AESI is one of scientific and medical interest specific event for understanding of the study drugs and may require close monitoring and rapid communication by the investigator to the sponsor. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Primary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    [14] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    45
    19
    213
    38
    40
    Units: Participants
        Any imTEAE
    13
    6
    73
    9
    14
        Any imTESAE
    4
    3
    22
    4
    8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With OR per Investigator Assessment

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    End point title
    		 Percentage of Participants With OR per Investigator Assessment
    End point description
    The OR is defined as best overall response of confirmed CR or confirmed PR based on RECIST v1.1. The CR is defined as disappearance of all target and non-target lesions and no new lesions. A confirmed CR is defined as two CRs that were separated by at least 28 days with no evidence of progression in-between. The PR is defined as >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new non-target lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days with no evidence of progression in-between. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    102
    45
    19
    213
    38
    40
    Units: Percentage of participants
        number (confidence interval 95%)
    16.7 (10.0 to 25.3)
    15.6 (6.5 to 29.5)
    0 (0 to 17.6)
    19.7 (14.6 to 25.7)
    7.9 (1.7 to 21.4)
    5.0 (0.6 to 16.9)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) per Investigator Assessment

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    End point title
    		 Duration of Response (DoR) per Investigator Assessment
    End point description
    The DoR is defined as duration from first documentation of OR (confirmed CR or PR) to first documented disease progression based on RECIST V 1.1 or death due to any cause, whichever occurred first. A confirmed CR is defined as 2 CRs (disappearance of all target and non-target lesions and no new lesions) and a confirmed PR is defined as 2 PRs (>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) or an un-confirmed PR and an un-confirmed CR, both CR and/or PR were separated by at least 28 days with no evidence of progression in-between. The DoR was estimated using Kaplan-Meier method. The arbitrary number "9999" signifies that upper limit of confidence interval was not calculated due to an insufficient number of participants achieved OR for the specified arm. As-treated population with participants who achieved OR per investigator assessment was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    17
    7
    0 [15]
    42
    3
    2
    Units: Weeks
        median (confidence interval 95%)
    126.1 (20.1 to 9999)
    24.4 (14.9 to 9999)
    ( to )
    54.1 (40.3 to 9999)
    23.0 (17.0 to 9999)
    45.8 (24.1 to 67.4)
    Notes
    [15] - No participant achieved OR, so no participant was analysed.
    No statistical analyses for this end point

    Secondary: DoR per BICR

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    End point title
    		 DoR per BICR [16]
    End point description
    The DoR is defined as duration from first documentation of OR (confirmed CR or PR) to first documented disease progression based on RECIST V 1.1 or death due to any cause, whichever occurred first. A confirmed CR is defined as 2 CRs (disappearance of all target and non-target lesions and no new lesions) and a confirmed PR is defined as 2 PRs (>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) or an un-confirmed PR and an un-confirmed CR, both CR and/or PR were separated by at least 28 days with no evidence of progression in-between. The DoR was estimated using Kaplan-Meier method. The arbitrary number "9999" signifies that upper limit of confidence interval was not calculated due to an insufficient number of participants achieved OR for the specified arm. As-treated population with participants who achieved OR per BICR was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    36
    2
    0 [17]
    Units: Weeks
        median (confidence interval 95%)
    123.0 (53.9 to 9999)
    9999 (9999 to 9999)
    ( to )
    Notes
    [17] - No participant achieved OR, so no participant was analysed.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Disease Control (DC) per Investigator Assessment

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    End point title
    		 Percentage of Participants with Disease Control (DC) per Investigator Assessment
    End point description
    Disease control is defined as a best overall response of confirmed CR, confirmed PR, or stable disease (SD) based on RECIST V 1.1. A confirmed CR is defined as two CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 28 days with no evidence of progression in-between. A confirmed PR is defined as two PRs (>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days with no evidence of progression in-between. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. The DC per investigator assessment is reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    102
    45
    19
    213
    38
    40
    Units: Percentage of participants
        number (confidence interval 95%)
    47.1 (37.1 to 57.2)
    57.8 (42.2 to 72.3)
    47.4 (24.4 to 71.1)
    54.9 (48.0 to 61.7)
    28.9 (15.4 to 45.9)
    45.0 (29.3 to 61.5)
    No statistical analyses for this end point

    Secondary: Percentage of participants with DC per BICR

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    End point title
    		 Percentage of participants with DC per BICR [18]
    End point description
    Disease control is defined as a best overall response of confirmed CR, confirmed PR, or SD based on RECIST V 1.1. A confirmed CR is defined as two CRs (disappearance of all target and non-target lesions and no new lesions) that were separated by at least 28 days with no evidence of progression in-between. A confirmed PR is defined as two PRs (>= 30% decrease in the sum of diameters of target lesions compared to baseline and no new non-target lesion) or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days with no evidence of progression in-between. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progression. The DC per BICR is reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [18] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    213
    38
    40
    Units: Percentage of participants
        number (confidence interval 95%)
    51.2 (44.3 to 58.1)
    28.9 (15.4 to 45.9)
    40.0 (24.9 to 56.7)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) per Investigator Assessment

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    End point title
    		 Progression-free Survival (PFS) per Investigator Assessment
    End point description
    The PFS is defined as the time from the start of study drug until the first documentation of disease progression based on RECIST V 1.1 or death due to any cause, whichever occurred first, regardless of whether the participant withdrew from study treatment or received another anticancer therapy prior to progression. PFS per investigator assessment is reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    80
    33
    16
    181
    33
    36
    Units: Months
        median (confidence interval 95%)
    2.6 (1.7 to 4.8)
    3.5 (1.7 to 7.2)
    2.8 (1.6 to 4.7)
    3.5 (1.8 to 4.0)
    1.7 (1.6 to 1.8)
    2.2 (1.6 to 3.5)
    No statistical analyses for this end point

    Secondary: PFS per BICR

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    End point title
    		 PFS per BICR [19]
    End point description
    The PFS is defined as the time from the start of study drug until the first documentation of disease progression based on RECIST V 1.1 or death due to any cause, whichever occurred first, regardless of whether the participant withdrew from study treatment or received another anticancer therapy prior to progression. PFS per BICR is reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    166
    31
    34
    Units: Months
        median (confidence interval 95%)
    3.5 (1.7 to 3.6)
    1.7 (1.6 to 2.6)
    2.0 (1.6 to 3.1)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The OS is defined as the time from the start of study treatment until death due to any cause. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    End point values
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Number of subjects analysed
    66
    24
    15
    126
    28
    31
    Units: Months
        median (confidence interval 95%)
    14.6 (8.7 to 23.0)
    22.1 (14.0 to 29.8)
    7.6 (4.4 to 17.9)
    14.3 (10.0 to 18.9)
    8.3 (6.0 to 10.4)
    8.5 (4.0 to 14.3)
    No statistical analyses for this end point

    Secondary: Number of Participants With TEAEs and TESAEs for Cohort B (Sequential Administration)

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    End point title
    		 Number of Participants With TEAEs and TESAEs for Cohort B (Sequential Administration) [20]
    End point description
    An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential)
    Number of subjects analysed
    213
    Units: Participants
        Any TEAE
    211
        Any TESAE
    120
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs for Cohort B (Sequential Administration)

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    End point title
    		 Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs for Cohort B (Sequential Administration) [21]
    End point description
    Number of participants with clinical laboratory abnormalities reported as TEAEs are reported. Clinical laboratory abnormalities are defined as any abnormal findings in analysis of serum chemistry, hematology, coagulation, and urine. The data for TEAEs >=5% frequency in any arm are reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [21] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential)
    Number of subjects analysed
    213
    Units: Participants
        Anemia
    41
        Alanine aminotransferase increased
    15
        Aspartate aminotransferase increased
    17
        Amylase increased
    28
        Lipase increased
    16
        Hyperglycemia
    11
        Hyponatremia
    12
        Hypokalemia
    11
        Hypercalcemia
    11
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAES for Cohort B (Sequential Administration)

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    End point title
    		 Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAES for Cohort B (Sequential Administration) [22]
    End point description
    Number of participants with abnormal vital signs and physical examinations reported as TEAEs are reported. Abnormal vital signs and physical examinations reported as TEAEs included any abnormal findings in body temperature, blood pressure, pulse rate, respiratory rate, and body weight. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential)
    Number of subjects analysed
    213
    Units: Participants
        Pyrexia
    33
        Hypotension
    11
        Hypoxia
    5
        Hypertension
    5
        Weight decreased
    19
        Palpitations
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal ECG Reported as TEAES for Cohort B (Sequential Administration)

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    End point title
    		 Number of Participants With Abnormal ECG Reported as TEAES for Cohort B (Sequential Administration) [23]
    End point description
    Number of participants with abnormal ECG reported as TEAEs are reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Notes
    [23] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential)
    Number of subjects analysed
    213
    Units: Participants
        Sinus tachycardia
    3
        Atrial fibrillation
    1
        Sinus bradycardia
    1
        Tachycardia
    7
        Bradycardia
    1
        Electrocardiogram T wave inversion
    2
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) of MEDI4736 After First Dose

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    End point title
    		 Maximum Observed Concentration (Cmax) of MEDI4736 After First Dose
    End point description
    The Cmax of MEDI4736 is reported. Pharmacokinetic evaluable population included all participants who received at least 1 dose of MEDI4736 and had any post-dose PK data point was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for the specified arm.
    End point type
    Secondary
    End point timeframe
    Escalation part (Q4W): Day 1 (predose and 10 minutes post MEDI4736 infusion), Days 8 and 15, and Day 29 (predose); Escalation part (Q2W) and Expansion part (Q4W): Day 1 (predose and 10 minutes post MEDI4736 infusion) and Day 29 (predose)
    End point values
    		 Escalation MEDI4736 Dose 1 (Q4W) Escalation MEDI4736 Dose 2 (Q4W) Escalation MEDI4736 Dose 3 (Q4W) Escalation & Expansion MEDI4736 Dose 4 (Q4W) Escalation MEDI4736 Dose 2 (Q2W)
    Number of subjects analysed
    2
    3
    35
    231
    27
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    67.3 ( 14.9 )
    259 ( 19.6 )
    296 ( 33.7 )
    409 ( 45.7 )
    224 ( 23.7 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve From Day 1 to Day 28 (AUC0-28) of MEDI4736 After First Dose

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    End point title
    		 Area Under the Concentration-time Curve From Day 1 to Day 28 (AUC0-28) of MEDI4736 After First Dose
    End point description
    The AUC0-28 of MEDI4736 is reported. Pharmacokinetic evaluable population included all participants who received at least 1 dose of MEDI4736 and had any post-dose PK data point was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for the specified arm.
    End point type
    Secondary
    End point timeframe
    Escalation part (Q4W): Day 1 (predose and 10 minutes post MEDI4736 infusion), Days 8 and 15, and Day 29 (predose); Escalation part (Q2W) and Expansion part (Q4W): Day 1 (predose and 10 minutes post MEDI4736 infusion) and Day 29 (predose)
    End point values
    		 Escalation MEDI4736 Dose 1 (Q4W) Escalation MEDI4736 Dose 2 (Q4W) Escalation MEDI4736 Dose 3 (Q4W) Escalation & Expansion MEDI4736 Dose 4 (Q4W) Escalation MEDI4736 Dose 2 (Q2W)
    Number of subjects analysed
    2
    3
    28
    24
    0 [24]
    Units: μg*day/mL
        geometric mean (geometric coefficient of variation)
    639 ( 7.45 )
    2728 ( 5.06 )
    3068 ( 21.9 )
    4209 ( 33.2 )
    ( )
    Notes
    [24] - No participant was analysed for this endpoint for this arm.
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Concentration (Tmax) of MEDI4736 After First Dose

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    End point title
    		 Time to Reach Maximum Observed Concentration (Tmax) of MEDI4736 After First Dose
    End point description
    The Tmax of MEDI4736 is reported. Pharmacokinetic evaluable population included all participants who received at least 1 dose of MEDI4736 and had any post-dose PK data point was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for the specified arm.
    End point type
    Secondary
    End point timeframe
    Escalation part (Q4W): Day 1 (predose and 10 minutes post MEDI4736 infusion), Days 8 and 15, and Day 29 (predose); Escalation part (Q2W) and Expansion part (Q4W): Day 1 (predose and 10 minutes post MEDI4736 infusion) and Day 29 (predose)
    End point values
    		 Escalation MEDI4736 Dose 1 (Q4W) Escalation MEDI4736 Dose 2 (Q4W) Escalation MEDI4736 Dose 3 (Q4W) Escalation & Expansion MEDI4736 Dose 4 (Q4W) Escalation MEDI4736 Dose 2 (Q2W)
    Number of subjects analysed
    2
    3
    35
    231
    27
    Units: Days
        geometric mean (geometric coefficient of variation)
    0.172 ( 1.7 )
    0.047 ( 4.3 )
    0.048 ( 11.1 )
    0.049 ( 24.5 )
    0.046 ( 8.70 )
    No statistical analyses for this end point

    Secondary: Trough serum concentration (Ctrough) of MEDI4736 After First Dose

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    End point title
    		 Trough serum concentration (Ctrough) of MEDI4736 After First Dose
    End point description
    The Ctrough of MEDI4736 is reported. Pharmacokinetic evaluable population included all participants who received at least 1 dose of MEDI4736 and had any post-dose PK data point was considered for this endpoint. The “Number of Participants Analysed” denotes the number of participants evaluated for the specified arm.
    End point type
    Secondary
    End point timeframe
    Escalation part (Q4W): Day 1 (predose and 10 minutes post MEDI4736 infusion), Days 8 and 15, and Day 29 (predose); Escalation part (Q2W) and Expansion part (Q4W): Day 1 (predose and 10 minutes post MEDI4736 infusion) and Day 29 (predose)
    End point values
    		 Escalation MEDI4736 Dose 1 (Q4W) Escalation MEDI4736 Dose 2 (Q4W) Escalation MEDI4736 Dose 3 (Q4W) Escalation & Expansion MEDI4736 Dose 4 (Q4W) Escalation MEDI4736 Dose 2 (Q2W)
    Number of subjects analysed
    2
    5
    29
    37
    0 [25]
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    8.72 ( 29.5 )
    36.5 ( 21.8 )
    43.0 ( 124 )
    55.5 ( 47.7 )
    ( )
    Notes
    [25] - No participant was analysed for this endpoint for this arm.
    No statistical analyses for this end point

    Secondary: Cmax of Tremelimumab After First Dose

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    End point title
    		 Cmax of Tremelimumab After First Dose
    End point description
    The Cmax of tremelimumab is reported. Pharmacokinetic evaluable population included all participants who received at least 1 dose of tremelimumab and had any post-dose PK data point was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for the specified arm.
    End point type
    Secondary
    End point timeframe
    Escalation part (Q4W): Day 1 (predose and 10 minutes post tremelimumab infusion), Days 8 and 15, and Day 29 (predose); Escalation part (Q4W) and Expansion part (Q4W): Day 1 (predose and 10 minutes post tremelimumab infusion) and Day 29 (predose)
    End point values
    		 Escalation Tremelimumab Dose 1 (Q4W) Escalation Tremelimumab Dose 2 (Q4W) Escalation Tremelimumab Dose 3 (Q4W) Expansion Tremelimumab Dose 1 (Q4W)
    Number of subjects analysed
    55
    32
    9
    200
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    22.5 ( 36.8 )
    57.5 ( 57.2 )
    192 ( 15.1 )
    20.3 ( 37.0 )
    No statistical analyses for this end point

    Secondary: Tmax of Tremelimumab After First Dose

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    End point title
    		 Tmax of Tremelimumab After First Dose
    End point description
    The Tmax of tremelimumab is reported. Pharmacokinetic evaluable population included all participants who received at least 1 dose of tremelimumab and had any post-dose PK data point was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for the specified arm.
    End point type
    Secondary
    End point timeframe
    Escalation part (Q4W): Day 1 (predose and 10 minutes post tremelimumab infusion), Days 8 and 15, and Day 29 (predose); Escalation part (Q4W) and Expansion part (Q4W): Day 1 (predose and 10 minutes post tremelimumab infusion) and Day 29 (predose)
    End point values
    		 Escalation Tremelimumab Dose 1 (Q4W) Escalation Tremelimumab Dose 2 (Q4W) Escalation Tremelimumab Dose 3 (Q4W) Expansion Tremelimumab Dose 1 (Q4W)
    Number of subjects analysed
    55
    32
    9
    200
    Units: Days
        geometric mean (geometric coefficient of variation)
    0.047 ( 12.7 )
    0.046 ( 8.81 )
    0.047 ( 11.3 )
    0.046 ( 13.3 )
    No statistical analyses for this end point

    Secondary: Ctrough of Tremelimumab After First Dose

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    End point title
    		 Ctrough of Tremelimumab After First Dose
    End point description
    The Ctrough of tremelimumab is reported. Pharmacokinetic evaluable population included all participants who received at least 1 dose of tremelimumab and had any post-dose PK data point was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for the specified arm.
    End point type
    Secondary
    End point timeframe
    Escalation part (Q4W): Day 1 (predose and 10 minutes post tremelimumab infusion), Days 8 and 15, and Day 29 (predose); Escalation part (Q4W) and Expansion part (Q4W): Day 1 (predose and 10 minutes post tremelimumab infusion) and Day 29 (predose)
    End point values
    		 Escalation Tremelimumab Dose 1 (Q4W) Escalation Tremelimumab Dose 2 (Q4W) Escalation Tremelimumab Dose 3 (Q4W) Expansion Tremelimumab Dose 1 (Q4W)
    Number of subjects analysed
    43
    22
    6
    19
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    2.65 ( 75.1 )
    9.51 ( 33.6 )
    19.5 ( 122 )
    3.26 ( 59.6 )
    No statistical analyses for this end point

    Secondary: AUC0-28 days of Tremelimumab After First Dose

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    End point title
    		 AUC0-28 days of Tremelimumab After First Dose
    End point description
    The AUC0-28 days of tremelimumab is reported. Pharmacokinetic evaluable population included all participants who received at least 1 dose of tremelimumab and had any post-dose PK data point was considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants evaluated for the specified arm.
    End point type
    Secondary
    End point timeframe
    Escalation part (Q4W): Day 1 (predose and 10 minutes post tremelimumab infusion), Days 8 and 15, and Day 29 (predose); Escalation part (Q4W) and Expansion part (Q4W): Day 1 (predose and 10 minutes post tremelimumab infusion) and Day 29 (predose)
    End point values
    		 Escalation Tremelimumab Dose 1 (Q4W) Escalation Tremelimumab Dose 2 (Q4W) Escalation Tremelimumab Dose 3 (Q4W) Expansion Tremelimumab Dose 1 (Q4W)
    Number of subjects analysed
    36
    17
    9
    14
    Units: μg*day/mL
        geometric mean (geometric coefficient of variation)
    203 ( 46.5 )
    625 ( 24.1 )
    1800 ( 25.1 )
    239 ( 33.1 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive Anti-drug Antibodies (ADA) to MEDI4736

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    End point title
    		 Number of Participants With Positive Anti-drug Antibodies (ADA) to MEDI4736
    End point description
    Number of participants with positive ADA titer to MEDI4736 are reported. ADA incidence is defined as either treatment-induced (post baseline ADA-positive only) or treatment-boosted ADA; treatment-boosted ADA is defined as baseline positive ADA titer that was boosted to a 4-fold or higher level following drug administration; persistent positive is defined as positive at >= 2 post-baseline assessments (with >= 16 weeks between first and last positive) or positive at last post-baseline assessment; and transient positive is defined as having at least one post-baseline ADA-positive assessment and not fulfilling the condition of persistent positive. The ADA evaluable population included all participants who received at least 1 dose of MEDI4736 and had any post-dose ADA data point was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    Escalation part: Days 1, 29, 85, 141, 169, 253, and 337, end of treatment (EOT), 90 days post EOT, and 6 months post last dose; Expansion part: Days 1, 85, and 169, EOT, 90 days post EOT, and 6 months post last dose (approximately 6 years)
    End point values
    		 Escalation MEDI4736 Dose 1 (Q4W) Escalation MEDI4736 Dose 2 (Q4W) Escalation MEDI4736 Dose 3 (Q4W) Escalation & Expansion MEDI4736 Dose 4 (Q4W) Escalation MEDI4736 Dose 2 (Q2W)
    Number of subjects analysed
    3
    5
    35
    247
    22
    Units: Participants
        ADA incidence
    0
    1
    4
    5
    1
        Treatment-boosted ADA
    0
    0
    2
    0
    0
        Persistent positive
    0
    1
    4
    6
    1
        Transient positive
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive ADA to Tremelimumab

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    End point title
    		 Number of Participants With Positive ADA to Tremelimumab
    End point description
    Number of participants with positive ADA titer to tremelimumab are reported. ADA incidence is defined as either treatment-induced (post baseline ADA-positive only) or treatment-boosted ADA; treatment-boosted ADA is defined as baseline positive ADA titer that was boosted to a 4-fold or higher level following drug administration; persistent positive is defined as positive at >= 2 post-baseline assessments (with >= 16 weeks between first and last positive) or positive at last post-baseline assessment; and transient positive is defined as having at least one post-baseline ADA-positive assessment and not fulfilling the condition of persistent positive. The ADA evaluable population included all participants who received at least 1 dose of tremelimumab and had any post-dose ADA data point was considered for this endpoint.
    End point type
    Secondary
    End point timeframe
    Escalation part: Days 1, 29, 85, 141, 169, 253, and 337, end of treatment (EOT), 90 days post EOT, and 6 months post last dose; Expansion part: Days 1, 85, and 169, EOT, 90 days post EOT, and 6 months post last dose (approximately 6 years)
    End point values
    		 Escalation Tremelimumab Dose 3 (Q4W) Escalation Tremelimumab Dose 1 (Q4W) Escalation Tremelimumab Dose 2 (Q4W) Expansion Tremelimumab Dose 1 (Q4W)
    Number of subjects analysed
    9
    47
    28
    211
    Units: Participants
        ADA incidence
    0
    6
    1
    14
        Treatment-boosted ADA
    0
    0
    0
    0
        Persistent positive
    0
    3
    0
    8
        Transient positive
    0
    3
    1
    6
    No statistical analyses for this end point

    Secondary: Number of Participants With Programmed Cell Death Ligand 1 (PD-L1) Disposition in Cohort B (Sequential Administration)

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    End point title
    		 Number of Participants With Programmed Cell Death Ligand 1 (PD-L1) Disposition in Cohort B (Sequential Administration) [26]
    End point description
    Number of participants with PD-L1 disposition are reported. It is reported as tumour cells disposition high (>=25%) and low/negative (<25%). As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) were considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants for whom a PD-L1 status was obtained.
    End point type
    Secondary
    End point timeframe
    Screening (Days -28 to -1), Day 50, Day 225
    Notes
    [26] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential)
    Number of subjects analysed
    193
    Units: Participants
        Tumour cells high (TC>=25%)
    57
        Tumour cells low/negative (TC<25%)
    136
    No statistical analyses for this end point

    Secondary: Cluster of differentiation (CD) 8 Cell densities in Cohort B (Sequential Administration)

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    End point title
    		 Cluster of differentiation (CD) 8 Cell densities in Cohort B (Sequential Administration) [27]
    End point description
    CD8 Cell densities are reported. As-treated population included all participants who received any dose of study drugs (MEDI4736 or tremelimumab) were considered for this endpoint. The “Number of Subjects Analysed” denotes the number of participants for whom CD8 cell density was obtained.
    End point type
    Secondary
    End point timeframe
    Screening (Days -28 to -1), Day 50, Day 225
    Notes
    [27] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Expansion Cohort B (Sequential)
    Number of subjects analysed
    83
    Units: Cells/mm^2
        arithmetic mean (standard deviation)
    357.7 ( 373.8 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 through 90 days after the last dose of study drug (approximately 6 years)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Total Escalation
    Reporting group description
    		 Participants received MEDI4736 IV escalation doses (Dose 1 or 2 or 3 or 4) every 4 weeks (Q4W; up to 13 doses) or every two weeks (Q2W; up to 26 doses) and IV tremelimumab dose (Dose 1, 2, or 3) Q4W for 6 doses and then every 12 weeks (Q12W) for 3 doses (up to 9 doses in total) for 12 months or until disease progression.

    Reporting group title
    Expansion Cohort A
    Reporting group description
    		 Treatment-naïve, non-epidermal growth factor receptor (non-EGFR) mutation positive, and non-anaplastic lymphoma kinase (non-ALK) rearrangement positive participants received IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort B (Coadmin)
    Reporting group description
    		 Immunotherapy-naive participants received co-administration of IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort B (Sequential)
    Reporting group description
    		 Immunotherapy-naive participants received sequential administration of IV MEDI4736 Dose 4 Q4W and IV tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W monotherapy for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort C (Refractory)
    Reporting group description
    		 Participants who were refractory to previous immunotherapy treatment received IV infusion of MEDI4736 Dose 4 Q4W and tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy or until disease progression.

    Reporting group title
    Expansion Cohort C (Relapsed)
    Reporting group description
    		 Participants whom disease was relapsed with the previous immunotherapy treatment received IV infusion of MEDI4736 Dose 4 Q4W and tremelimumab Dose 1 Q4W for up to 4 doses each, followed by monotherapy with IV MEDI4736 Dose 4 Q4W for 9 doses to complete a total of 12 months of therapy.

    Serious adverse events
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 102 (66.67%)
    20 / 45 (44.44%)
    11 / 19 (57.89%)
    120 / 213 (56.34%)
    26 / 38 (68.42%)
    22 / 40 (55.00%)
         number of deaths (all causes)
    66
    24
    15
    126
    28
    31
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extradural neoplasm
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    10 / 213 (4.69%)
    1 / 38 (2.63%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 15
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 8
    0 / 0
    0 / 2
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    11 / 102 (10.78%)
    5 / 45 (11.11%)
    3 / 19 (15.79%)
    47 / 213 (22.07%)
    7 / 38 (18.42%)
    7 / 40 (17.50%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 5
    0 / 5
    0 / 61
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 10
    0 / 3
    0 / 3
    0 / 29
    0 / 6
    0 / 7
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    1 / 38 (2.63%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 1
    Pericarditis malignant
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung carcinoma cell type unspecified stage IV
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer stage IV
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular compression
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    4 / 213 (1.88%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 102 (3.92%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 102 (3.92%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial disorder
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 102 (5.88%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    8 / 213 (3.76%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 1
    0 / 0
    0 / 9
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 45 (0.00%)
    2 / 19 (10.53%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 4
    2 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    2 / 19 (10.53%)
    6 / 213 (2.82%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 102 (4.90%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    4 / 213 (1.88%)
    2 / 38 (5.26%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    0 / 0
    4 / 4
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 45 (4.44%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 45 (4.44%)
    3 / 19 (15.79%)
    2 / 213 (0.94%)
    2 / 38 (5.26%)
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 3
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 102 (1.96%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    2 / 19 (10.53%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    2 / 19 (10.53%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 45 (4.44%)
    4 / 19 (21.05%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 102 (1.96%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuromyopathy
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocoagulable state
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal mass
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    1 / 38 (2.63%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    10 / 102 (9.80%)
    4 / 45 (8.89%)
    1 / 19 (5.26%)
    6 / 213 (2.82%)
    1 / 38 (2.63%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    12 / 12
    4 / 4
    1 / 1
    7 / 7
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 45 (4.44%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    10 / 102 (9.80%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    5 / 213 (2.35%)
    1 / 38 (2.63%)
    3 / 40 (7.50%)
         occurrences causally related to treatment / all
    10 / 11
    1 / 1
    0 / 0
    5 / 6
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    3 / 19 (15.79%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 3
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 45 (4.44%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    2 / 213 (0.94%)
    1 / 38 (2.63%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 45 (4.44%)
    1 / 19 (5.26%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    0 / 1
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraneoplastic arthritis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polymyositis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    6 / 213 (2.82%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    13 / 213 (6.10%)
    7 / 38 (18.42%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 14
    1 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteus infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 102 (1.96%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis viral
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 102 (4.90%)
    0 / 45 (0.00%)
    2 / 19 (10.53%)
    4 / 213 (1.88%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    1 / 2
    0 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total Escalation Expansion Cohort A Expansion Cohort B (Coadmin) Expansion Cohort B (Sequential) Expansion Cohort C (Refractory) Expansion Cohort C (Relapsed)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    98 / 102 (96.08%)
    44 / 45 (97.78%)
    18 / 19 (94.74%)
    208 / 213 (97.65%)
    35 / 38 (92.11%)
    38 / 40 (95.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    4 / 213 (1.88%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    4
    2
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    3 / 213 (1.41%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    1
    3
    1
    0
    Hypertension
         subjects affected / exposed
    6 / 102 (5.88%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    5 / 213 (2.35%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    6
    1
    0
    17
    2
    3
    Hypotension
         subjects affected / exposed
    5 / 102 (4.90%)
    1 / 45 (2.22%)
    3 / 19 (15.79%)
    11 / 213 (5.16%)
    1 / 38 (2.63%)
    3 / 40 (7.50%)
         occurrences all number
    6
    1
    4
    15
    1
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 102 (5.88%)
    0 / 45 (0.00%)
    2 / 19 (10.53%)
    46 / 213 (21.60%)
    1 / 38 (2.63%)
    3 / 40 (7.50%)
         occurrences all number
    6
    0
    4
    85
    1
    5
    Chills
         subjects affected / exposed
    5 / 102 (4.90%)
    2 / 45 (4.44%)
    1 / 19 (5.26%)
    8 / 213 (3.76%)
    2 / 38 (5.26%)
    2 / 40 (5.00%)
         occurrences all number
    5
    2
    1
    8
    2
    2
    Fatigue
         subjects affected / exposed
    35 / 102 (34.31%)
    15 / 45 (33.33%)
    8 / 19 (42.11%)
    63 / 213 (29.58%)
    14 / 38 (36.84%)
    13 / 40 (32.50%)
         occurrences all number
    62
    21
    13
    96
    15
    15
    Influenza like illness
         subjects affected / exposed
    6 / 102 (5.88%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    6
    0
    0
    3
    0
    1
    Malaise
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    1
    3
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 102 (0.98%)
    4 / 45 (8.89%)
    0 / 19 (0.00%)
    16 / 213 (7.51%)
    2 / 38 (5.26%)
    2 / 40 (5.00%)
         occurrences all number
    1
    4
    0
    17
    3
    2
    Oedema
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    4
    0
    1
    1
    0
    2
    Oedema peripheral
         subjects affected / exposed
    11 / 102 (10.78%)
    11 / 45 (24.44%)
    0 / 19 (0.00%)
    18 / 213 (8.45%)
    2 / 38 (5.26%)
    4 / 40 (10.00%)
         occurrences all number
    12
    12
    0
    22
    2
    4
    Pyrexia
         subjects affected / exposed
    17 / 102 (16.67%)
    4 / 45 (8.89%)
    2 / 19 (10.53%)
    31 / 213 (14.55%)
    4 / 38 (10.53%)
    2 / 40 (5.00%)
         occurrences all number
    20
    4
    2
    33
    4
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    4 / 213 (1.88%)
    2 / 38 (5.26%)
    0 / 40 (0.00%)
         occurrences all number
    2
    0
    0
    4
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    2 / 38 (5.26%)
    0 / 40 (0.00%)
         occurrences all number
    0
    3
    0
    2
    3
    0
    Cough
         subjects affected / exposed
    19 / 102 (18.63%)
    10 / 45 (22.22%)
    4 / 19 (21.05%)
    39 / 213 (18.31%)
    8 / 38 (21.05%)
    7 / 40 (17.50%)
         occurrences all number
    23
    13
    5
    46
    8
    9
    Dry throat
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    2
    0
    1
    2
    0
    1
    Dyspnoea
         subjects affected / exposed
    20 / 102 (19.61%)
    18 / 45 (40.00%)
    6 / 19 (31.58%)
    59 / 213 (27.70%)
    10 / 38 (26.32%)
    11 / 40 (27.50%)
         occurrences all number
    27
    35
    8
    80
    18
    12
    Dyspnoea exertional
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    8 / 213 (3.76%)
    0 / 38 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    2
    0
    1
    9
    0
    4
    Haemoptysis
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 45 (6.67%)
    0 / 19 (0.00%)
    15 / 213 (7.04%)
    3 / 38 (7.89%)
    1 / 40 (2.50%)
         occurrences all number
    1
    4
    0
    18
    3
    2
    Hypoxia
         subjects affected / exposed
    4 / 102 (3.92%)
    2 / 45 (4.44%)
    1 / 19 (5.26%)
    3 / 213 (1.41%)
    2 / 38 (5.26%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    1
    3
    2
    2
    Laryngeal haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    2 / 213 (0.94%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    Nasal congestion
         subjects affected / exposed
    6 / 102 (5.88%)
    5 / 45 (11.11%)
    1 / 19 (5.26%)
    3 / 213 (1.41%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    7
    5
    1
    3
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 45 (6.67%)
    0 / 19 (0.00%)
    6 / 213 (2.82%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    1
    3
    0
    6
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 45 (4.44%)
    0 / 19 (0.00%)
    9 / 213 (4.23%)
    4 / 38 (10.53%)
    1 / 40 (2.50%)
         occurrences all number
    0
    3
    0
    14
    6
    1
    Pneumonitis
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 45 (6.67%)
    0 / 19 (0.00%)
    5 / 213 (2.35%)
    1 / 38 (2.63%)
    3 / 40 (7.50%)
         occurrences all number
    2
    4
    0
    5
    1
    4
    Productive cough
         subjects affected / exposed
    8 / 102 (7.84%)
    5 / 45 (11.11%)
    1 / 19 (5.26%)
    14 / 213 (6.57%)
    5 / 38 (13.16%)
    1 / 40 (2.50%)
         occurrences all number
    9
    5
    1
    15
    6
    1
    Wheezing
         subjects affected / exposed
    2 / 102 (1.96%)
    6 / 45 (13.33%)
    1 / 19 (5.26%)
    4 / 213 (1.88%)
    3 / 38 (7.89%)
    1 / 40 (2.50%)
         occurrences all number
    3
    11
    1
    4
    3
    2
    Pulmonary embolism
         subjects affected / exposed
    4 / 102 (3.92%)
    2 / 45 (4.44%)
    0 / 19 (0.00%)
    4 / 213 (1.88%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    0
    4
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 102 (7.84%)
    3 / 45 (6.67%)
    2 / 19 (10.53%)
    8 / 213 (3.76%)
    3 / 38 (7.89%)
    1 / 40 (2.50%)
         occurrences all number
    8
    3
    2
    8
    3
    1
    Depression
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    11 / 213 (5.16%)
    3 / 38 (7.89%)
    1 / 40 (2.50%)
         occurrences all number
    3
    0
    0
    12
    3
    1
    Insomnia
         subjects affected / exposed
    8 / 102 (7.84%)
    5 / 45 (11.11%)
    2 / 19 (10.53%)
    17 / 213 (7.98%)
    4 / 38 (10.53%)
    2 / 40 (5.00%)
         occurrences all number
    10
    8
    2
    18
    4
    2
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    2 / 19 (10.53%)
    3 / 213 (1.41%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    3
    3
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 102 (12.75%)
    4 / 45 (8.89%)
    1 / 19 (5.26%)
    15 / 213 (7.04%)
    0 / 38 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    19
    4
    1
    23
    0
    3
    Amylase increased
         subjects affected / exposed
    19 / 102 (18.63%)
    8 / 45 (17.78%)
    1 / 19 (5.26%)
    28 / 213 (13.15%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    23
    14
    2
    65
    3
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 102 (9.80%)
    2 / 45 (4.44%)
    2 / 19 (10.53%)
    17 / 213 (7.98%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    18
    2
    2
    22
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 102 (3.92%)
    3 / 45 (6.67%)
    3 / 19 (15.79%)
    8 / 213 (3.76%)
    1 / 38 (2.63%)
    3 / 40 (7.50%)
         occurrences all number
    6
    3
    3
    12
    1
    5
    Blood cholesterol increased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    4 / 213 (1.88%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    4
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    11 / 102 (10.78%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    8 / 213 (3.76%)
    2 / 38 (5.26%)
    3 / 40 (7.50%)
         occurrences all number
    20
    1
    2
    15
    2
    5
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    6 / 102 (5.88%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    7 / 213 (3.29%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    6
    1
    0
    7
    0
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    7 / 102 (6.86%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    7
    3
    1
    1
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    1
    0
    0
    1
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    10 / 102 (9.80%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    10 / 213 (4.69%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    14
    1
    1
    14
    2
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    2 / 19 (10.53%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    2
    3
    0
    0
    Lipase increased
         subjects affected / exposed
    15 / 102 (14.71%)
    6 / 45 (13.33%)
    3 / 19 (15.79%)
    16 / 213 (7.51%)
    1 / 38 (2.63%)
    4 / 40 (10.00%)
         occurrences all number
    23
    7
    3
    44
    4
    8
    Transaminases increased
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    6 / 102 (5.88%)
    4 / 45 (8.89%)
    3 / 19 (15.79%)
    19 / 213 (8.92%)
    5 / 38 (13.16%)
    5 / 40 (12.50%)
         occurrences all number
    6
    4
    4
    23
    6
    5
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    5 / 213 (2.35%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    1
    2
    0
    5
    0
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    3 / 213 (1.41%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    1
    3
    1
    0
    Head injury
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    13 / 213 (6.10%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    1
    1
    2
    16
    0
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    5 / 102 (4.90%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    1 / 38 (2.63%)
    2 / 40 (5.00%)
         occurrences all number
    6
    1
    0
    2
    1
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 102 (9.80%)
    4 / 45 (8.89%)
    0 / 19 (0.00%)
    18 / 213 (8.45%)
    2 / 38 (5.26%)
    5 / 40 (12.50%)
         occurrences all number
    11
    5
    0
    24
    2
    5
    Dysgeusia
         subjects affected / exposed
    5 / 102 (4.90%)
    4 / 45 (8.89%)
    0 / 19 (0.00%)
    6 / 213 (2.82%)
    1 / 38 (2.63%)
    1 / 40 (2.50%)
         occurrences all number
    5
    4
    0
    6
    1
    1
    Headache
         subjects affected / exposed
    12 / 102 (11.76%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    17 / 213 (7.98%)
    1 / 38 (2.63%)
    3 / 40 (7.50%)
         occurrences all number
    18
    1
    1
    21
    1
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    2 / 19 (10.53%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    2
    1
    0
    0
    Seizure
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Visual field defect
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    6 / 213 (2.82%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    3
    0
    0
    6
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 102 (19.61%)
    5 / 45 (11.11%)
    2 / 19 (10.53%)
    40 / 213 (18.78%)
    2 / 38 (5.26%)
    6 / 40 (15.00%)
         occurrences all number
    30
    9
    2
    70
    5
    12
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 102 (7.84%)
    3 / 45 (6.67%)
    3 / 19 (15.79%)
    25 / 213 (11.74%)
    3 / 38 (7.89%)
    5 / 40 (12.50%)
         occurrences all number
    10
    3
    6
    27
    3
    5
    Abdominal pain upper
         subjects affected / exposed
    5 / 102 (4.90%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    6 / 213 (2.82%)
    1 / 38 (2.63%)
    2 / 40 (5.00%)
         occurrences all number
    6
    0
    1
    6
    1
    2
    Constipation
         subjects affected / exposed
    13 / 102 (12.75%)
    12 / 45 (26.67%)
    4 / 19 (21.05%)
    44 / 213 (20.66%)
    4 / 38 (10.53%)
    12 / 40 (30.00%)
         occurrences all number
    13
    16
    4
    59
    4
    13
    Diarrhoea
         subjects affected / exposed
    42 / 102 (41.18%)
    13 / 45 (28.89%)
    8 / 19 (42.11%)
    49 / 213 (23.00%)
    10 / 38 (26.32%)
    13 / 40 (32.50%)
         occurrences all number
    89
    22
    14
    76
    14
    22
    Dry mouth
         subjects affected / exposed
    8 / 102 (7.84%)
    6 / 45 (13.33%)
    2 / 19 (10.53%)
    17 / 213 (7.98%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    8
    6
    2
    20
    1
    0
    Enterocolitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Nausea
         subjects affected / exposed
    27 / 102 (26.47%)
    12 / 45 (26.67%)
    4 / 19 (21.05%)
    39 / 213 (18.31%)
    9 / 38 (23.68%)
    9 / 40 (22.50%)
         occurrences all number
    30
    17
    6
    50
    11
    10
    Stomatitis
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    9 / 213 (4.23%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    2
    0
    1
    9
    0
    1
    Vomiting
         subjects affected / exposed
    15 / 102 (14.71%)
    6 / 45 (13.33%)
    2 / 19 (10.53%)
    20 / 213 (9.39%)
    8 / 38 (21.05%)
    8 / 40 (20.00%)
         occurrences all number
    19
    9
    3
    23
    9
    10
    Colitis
         subjects affected / exposed
    4 / 102 (3.92%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    5 / 213 (2.35%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    6
    1
    0
    6
    0
    2
    Flatulence
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    3
    0
    0
    4
    0
    2
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    6 / 102 (5.88%)
    2 / 45 (4.44%)
    1 / 19 (5.26%)
    12 / 213 (5.63%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    8
    2
    1
    15
    2
    1
    Night sweats
         subjects affected / exposed
    2 / 102 (1.96%)
    3 / 45 (6.67%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    2
    3
    0
    2
    1
    0
    Pruritus
         subjects affected / exposed
    26 / 102 (25.49%)
    9 / 45 (20.00%)
    0 / 19 (0.00%)
    44 / 213 (20.66%)
    8 / 38 (21.05%)
    5 / 40 (12.50%)
         occurrences all number
    41
    13
    0
    64
    9
    7
    Rash
         subjects affected / exposed
    22 / 102 (21.57%)
    2 / 45 (4.44%)
    1 / 19 (5.26%)
    35 / 213 (16.43%)
    4 / 38 (10.53%)
    2 / 40 (5.00%)
         occurrences all number
    37
    2
    1
    49
    4
    3
    Rash macular
         subjects affected / exposed
    0 / 102 (0.00%)
    3 / 45 (6.67%)
    0 / 19 (0.00%)
    1 / 213 (0.47%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    4
    0
    1
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    9 / 102 (8.82%)
    11 / 45 (24.44%)
    1 / 19 (5.26%)
    6 / 213 (2.82%)
    3 / 38 (7.89%)
    1 / 40 (2.50%)
         occurrences all number
    13
    12
    1
    7
    3
    3
    Urticaria
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    1
    3
    0
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    4 / 213 (1.88%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    4
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    2 / 19 (10.53%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 45 (6.67%)
    1 / 19 (5.26%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    3
    1
    2
    0
    0
    Polyuria
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    5 / 102 (4.90%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    8
    1
    1
    1
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    4 / 102 (3.92%)
    2 / 45 (4.44%)
    2 / 19 (10.53%)
    23 / 213 (10.80%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    4
    2
    2
    32
    0
    1
    Hypothyroidism
         subjects affected / exposed
    12 / 102 (11.76%)
    1 / 45 (2.22%)
    3 / 19 (15.79%)
    27 / 213 (12.68%)
    4 / 38 (10.53%)
    3 / 40 (7.50%)
         occurrences all number
    13
    3
    3
    32
    4
    3
    Adrenal insufficiency
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    0 / 19 (0.00%)
    2 / 213 (0.94%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    2
    0
    0
    2
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 102 (12.75%)
    6 / 45 (13.33%)
    1 / 19 (5.26%)
    36 / 213 (16.90%)
    3 / 38 (7.89%)
    9 / 40 (22.50%)
         occurrences all number
    19
    10
    1
    55
    3
    15
    Back pain
         subjects affected / exposed
    10 / 102 (9.80%)
    7 / 45 (15.56%)
    4 / 19 (21.05%)
    31 / 213 (14.55%)
    3 / 38 (7.89%)
    2 / 40 (5.00%)
         occurrences all number
    14
    9
    5
    37
    3
    2
    Bone pain
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    7 / 213 (3.29%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    9
    0
    1
    Muscle spasms
         subjects affected / exposed
    9 / 102 (8.82%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    4 / 213 (1.88%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    9
    2
    2
    4
    0
    0
    Muscular weakness
         subjects affected / exposed
    4 / 102 (3.92%)
    2 / 45 (4.44%)
    1 / 19 (5.26%)
    8 / 213 (3.76%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    5
    2
    1
    10
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    10 / 102 (9.80%)
    6 / 45 (13.33%)
    0 / 19 (0.00%)
    15 / 213 (7.04%)
    4 / 38 (10.53%)
    5 / 40 (12.50%)
         occurrences all number
    11
    9
    0
    16
    4
    7
    Musculoskeletal pain
         subjects affected / exposed
    7 / 102 (6.86%)
    1 / 45 (2.22%)
    0 / 19 (0.00%)
    19 / 213 (8.92%)
    3 / 38 (7.89%)
    1 / 40 (2.50%)
         occurrences all number
    9
    1
    0
    20
    5
    1
    Myalgia
         subjects affected / exposed
    5 / 102 (4.90%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    14 / 213 (6.57%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    7
    1
    1
    15
    0
    1
    Neck pain
         subjects affected / exposed
    5 / 102 (4.90%)
    1 / 45 (2.22%)
    2 / 19 (10.53%)
    3 / 213 (1.41%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    5
    2
    2
    5
    0
    0
    Pain in extremity
         subjects affected / exposed
    7 / 102 (6.86%)
    3 / 45 (6.67%)
    1 / 19 (5.26%)
    9 / 213 (4.23%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    8
    4
    1
    10
    1
    0
    Pain in jaw
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    0 / 213 (0.00%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 102 (2.94%)
    3 / 45 (6.67%)
    0 / 19 (0.00%)
    3 / 213 (1.41%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    4
    6
    0
    4
    3
    1
    Candida infection
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 45 (2.22%)
    2 / 19 (10.53%)
    0 / 213 (0.00%)
    1 / 38 (2.63%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    2
    0
    1
    1
    Lung infection
         subjects affected / exposed
    3 / 102 (2.94%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    9 / 213 (4.23%)
    0 / 38 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    3
    1
    2
    11
    0
    4
    Oral candidiasis
         subjects affected / exposed
    3 / 102 (2.94%)
    1 / 45 (2.22%)
    1 / 19 (5.26%)
    8 / 213 (3.76%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    3
    1
    1
    8
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    1 / 213 (0.47%)
    0 / 38 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    Pneumonia
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    10 / 213 (4.69%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    3
    0
    1
    10
    2
    1
    Sinusitis
         subjects affected / exposed
    3 / 102 (2.94%)
    3 / 45 (6.67%)
    0 / 19 (0.00%)
    4 / 213 (1.88%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    3
    3
    0
    5
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 102 (4.90%)
    5 / 45 (11.11%)
    1 / 19 (5.26%)
    17 / 213 (7.98%)
    2 / 38 (5.26%)
    3 / 40 (7.50%)
         occurrences all number
    5
    6
    1
    21
    2
    4
    Urinary tract infection
         subjects affected / exposed
    6 / 102 (5.88%)
    4 / 45 (8.89%)
    0 / 19 (0.00%)
    7 / 213 (3.29%)
    2 / 38 (5.26%)
    1 / 40 (2.50%)
         occurrences all number
    8
    4
    0
    7
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 102 (20.59%)
    10 / 45 (22.22%)
    6 / 19 (31.58%)
    61 / 213 (28.64%)
    8 / 38 (21.05%)
    9 / 40 (22.50%)
         occurrences all number
    25
    12
    8
    84
    9
    10
    Dehydration
         subjects affected / exposed
    5 / 102 (4.90%)
    1 / 45 (2.22%)
    2 / 19 (10.53%)
    6 / 213 (2.82%)
    3 / 38 (7.89%)
    2 / 40 (5.00%)
         occurrences all number
    11
    1
    2
    7
    3
    2
    Hyperglycaemia
         subjects affected / exposed
    10 / 102 (9.80%)
    3 / 45 (6.67%)
    2 / 19 (10.53%)
    11 / 213 (5.16%)
    2 / 38 (5.26%)
    4 / 40 (10.00%)
         occurrences all number
    21
    5
    2
    15
    5
    4
    Hyperkalaemia
         subjects affected / exposed
    2 / 102 (1.96%)
    2 / 45 (4.44%)
    1 / 19 (5.26%)
    7 / 213 (3.29%)
    1 / 38 (2.63%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    3
    10
    1
    4
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 45 (0.00%)
    2 / 19 (10.53%)
    7 / 213 (3.29%)
    1 / 38 (2.63%)
    2 / 40 (5.00%)
         occurrences all number
    4
    0
    2
    7
    1
    2
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    3 / 45 (6.67%)
    2 / 19 (10.53%)
    7 / 213 (3.29%)
    0 / 38 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    2
    12
    0
    6
    Hypocalcaemia
         subjects affected / exposed
    1 / 102 (0.98%)
    2 / 45 (4.44%)
    1 / 19 (5.26%)
    5 / 213 (2.35%)
    0 / 38 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    2
    1
    5
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 45 (0.00%)
    1 / 19 (5.26%)
    3 / 213 (1.41%)
    1 / 38 (2.63%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    3
    1
    0
    Hypokalaemia
         subjects affected / exposed
    5 / 102 (4.90%)
    5 / 45 (11.11%)
    1 / 19 (5.26%)
    11 / 213 (5.16%)
    3 / 38 (7.89%)
    7 / 40 (17.50%)
         occurrences all number
    8
    6
    1
    17
    4
    10
    Hypomagnesaemia
         subjects affected / exposed
    8 / 102 (7.84%)
    2 / 45 (4.44%)
    0 / 19 (0.00%)
    4 / 213 (1.88%)
    5 / 38 (13.16%)
    2 / 40 (5.00%)
         occurrences all number
    9
    2
    0
    5
    5
    3
    Hyponatraemia
         subjects affected / exposed
    7 / 102 (6.86%)
    5 / 45 (11.11%)
    2 / 19 (10.53%)
    11 / 213 (5.16%)
    5 / 38 (13.16%)
    3 / 40 (7.50%)
         occurrences all number
    11
    5
    2
    17
    7
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2013
    Updated exclusion criteria for participants with non-small cell lung cancer with tumors harboring anaplastic lymphoma kinase gene rearrangements or epidermal growth factor receptor sensitizing mutations, and added dose-limiting toxicity criteria for any pneumonitis.
    19 Dec 2013
    The synopsis was updated to match the body of the protocol. The clinical summary sections were updated. Updated the DLT evaluation period and added the rationale for DLT period.
    29 May 2014
    Removed immunotherapy pretreated cohorts. Added Q2W dosing schedule. Updated primary objectives for dosing schedule information, secondary objectives for the antitumor objective to specify RECIST version 1.1, and exploratory objectives for immune-response RECIST criteria. Sample size increased to 180. Added an alternative Q2W dose-escalation schedule for dose-escalation phase. Defined 2 cohorts for the dose-expansion phase (treatment- naïve participants, and participants who received 1 or 2 prior lines of therapy). Expanded the rule for main Q4W Schedule dose-escalation and de-escalation for MEDI4736. Updated the escalation and de-escalation rules for Q2W cohorts. Clarified that the MTD will be determined for both dosing schedules (Q4W and Q2W). Added an alternative Q2W dose-escalation schedule. Added global lung cancer incidence data. Updated inclusion and exclusion criteria, medical history, smoking history, and physical examination text. Removed patient-reported outcomes. Updated the text related to participants with known central nervous system metastases. Updated the methods for assigning treatment groups, prohibited concomitant medications, and analysis text.
    20 Apr 2015
    Added the selected dose for the expansion phase. Added the immunotherapy pretreated cohort to the protocol because safety data are needed in immunotherapy pretreated participants. Added a monotherapy cross-over cohort for participants who experienced irAEs during combination to allow continued immunotherapy treatment. Updated Section “Benefit-risk Evaluation”. Added secondary objective and end point of safety for MEDI4736 monotherapy. Updated study enrollment. Added description of the dose-expansion dose and the co-administration group. Added Sections “Treatment Beyond Progression” and “Treatment of Subjects after an Immune-related Adverse Event”. Added MTD evaluation during dose-expansion phase. Modified the discussion related to handling the laboratory abnormalities. Updated sample size. Updated enrollment/screening, inclusion, exclusion, and study treatment discontinuation criteria. Updated Section “Follow-up Period for Q4W and Q2W Schedules”. Removed patient-reported outcomes. Updated prohibited concomitant medications. Added gastrointestinal disorders as AESIs.
    25 Sep 2015
    Updated the evaluation of clinical activity of the MEDI4736 and tremelimumab combination in PD-L1-negative and PD-L1-positive NSCLC participants. Inclusion of both PD-L1-positive and PD-L1-negative participants allowed the assessment activity of the MEDI4736 and tremelimumab combination in the overall population and that seek to determine response rate differences, if any, between the 2 participant subgroups. Updated the primary objectives in the dose-expansion phase to describe objectives separately by cohort. Clarified the secondary objectives to describe objectives separately by cohort. Added the primary endpoint for Cohort B. Clarified the first secondary endpoint for assessment of antitumor activity to describe endpoints by cohort. Updated enrollment criteria, number of participants, and treatment regimen for Cohort B in dose-expansion phase. Added treatment beyond progression statement. Updated sample size and number of centers. Updated enrollment/screening, and inclusion, exclusion criteria. Clarified the study assessments for dose expansion phase.
    05 Feb 2016
    Justification for conducting Cohort C. Updated sample size and number of centers. Updated enrollment/screening, inclusion, exclusion, and dose modification criteria; and follow-up assessments. Updated analaysis statements.
    11 Feb 2016
    Updated the tremelimumab clinical data to be consistent with the current tremelimumab Investigator’s Brochure. Revised the toxicity management guidelines.

    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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