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    Clinical Trial Results:
    A Phase 1/2 Study of Nivolumab (IND# 124729) in Children, Adolescents, and Young Adults with Recurrent or Refractory Solid Tumors as a Single Agent and in Combination with Ipilimumab

    Summary
    EudraCT number
    		 2014-005674-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    02 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2023
    First version publication date
    18 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-070
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02304458
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    National Cancer Institute (NCI)
    Sponsor organisation address
    9609 Medical Center Drive, Bethesda, United States,
    Public contact
    National Cancer Institute, National Institutes of Health, National Cancer Institute (NCI), 001 1-800-422-6237, NCIinfo@nih.gov
    Scientific contact
    National Cancer Institute, National Institutes of Health, National Cancer Institute (NCI), 001 1-800-422-6237, NCIinfo@nih.gov
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001407-PIP01-12
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - Determine the tolerability, define and describe the toxicities of nivolumab administered as a single agent at 3 mg/kg. - Determine if systemic nivolumab exposure in children is similar to the systemic exposure in adults following a 3 mg/kg dose. - Determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) and define and describe the toxicities of nivolumab plus ipilimumab - Assess antitumor effects of nivolumab across selected childhood solid tumors - Assess antitumor effects of nivolumab in combination with ipilimumab across selected childhood solid tumors in two dose combinations - Characterize the pharmacokinetics of nivolumab alone and in combination with ipilimumab, including AUC, Cmax, Cmin, using intensive sampling. - Assess immunogenicity of nivolumab alone and in combination with ipilimumab by measuring anti-drug antibody (ADA) levels
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 133
    Worldwide total number of subjects
    134
    EEA total number of subjects
    0
    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)
    1
    Children (2-11 years)
    44
    Adolescents (12-17 years)
    55
    Adults (18-64 years)
    34
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Note: The Neuroblastoma cohorts D1 and D6, and Non-Hodgkin’s Lymphoma cohort D5 were not opened to accrual as they did not meet the threshold for the statistical design. So no data were available for the Non-Hodgkin Lymphoma and Neuroblastoma cohorts. AE- Adverse event PD- Progressive disease

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: Nivo 3 mg/kg
    Arm description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg Q2 week IV. A cycle was considered 28 days. A1: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q2 week

    Arm title
    		 Part B: Nivo 3 mg/kg
    Arm description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg Q2 week IV. A cycle was considered 28 days. B1: Relapsed or refractory neuroblastoma B2: Relapsed or refractory osteosarcoma B3: Relapsed or refractory rhabdomyosarcoma B4: Relapsed or refractory Ewing sarcoma or Peripheral PNET B5: Relapsed or refractory Hodgkin Lymphoma B6: Relapsed or refractory non-Hodgkin Lymphoma B7: Unresectable melanoma or metastatic melanoma or relapsed melanoma or refractory melanoma B8: Relapsed or refractory neuroblastoma (MIBG evaluable without RECIST evaluable disease)
    Arm type
    		 Experimental

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q2 week

    Arm title
    		 Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg
    Arm description
    		 Participants in the below cohorts receive nivolumab 1 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part C, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. C1: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q2 week

    Investigational medicinal product name
    ipilumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q2 week

    Arm title
    		 Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg
    Arm description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part C, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. C2: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ipilumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q2 week

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q2 week

    Arm title
    		 Part D: Nivo 3 mg/kg + Ipi 1 mg/kg
    Arm description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part D, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. D1: Relapsed or refractory neuroblastoma D2: Relapsed or refractory osteosarcoma D3: Relapsed or refractory rhabdomyosarcoma D4: Relapsed or refractory Ewing Sarcoma or Peripheral PNET D5: Relapsed or refractory non-Hodgkin Lymphoma D6: Relapsed or refractory neuroblastoma (MIBG evaluable without RECIST evaluable disease)
    Arm type
    		 Experimental

    Investigational medicinal product name
    ipilumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q2 week

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q2 week

    Arm title
    		 Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Arm description
    		 Participants in the below cohorts receive nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part E; in cycle 5 and for subsequent cycles, cycle length was 28 days and nivolumab 3 mg/kg was to be administered on days 1 and 15 of each cycle. E3: Relapsed or refractory rhabdomyosarcoma E4: Relapsed or refractory Ewing Sarcoma or Peripheral PNET
    Arm type
    		 Experimental

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q2 week

    Investigational medicinal product name
    ipilumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q2 week

    Number of subjects in period 1
    		Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Started
    12
    68
    6
    12
    28
    8
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    12
    68
    6
    12
    28
    8
         PD > 12 weeks after start of protocol therapy
    3
    8
    2
    2
    4
    -
         5th anniversary of study entry
    -
    1
    -
    -
    -
    -
         Physician decision
    1
    14
    1
    -
    2
    -
         Death
    1
    3
    -
    -
    1
    -
         PD > 40% increase from baseline target lesions
    6
    29
    3
    10
    17
    4
         AE requiring removal from protocol therapy
    -
    7
    -
    -
    3
    4
         Refusal of further protocol therapy
    1
    6
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: Nivo 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg Q2 week IV. A cycle was considered 28 days. A1: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Reporting group title
    Part B: Nivo 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg Q2 week IV. A cycle was considered 28 days. B1: Relapsed or refractory neuroblastoma B2: Relapsed or refractory osteosarcoma B3: Relapsed or refractory rhabdomyosarcoma B4: Relapsed or refractory Ewing sarcoma or Peripheral PNET B5: Relapsed or refractory Hodgkin Lymphoma B6: Relapsed or refractory non-Hodgkin Lymphoma B7: Unresectable melanoma or metastatic melanoma or relapsed melanoma or refractory melanoma B8: Relapsed or refractory neuroblastoma (MIBG evaluable without RECIST evaluable disease)

    Reporting group title
    Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 1 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part C, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. C1: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Reporting group title
    Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part C, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. C2: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Reporting group title
    Part D: Nivo 3 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part D, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. D1: Relapsed or refractory neuroblastoma D2: Relapsed or refractory osteosarcoma D3: Relapsed or refractory rhabdomyosarcoma D4: Relapsed or refractory Ewing Sarcoma or Peripheral PNET D5: Relapsed or refractory non-Hodgkin Lymphoma D6: Relapsed or refractory neuroblastoma (MIBG evaluable without RECIST evaluable disease)

    Reporting group title
    Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part E; in cycle 5 and for subsequent cycles, cycle length was 28 days and nivolumab 3 mg/kg was to be administered on days 1 and 15 of each cycle. E3: Relapsed or refractory rhabdomyosarcoma E4: Relapsed or refractory Ewing Sarcoma or Peripheral PNET

    Reporting group values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg Total
    Number of subjects
    		 12 68 6 12 28 8 134
    Age Categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 0 1 0 0 0 0 1
        Children (2-11 years)
    		 6 24 0 6 7 1 44
        Adolescents (12-17 years)
    		 6 27 6 6 8 2 55
        Adults (18-64 years)
    		 0 16 0 0 13 5 34
    Gender Categorical
    Units: Subjects
        Female
    		 5 26 1 7 8 5 52
        Male
    		 7 42 5 5 20 3 82
    Race Categorical
    Units: Subjects
        White
    		 12 48 3 8 22 8 101
        Black or African American
    		 0 9 1 1 2 0 13
        American Indian or Alaska Native
    		 0 0 0 1 0 0 1
        Asian
    		 0 6 1 1 0 0 8
        Unkown/Not Reported
    		 0 5 1 1 4 0 11
    Ethnicity Categorical
    Units: Subjects
        Hispanic or Latino
    		 2 9 1 2 5 1 20
        Not Hispanic or Latino
    		 10 58 5 10 21 5 109
        Unkown/Not Reported
    		 0 1 0 0 2 2 5

    End points

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    End points reporting groups
    Reporting group title
    Part A: Nivo 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg Q2 week IV. A cycle was considered 28 days. A1: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Reporting group title
    Part B: Nivo 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg Q2 week IV. A cycle was considered 28 days. B1: Relapsed or refractory neuroblastoma B2: Relapsed or refractory osteosarcoma B3: Relapsed or refractory rhabdomyosarcoma B4: Relapsed or refractory Ewing sarcoma or Peripheral PNET B5: Relapsed or refractory Hodgkin Lymphoma B6: Relapsed or refractory non-Hodgkin Lymphoma B7: Unresectable melanoma or metastatic melanoma or relapsed melanoma or refractory melanoma B8: Relapsed or refractory neuroblastoma (MIBG evaluable without RECIST evaluable disease)

    Reporting group title
    Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 1 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part C, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. C1: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Reporting group title
    Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part C, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. C2: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Reporting group title
    Part D: Nivo 3 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part D, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. D1: Relapsed or refractory neuroblastoma D2: Relapsed or refractory osteosarcoma D3: Relapsed or refractory rhabdomyosarcoma D4: Relapsed or refractory Ewing Sarcoma or Peripheral PNET D5: Relapsed or refractory non-Hodgkin Lymphoma D6: Relapsed or refractory neuroblastoma (MIBG evaluable without RECIST evaluable disease)

    Reporting group title
    Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part E; in cycle 5 and for subsequent cycles, cycle length was 28 days and nivolumab 3 mg/kg was to be administered on days 1 and 15 of each cycle. E3: Relapsed or refractory rhabdomyosarcoma E4: Relapsed or refractory Ewing Sarcoma or Peripheral PNET

    Subject analysis set title
    Part B1: Nivo 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with neuroblastoma receive nivolumab 3 mg/kg Q2 week IV

    Subject analysis set title
    Part B2: Nivo 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with osteosarcoma receive nivolumab 3 mg/kg Q2 week IV

    Subject analysis set title
    Part B3: Nivo 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with rhabdomyosarcoma receive nivolumab 3 mg/kg Q2 week IV

    Subject analysis set title
    Part B4: Nivo 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Ewing sarcoma receive nivolumab 3 mg/kg Q2 week IV

    Subject analysis set title
    Part B5: Nivo 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with Hodgkin lymphoma receive nivolumab 3 mg/kg Q2 week IV

    Subject analysis set title
    Part B6: Nivo 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with non-Hodgkin lymphoma receive nivolumab 3 mg/kg Q2 week IV

    Subject analysis set title
    Part B7: Nivo 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with melanoma receive nivolumab 3 mg/kg Q2 week IV

    Subject analysis set title
    Part B8: Nivo 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with evaluable disease without measurable disease in patients with neuroblastoma receive nivolumab 3 mg/kg Q2 week IV

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [1] [2]
    End point description
    The percentage of participants with a best overall response of partial or complete response assessed per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI. Complete Response (CR) = Disappearance of all target lesions. Partial Response (PR) = >=30% decrease in the sum of the longest diameter of target lesions.
    End point type
    Primary
    End point timeframe
    From first dose until disease progression/recurrence (up to approximately 7 years)
    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: Only summary statistics planned for this endpoint
    [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: Endpoint is specific to only certain study arms
    End point values
    		 Part A: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg Part B1: Nivo 3 mg/kg Part B2: Nivo 3 mg/kg Part B3: Nivo 3 mg/kg Part B4: Nivo 3 mg/kg Part B5: Nivo 3 mg/kg Part B6: Nivo 3 mg/kg Part B7: Nivo 3 mg/kg Part B8: Nivo 3 mg/kg
    Number of subjects analysed
    12
    6
    12
    28
    8
    10
    10
    10
    10
    10
    10
    1
    7
    Units: Percentage of Participants
        number (confidence interval 95%)
    0.0 (0.0 to 26.5)
    0.0 (0.0 to 45.9)
    0.0 (0.0 to 26.5)
    7.1 (0.9 to 23.5)
    0.0 (0.0 to 36.9)
    0.0 (0.0 to 30.8)
    0.0 (0.0 to 30.8)
    0.0 (0.0 to 30.8)
    0.0 (0.0 to 30.8)
    30.0 (6.7 to 65.2)
    10.0 (0.3 to 44.5)
    0.0 (0.0 to 97.5)
    0.0 (0.0 to 41.0)
    No statistical analyses for this end point

    Primary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR) [3] [4]
    End point description
    The time from the date of first dose of study medication to the first response date (CR or PR whichever occurred first), as assessed by the investigator and confirmed by Central Review. TTR will be evaluated for responders only. Complete Response (CR) = Disappearance of all target lesions. Partial Response (PR) = >=30% decrease in the sum of the longest diameter of target lesions. Note: 99999 = N/A
    End point type
    Primary
    End point timeframe
    From first dose to the date the response was first observed (up to approximately 7 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: Only summary statistics planned for this endpoint
    [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: Endpoint is specific to only certain study arms
    End point values
    		 Part A: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg Part B1: Nivo 3 mg/kg Part B2: Nivo 3 mg/kg Part B3: Nivo 3 mg/kg Part B4: Nivo 3 mg/kg Part B5: Nivo 3 mg/kg Part B6: Nivo 3 mg/kg Part B7: Nivo 3 mg/kg Part B8: Nivo 3 mg/kg
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    2
    0 [8]
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    3
    1
    0 [13]
    0 [14]
    Units: Months
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    2.09 ( 0.02 )
    ( )
    ( )
    ( )
    ( )
    ( )
    2.25 ( 0.40 )
    8.64 ( 99999 )
    ( )
    ( )
    Notes
    [5] - No participants had a response (CR/PR).
    [6] - No participants had a response (CR/PR).
    [7] - No participants had a response (CR/PR).
    [8] - No participants had a response (CR/PR).
    [9] - No participants had a response (CR/PR).
    [10] - No participants had a response (CR/PR).
    [11] - No participants had a response (CR/PR).
    [12] - No participants had a response (CR/PR).
    [13] - No participants had a response (CR/PR).
    [14] - No participants had a response (CR/PR).
    No statistical analyses for this end point

    Primary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR) [15] [16]
    End point description
    The time between the first response date (CR or PR whichever is recorded first), as determined by the investigator and confirmed by Central Review, to the date of the first documented tumor progression or death due to any cause, whichever occurs first. Subjects who die without a reported prior progression will be considered to have progressed on the date of their death. For subjects who neither progress nor die, DOR will be censored on the date of their last evaluable tumor assessment. DOR will be evaluated for responders only. Complete Response (CR) = Disappearance of all target lesions. Partial Response (PR) = >=30% decrease in the sum of the longest diameter of target lesions. Note: 99999 = N/A
    End point type
    Primary
    End point timeframe
    From first dose to the date of the first documented tumor progression or death due to any cause, whichever occurs first (up to approximately 7 years)
    Notes
    [15] - 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: Only summary statistics planned for this endpoint
    [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: Endpoint is specific to only certain study arms
    End point values
    		 Part A: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg Part B1: Nivo 3 mg/kg Part B2: Nivo 3 mg/kg Part B3: Nivo 3 mg/kg Part B4: Nivo 3 mg/kg Part B5: Nivo 3 mg/kg Part B6: Nivo 3 mg/kg Part B7: Nivo 3 mg/kg Part B8: Nivo 3 mg/kg
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    2
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    3
    1
    0 [25]
    0 [26]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    99999 (99999 to 99999)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    1.87 (0.95 to 99999)
    99999 (99999 to 99999)
    ( to )
    ( to )
    Notes
    [17] - No participants had a response (CR/PR).
    [18] - No participants had a response (CR/PR).
    [19] - No participants had a response (CR/PR).
    [20] - No participants had a response (CR/PR).
    [21] - No participants had a response (CR/PR).
    [22] - No participants had a response (CR/PR).
    [23] - No participants had a response (CR/PR).
    [24] - No participants had a response (CR/PR).
    [25] - No participants had a response (CR/PR).
    [26] - No participants had a response (CR/PR).
    No statistical analyses for this end point

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [27] [28]
    End point description
    The time from the date of first dose of study medication to the date of death from any cause. For subjects that are alive, their survival time will be censored at the date of last contact date (or “last known alive date”). Note: -99999 and 99999 = N/A
    End point type
    Primary
    End point timeframe
    From the date of first dose to the date of death from any cause (up to approximately 7 years)
    Notes
    [27] - 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: Only summary statistics planned for this endpoint
    [28] - 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: Endpoint is specific to only certain study arms
    End point values
    		 Part A: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg Part B1: Nivo 3 mg/kg Part B2: Nivo 3 mg/kg Part B3: Nivo 3 mg/kg Part B4: Nivo 3 mg/kg Part B5: Nivo 3 mg/kg Part B6: Nivo 3 mg/kg Part B7: Nivo 3 mg/kg Part B8: Nivo 3 mg/kg
    Number of subjects analysed
    12
    6
    12
    28
    8
    10
    10
    10
    10
    10
    10
    1
    7
    Units: Months
        median (confidence interval 95%)
    27.63 (1.87 to 99999)
    18.50 (8.25 to 99999)
    8.25 (5.45 to 99999)
    6.44 (3.32 to 19.91)
    99999 (1.12 to 99999)
    7.00 (2.33 to 14.06)
    6.67 (2.23 to 7.39)
    3.58 (0.76 to 6.37)
    6.47 (0.10 to 99999)
    99999 (99999 to 99999)
    22.47 (0.89 to 99999)
    4.99 (-99999 to 99999)
    99999 (2.99 to 99999)
    No statistical analyses for this end point

    Primary: The Number of Participants Experiencing Adverse Events (AE)

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    End point title
    		 The Number of Participants Experiencing Adverse Events (AE) [29]
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in participants administered a study drug and that does not necessarily have a causal relationship with the treatment. The select Adverse Events (select AEs) consist of a list of preferred terms grouped by specific category (e.g., pulmonary events, gastrointestinal events categories, etc.). Other events of special interest (OEOSI) consist of a list of preferred terms grouped by specific category (e.g., Myositis Event, Myocarditis Event, Demyelination Event, Guillain-Barre Syndrome, Pancreatitis Event, Uveitis Event, Encephalitis Event, Myasthenic Syndrome, Rhabdomyolysis Event, Graft Versus Host Disease). Note: Events only included in the below table if a participants experienced an event of interest.
    End point type
    Primary
    End point timeframe
    From first dose to 100 days after last dose of study therapy (up to approximately 63 months)
    Notes
    [29] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    12
    68
    6
    12
    28
    8
    Units: Participants
        Adverse Events (AE)
    12
    68
    6
    12
    28
    8
        Serious Adverse Events (SAE)
    7
    39
    3
    5
    15
    6
        Drug-Related AE
    12
    60
    6
    12
    28
    7
        Drug-Related SAE
    3
    14
    1
    2
    6
    5
        AE Leading to Discontinuation
    1
    14
    0
    1
    5
    0
        Drug-Related Gastrointestinal AE
    2
    4
    0
    0
    4
    3
        Drug-Related Heptaic AE
    6
    26
    1
    4
    8
    6
        Drug-Related Pulmonary AE
    0
    0
    0
    0
    1
    1
        Drug-Related Renal AE
    1
    6
    1
    1
    5
    1
        Drug-Related Skin AE
    6
    10
    3
    4
    5
    2
        Drug-Related Hypersensitivity/Infusion Reaction AE
    1
    3
    0
    1
    1
    1
        Pancreatitis Event
    1
    1
    0
    0
    2
    0
        Uveitis Event
    0
    0
    1
    0
    0
    0
        Graft Versus Host Disease Event
    0
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: The Number of Participants with Dose Limiting Toxicities (DLT) During the First Cycle of Therapy

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    End point title
    		 The Number of Participants with Dose Limiting Toxicities (DLT) During the First Cycle of Therapy [30] [31]
    End point description
    A DLT will be defined as any specific events that are possibly, probably, or definitely attributable to protocol therapy.
    End point type
    Primary
    End point timeframe
    From first dose of study drug through the first 28 days for Part A and 21 days for Part C of treatment.
    Notes
    [30] - 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: Only summary statistics planned for this endpoint
    [31] - 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: Endpoint is specific to only certain study arms
    End point values
    		 Part A: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg
    Number of subjects analysed
    12
    6
    12
    Units: Participants
    0
    0
    1
    No statistical analyses for this end point

    Primary: Frequency of PD-L1 Tumor Cell Expression Status

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    End point title
    		 Frequency of PD-L1 Tumor Cell Expression Status [32]
    End point description
    PD-L1 expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression. Analyzed in participants WITH PD-L1 QUANTIFIABLE AT BASELINE only.
    End point type
    Primary
    End point timeframe
    Pre-study, and if a participant requires a biopsy for surgery and tumor tissue is removed, tissue will be analyzed for PD-L1 Expression (up to approximately 7 years)
    Notes
    [32] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    9
    54
    5
    10
    24
    7
    Units: Percent of tumor cells
        arithmetic mean (standard deviation)
    10.0 ( 22.2 )
    22.2 ( 39.9 )
    2.2 ( 4.9 )
    10.7 ( 31.4 )
    1.3 ( 5.1 )
    0.0 ( 0.0 )
    No statistical analyses for this end point

    Primary: The Numbers of Participants who Died During the Study

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    End point title
    		 The Numbers of Participants who Died During the Study [33]
    End point description
    The numbers of participants who died during the study.
    End point type
    Primary
    End point timeframe
    From first dose to 100 days after last dose of study therapy (up to approximately 63 months)
    Notes
    [33] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    12
    68
    6
    12
    28
    8
    Units: Participants
    2
    16
    0
    0
    8
    1
    No statistical analyses for this end point

    Primary: Cmax - Maximum Observed Serum Concentration

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    End point title
    		 Cmax - Maximum Observed Serum Concentration [34]
    End point description
    One cycle = 4 weeks for Nivolumab %CV is regular coefficient of variation expressed in percentage (ratio of the sample standard deviation to the sample mean of the original non-transformed data).
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 Cycle 2 Day 1
    Notes
    [34] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    12 [35]
    64 [36]
    0 [37]
    0 [38]
    0 [39]
    0 [40]
    Units: ug/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    63.238 ( 25.4 )
    59.024 ( 23.6 )
    ( )
    ( )
    ( )
    ( )
        Cycle 2 Day 1
    97.877 ( 24.2 )
    88.070 ( 25.2 )
    ( )
    ( )
    ( )
    ( )
    Notes
    [35] - Cycle 1 Day 1 n = 12 Cycle 2 Day 1 n = 8
    [36] - Cycle 1 Day 1 n = 64 Cycle 2 Day 1 n = 31
    [37] - Data not collected.
    [38] - Data not collected.
    [39] - Data not collected.
    [40] - Data not collected.
    No statistical analyses for this end point

    Primary: AUC(0-T) -Area Under the Concentration-Time Curve from Time Zero to the Last Time of the Last Quantifiable Concentration

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    End point title
    		 AUC(0-T) -Area Under the Concentration-Time Curve from Time Zero to the Last Time of the Last Quantifiable Concentration [41]
    End point description
    One cycle = 4 weeks for Nivolumab %CV is regular coefficient of variation expressed in percentage (ratio of the sample standard deviation to the sample mean of the original non-transformed data).
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 Cycle 2 Day 1
    Notes
    [41] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    12 [42]
    64 [43]
    0 [44]
    0 [45]
    0 [46]
    0 [47]
    Units: h*ug/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    9841.8 ( 28.1 )
    8078.1 ( 33.9 )
    ( )
    ( )
    ( )
    ( )
        Cycle 2 Day 1
    11439.7 ( 29.5 )
    9524.4 ( 32.3 )
    ( )
    ( )
    ( )
    ( )
    Notes
    [42] - Cycle 1 Day 1 n = 12 Cycle 2 Day 1 n = 8
    [43] - Cycle 1 Day 1 n = 64 Cycle 2 Day 1 n = 31
    [44] - Data not collected.
    [45] - Data not collected.
    [46] - Data not collected.
    [47] - Data not collected.
    No statistical analyses for this end point

    Primary: Tmax - Time of Maximum Observed Serum Concentration

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    End point title
    		 Tmax - Time of Maximum Observed Serum Concentration [48]
    End point description
    One cycle = 4 weeks for Nivolumab
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 Cycle 2 Day 1
    Notes
    [48] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    12 [49]
    64 [50]
    0 [51]
    0 [52]
    0 [53]
    0 [54]
    Units: Hour
    median (full range (min-max))
        Cycle 1 Day 1
    1.1420 (1.000 to 1.550)
    1.330 (0.967 to 73.317)
    ( to )
    ( to )
    ( to )
    ( to )
        Cycle 2 Day 1
    1.0830 (1.000 to 23.083)
    1.1000 (0.867 to 44.917)
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [49] - Cycle 1 Day 1 n = 12 Cycle 2 Day 1 n = 8
    [50] - Cycle 1 Day 1 n = 64 Cycle 2 Day 1 n = 31
    [51] - Data not collected.
    [52] - Data not collected.
    [53] - Data not collected.
    [54] - Data not collected.
    No statistical analyses for this end point

    Primary: CTAU

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    End point title
    		 CTAU [55]
    End point description
    One cycle = 4 weeks for Nivolumab. %CV is regular coefficient of variation expressed in percentage (ratio of the sample standard deviation to the sample mean of the original non-transformed data).
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [55] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    12
    52
    0 [56]
    0 [57]
    0 [58]
    0 [59]
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    18.648 ( 34.4 )
    19.736 ( 26.6 )
    ( )
    ( )
    ( )
    ( )
    Notes
    [56] - Data not collected.
    [57] - Data not collected.
    [58] - Data not collected.
    [59] - Data not collected.
    No statistical analyses for this end point

    Primary: AUC(TAU) - Area Under the Concentration-Time Curve in One Dosing Interval

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    End point title
    		 AUC(TAU) - Area Under the Concentration-Time Curve in One Dosing Interval [60]
    End point description
    One cycle = 4 weeks for Nivolumab. %CV is regular coefficient of variation expressed in percentage (ratio of the sample standard deviation to the sample mean of the original non-transformed data)
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1
    Notes
    [60] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    12
    53
    0 [61]
    0 [62]
    0 [63]
    0 [64]
    Units: h*ug/mL
        geometric mean (geometric coefficient of variation)
    9841.8 ( 28.1 )
    9416.0 ( 22.8 )
    ( )
    ( )
    ( )
    ( )
    Notes
    [61] - Data not collected.
    [62] - Data not collected.
    [63] - Data not collected.
    [64] - Data not collected.
    No statistical analyses for this end point

    Primary: Summary Statistics for Varicella-Zoster V Ab IgG (Index) Titer

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    End point title
    		 Summary Statistics for Varicella-Zoster V Ab IgG (Index) Titer [65]
    End point description
    Summary statistics are measuring the concentration of antibodies in a person's blood sample. All treated subjects with evaluable result at the considered timepoint are included in this analysis. Cases with titer values below detection level or otherwise marked as non-quantifiable considered missing.
    End point type
    Primary
    End point timeframe
    Cycle 2 Day 1
    Notes
    [65] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    0 [66]
    6
    0 [67]
    1
    8
    1
    Units: Index
        median (full range (min-max))
    ( to )
    720.0 (168 to 1225)
    ( to )
    2175.0 (2175 to 2175)
    813.0 (145 to 2949)
    283.0 (283 to 283)
    Notes
    [66] - 0 participants with evaluable result at this timepoint
    [67] - 0 participants with evaluable result at this timepoint
    No statistical analyses for this end point

    Primary: Summary Statistics for Rubella Antibodies IgG (Index) Titer at Each Timepoint

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    End point title
    		 Summary Statistics for Rubella Antibodies IgG (Index) Titer at Each Timepoint [68]
    End point description
    Summary statistics are measuring the concentration of antibodies in a person's blood sample. All treated subjects with evaluable result at the considered timepoint are included in this analysis. Cases with titer values below detection level or otherwise marked as non-quantifiable considered missing.
    End point type
    Primary
    End point timeframe
    Cycle 2 Day 1
    Notes
    [68] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    5
    19
    1
    5
    11
    2
    Units: Index
        median (full range (min-max))
    5.810 (1.49 to 7.49)
    3.000 (1.05 to 17.70)
    15.100 (15.10 to 15.10)
    1.810 (0.92 to 9.27)
    2.020 (0.82 to 10.90)
    1.605 (1.52 to 1.69)
    No statistical analyses for this end point

    Primary: Summary Statistics for Rubeola Antibodies IgG (AU/mL) Titer at Each Timepoint

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    End point title
    		 Summary Statistics for Rubeola Antibodies IgG (AU/mL) Titer at Each Timepoint [69]
    End point description
    Summary statistics are measuring the concentration of antibodies in a person's blood sample. All treated subjects with evaluable result at the considered timepoint are included in this analysis. Cases with titer values below detection level or otherwise marked as non-quantifiable considered missing.
    End point type
    Primary
    End point timeframe
    Cycle 2 Day 1
    Notes
    [69] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    1
    5
    0 [70]
    2
    4
    1
    Units: AU/mL
        median (full range (min-max))
    30.40 (30.4 to 30.4)
    136.00 (71.7 to 208.0)
    ( to )
    43.10 (32.1 to 54.1)
    105.65 (36.9 to 190.0)
    47.90 (47.9 to 47.9)
    Notes
    [70] - 0 participants with evaluable result at this timepoint
    No statistical analyses for this end point

    Primary: Summary Statistics for Mumps Antibodies IgG (AU/mL) Titer at Each Timepoint

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    End point title
    		 Summary Statistics for Mumps Antibodies IgG (AU/mL) Titer at Each Timepoint [71]
    End point description
    Summary statistics are measuring the concentration of antibodies in a person's blood sample. All treated subjects with evaluable result at the considered timepoint are included in this analysis. Cases with titer values below detection level or otherwise marked as non-quantifiable considered missing.
    End point type
    Primary
    End point timeframe
    Cycle 2 Day 1
    Notes
    [71] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    4
    18
    1
    3
    10
    2
    Units: AU/mL
        median (full range (min-max))
    43.00 (34.1 to 97.1)
    56.25 (9.0 to 259.0)
    92.20 (92.2 to 92.2)
    66.00 (21.3 to 110.0)
    96.80 (13.1 to 235.0)
    112.10 (52.2 to 172.0)
    No statistical analyses for this end point

    Primary: Number of Subjects Who Lost Their Positivity/Immune Level for Varicella-Zoster V Ab IgG (Index)

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    End point title
    		 Number of Subjects Who Lost Their Positivity/Immune Level for Varicella-Zoster V Ab IgG (Index) [72]
    End point description
    All treated subjects who had titer above the positivity/immune level at baseline were included in this analysis. Baseline is defined as evaluations or events that occur before the date and time of the first dose of study treatment. Negative/non-immune: titer is strictly below the detection level 135 Index. Equivocal: antibody titer is in the ranges [135-165] Index. Positive/immune: titer is strictly above the positivity/immune level 165 Index.
    End point type
    Primary
    End point timeframe
    Cycle 2 Day 1
    Notes
    [72] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    0 [73]
    13
    2
    1
    10
    3
    Units: Index
        NEGATIVE/NON-IMMUNE
    0
    0
    0
    0
    0
        EQUIVOCAL
    0
    0
    0
    1
    0
        POSITIVE/IMMUNE
    5
    0
    0
    6
    2
        NOT REPORTED
    8
    2
    1
    3
    1
    Notes
    [73] - No participants with Titer Above the Positivity/Immune Level at Baseline
    No statistical analyses for this end point

    Primary: Number of Subjects Who Lost Their Positivity/Immune Level for Rubella Antibodies IgG (Index)

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    End point title
    		 Number of Subjects Who Lost Their Positivity/Immune Level for Rubella Antibodies IgG (Index) [74]
    End point description
    All treated subjects who had titer above the positivity/immune level at baseline were included in this analysis. Baseline is defined as evaluations or events that occur before the date and time of the first dose of study treatment. Negative/non-immune: titer is strictly below the detection level 25.0 AU/mL or 13.5 AU/mL. Equivocal: antibody titer is in the ranges [25.0-29.9] AU/mL or [13.5-16.4] AU/mL. Positive/immune: titer is strictly above the positivity/immune level 29.9 AU/mL or 16.4 AU/mL. Different thresholds for Rubeola Antibodies IgG are used for different samples.
    End point type
    Primary
    End point timeframe
    Cycle 2 Day 1
    Notes
    [74] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    9
    37
    6
    7
    15
    4
    Units: Participants
        NEGATIVE/NON-IMMUNE
    0
    0
    0
    1
    0
    0
        EQUIVOCAL
    0
    0
    0
    0
    0
    0
        POSITIVE/IMMUNE
    5
    19
    1
    3
    10
    2
        NOT REPORTED
    4
    18
    5
    3
    5
    2
    No statistical analyses for this end point

    Primary: Number of Participants Who Lost Their Positivity/Immune Level for Rubeola Antibodies IgG (AU/mL)

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    End point title
    		 Number of Participants Who Lost Their Positivity/Immune Level for Rubeola Antibodies IgG (AU/mL) [75]
    End point description
    All treated subjects who had titer above the positivity/immune level at baseline were included in this analysis. Baseline is defined as evaluations or events that occur before the date and time of the first dose of study treatment. Negative/non-immune: titer is strictly below the detection level 25.0 AU/mL or 13.5 AU/mL. Equivocal: antibody titer is in the ranges [25.0-29.9] AU/mL or [13.5-16.4] AU/mL. Positive/immune: titer is strictly above the positivity/immune level 29.9 AU/mL or 16.4 AU/mL. Different thresholds for Rubeola Antibodies IgG are used for different samples.
    End point type
    Primary
    End point timeframe
    Cycle 2 Day 1
    Notes
    [75] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    1
    19
    1
    1
    10
    3
    Units: Participants
        NEGATIVE/NON-IMMUNE
    0
    1
    0
    0
    1
    0
        EQUIVOCAL
    0
    0
    0
    0
    0
    0
        POSITIVE/IMMUNE
    0
    6
    0
    0
    6
    2
        NOT REPORTED
    1
    12
    1
    1
    3
    1
    No statistical analyses for this end point

    Primary: Number of Subjects Who Lost Their Positivity/Immune Level for Mumps Antibodies IgG (AU/mL)

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    End point title
    		 Number of Subjects Who Lost Their Positivity/Immune Level for Mumps Antibodies IgG (AU/mL) [76]
    End point description
    All treated subjects who had titer above the positivity/immune level at baseline were included in this analysis. Baseline is defined as evaluations or events that occur before the date and time of the first dose of study treatment. Negative/non-immune: titer is strictly below the detection level 9.0 AU/mL. Equivocal: antibody titer is in the ranges [9.0-10.9] AU/mL. Positive/immune: titer is strictly above the positivity/immune level 10.9 AU/mL.
    End point type
    Primary
    End point timeframe
    Cycle 2 Day 1
    Notes
    [76] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    8
    35
    5
    7
    14
    3
    Units: Participants
        NEGATIVE/NON-IMMUNE
    0
    0
    0
    0
    0
    0
        EQUIVOCAL
    0
    1
    0
    0
    0
    0
        POSITIVE/IMMUNE
    4
    18
    1
    3
    10
    2
        NOT REPORTED
    4
    16
    4
    4
    4
    1
    No statistical analyses for this end point

    Primary: The Number of Participants with Antidrug Antibody (ADA) Measurements (Nivolumab)

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    End point title
    		 The Number of Participants with Antidrug Antibody (ADA) Measurements (Nivolumab) [77]
    End point description
    Baseline ADA Positive: A subject with baseline ADA-positive sample; ADA Positive: A subject with at least one ADA-positive sample relative to baseline (ADA negative at baseline or ADA titer to be at least 4-fold or greater (>=) than baseline positive titer) at any time after initiation of treatment. Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies detected post-baseline; ADA Negative: A subject with no ADA-positive sample after initiation of treatment.
    End point type
    Primary
    End point timeframe
    In Parts A and B, serum samples were collected prior to Day 1 nivolumab infusion in each cycle. In Parts C and D, serum samples were collected prior to Day 1 nivolumab infusion in each cycle for ADA assessment of both Nivolumab and Ipilimumab.
    Notes
    [77] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    10
    41
    2
    9
    24
    6
    Units: Participants
        BASELINE ADA POSITIVE
    1
    2
    0
    1
    1
    0
        ADA POSITIVE
    0
    1
    1
    0
    0
    0
        NEUTRALIZING POSITIVE
    0
    0
    0
    0
    0
    0
        ADA NEGATIVE
    10
    40
    1
    9
    24
    6
    No statistical analyses for this end point

    Primary: The Number of Participants with Antidrug Antibody (ADA) Measurements (Ipilimumab)

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    End point title
    		 The Number of Participants with Antidrug Antibody (ADA) Measurements (Ipilimumab) [78] [79]
    End point description
    Baseline ADA Positive: A subject with baseline ADA-positive sample; ADA Positive: A subject with at least one ADA-positive sample relative to baseline (ADA negative at baseline or ADA titer to be at least 4-fold or greater (>=) than baseline positive titer) at any time after initiation of treatment. Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies detected post-baseline; ADA Negative: A subject with no ADA-positive sample after initiation of treatment.
    End point type
    Primary
    End point timeframe
    In Parts A and B, serum samples were collected prior to Day 1 nivolumab infusion in each cycle. In Parts C and D, serum samples were collected prior to Day 1 nivolumab infusion in each cycle for ADA assessment of both Nivolumab and Ipilimumab.
    Notes
    [78] - 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: Only summary statistics planned for this endpoint
    [79] - 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: Endpoint is specific to only certain study arms
    End point values
    		 Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    2
    8
    23
    6
    Units: Participants
        BASELINE ADA POSITIVE
    0
    1
    0
    0
        ADA POSITIVE
    0
    0
    0
    0
        NEUTRALIZING POSITIVE
    0
    0
    0
    0
        ADA NEGATIVE
    2
    8
    23
    6
    No statistical analyses for this end point

    Primary: Biomarker Expression Analysis of Nivolumab as a Singel Agent or in Combination with Ipilimumab

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    End point title
    		 Biomarker Expression Analysis of Nivolumab as a Singel Agent or in Combination with Ipilimumab [80]
    End point description
    Data were not and will never be collected.
    End point type
    Primary
    End point timeframe
    Cycle 1 (21 days)
    Notes
    [80] - 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: Only summary statistics planned for this endpoint
    End point values
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Number of subjects analysed
    0 [81]
    0 [82]
    0 [83]
    0 [84]
    0 [85]
    0 [86]
    Units: Participants
    Notes
    [81] - Data were not and will never be collected.
    [82] - Data were not and will never be collected.
    [83] - Data were not and will never be collected.
    [84] - Data were not and will never be collected.
    [85] - Data were not and will never be collected.
    [86] - Data were not and will never be collected.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs were assessed from first dose to 100 days after last dose of study therapy (up to approximately 63 months)
    Adverse event reporting additional description
    The below Non-Serious AEs could not be coded therefore have been categorized as “unassigned” and are outlined below: Reported below are the # of subjects affected (#A) and the # of occurrences (all) (#O). Part A: (#A=2) (#O=2) Part B: (#A=8) (#O=13) Part C1: (#A=0) (#O=0) Part C2: (#A=2) (#O=2) Part D: (#A=2) (#O=2) Part E: (#A=4) (#O=6)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Part A: Nivo 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg Q2 week IV. A cycle was considered 28 days. A1: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Reporting group title
    Part B: Nivo 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg Q2 week IV. A cycle was considered 28 days. B1: Relapsed or refractory neuroblastoma B2: Relapsed or refractory osteosarcoma B3: Relapsed or refractory rhabdomyosarcoma B4: Relapsed or refractory Ewing sarcoma or Peripheral PNET B5: Relapsed or refractory Hodgkin Lymphoma B6: Relapsed or refractory non-Hodgkin Lymphoma B7: Unresectable melanoma or metastatic melanoma or relapsed melanoma or refractory melanoma B8: Relapsed or refractory neuroblastoma (MIBG evaluable without RECIST evaluable disease)

    Reporting group title
    Part E: Nivo 1 mg/kg + Ipi 3 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 1 mg/kg + ipilimumab 3 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part E; in cycle 5 and for subsequent cycles, cycle length was 28 days and nivolumab 3 mg/kg was to be administered on days 1 and 15 of each cycle. E3: Relapsed or refractory rhabdomyosarcoma E4: Relapsed or refractory Ewing Sarcoma or Peripheral PNET

    Reporting group title
    Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part C, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. C2: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Reporting group title
    Part D: Nivo 3 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part D, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. D1: Relapsed or refractory neuroblastoma D2: Relapsed or refractory osteosarcoma D3: Relapsed or refractory rhabdomyosarcoma D4: Relapsed or refractory Ewing Sarcoma or Peripheral PNET D5: Relapsed or refractory non-Hodgkin Lymphoma D6: Relapsed or refractory neuroblastoma (MIBG evaluable without RECIST evaluable disease)

    Reporting group title
    Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg
    Reporting group description
    		 Participants in the below cohorts receive nivolumab 1 mg/kg + ipilimumab 1 mg/kg Q3 week x 4 followed by nivolumab 3 mg/kg Q2 week IV. Note that cycle length was 21 days for the first 4 cycles of Part C, whereas reverted to 28 days for subsequent cycles which comprised two doses of nivolumab, and was the same regimen used in Part A and B. C1: Recurrent or refractory solid tumors, without CNS tumors or known CNS metastases.

    Serious adverse events
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 12 (58.33%)
    39 / 68 (57.35%)
    6 / 8 (75.00%)
    5 / 12 (41.67%)
    15 / 28 (53.57%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    6
    38
    1
    8
    18
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 12 (8.33%)
    7 / 68 (10.29%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 8
    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
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (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
    Haematoma
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (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
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    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
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    2 / 12 (16.67%)
    14 / 68 (20.59%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    6 / 28 (21.43%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 14
    0 / 1
    0 / 0
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 14
    0 / 1
    0 / 0
    0 / 6
    0 / 0
    Chills
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (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
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    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
    Pyrexia
         subjects affected / exposed
    3 / 12 (25.00%)
    10 / 68 (14.71%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 11
    2 / 2
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Cytokine release syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Oedema genital
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Cough
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    1 / 1
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Laryngeal oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Hypoxia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Pleural effusion
         subjects affected / exposed
    3 / 12 (25.00%)
    4 / 68 (5.88%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    5 / 28 (17.86%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 4
    0 / 0
    0 / 0
    3 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Pneumonitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Pleuritic pain
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    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
    Respiratory failure
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (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 / 2
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Anxiety
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Blood creatinine increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Lipase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Ejection fraction decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Neutrophil count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    Platelet count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Weight decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    White blood cell count decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Contusion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Cardiac disorders
    Ventricular fibrillation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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 arrest
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Pericardial effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (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
    Cervical cord compression
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Nervous system disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Spinal cord compression
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Seizure
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (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
    Presyncope
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Phantom limb syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Syncope
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 68 (5.88%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
    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
    Eye disorders
    Eye swelling
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Gastrointestinal disorders
    Duodenitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Diarrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 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
    Ascites
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Anal fistula
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Abdominal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Gastritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Stomatitis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    Pancreatitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Nausea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Haematuria
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    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 colic
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Pollakiuria
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Urinary tract obstruction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (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
    Urinary retention
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Bone pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Musculoskeletal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Flank pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Neck pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         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
    Pain in extremity
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Bronchitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (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
    Device related infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Enterocolitis infectious
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Sepsis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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
    Pneumonia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Periorbital cellulitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (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 infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         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
    Urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Dehydration
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Hypermagnesaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Hyperuricaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Hypokalaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Hypomagnesaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A: Nivo 3 mg/kg Part B: Nivo 3 mg/kg Part E: Nivo 1 mg/kg + Ipi 3 mg/kg Part C2: Nivo 3 mg/kg + Ipi 1 mg/kg Part D: Nivo 3 mg/kg + Ipi 1 mg/kg Part C1: Nivo 1 mg/kg + Ipi 1 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    68 / 68 (100.00%)
    8 / 8 (100.00%)
    12 / 12 (100.00%)
    28 / 28 (100.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    2 / 6 (33.33%)
         occurrences all number
    0
    5
    1
    0
    3
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
    11 / 68 (16.18%)
    3 / 8 (37.50%)
    1 / 12 (8.33%)
    7 / 28 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    20
    4
    1
    17
    0
    Flushing
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Hypertension
         subjects affected / exposed
    6 / 12 (50.00%)
    13 / 68 (19.12%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
    11 / 28 (39.29%)
    1 / 6 (16.67%)
         occurrences all number
    12
    24
    2
    3
    25
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 68 (7.35%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    6 / 28 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    2
    5
    3
    1
    6
    0
    Malaise
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    1
    1
    0
    0
    Facial pain
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    8 / 12 (66.67%)
    41 / 68 (60.29%)
    7 / 8 (87.50%)
    6 / 12 (50.00%)
    16 / 28 (57.14%)
    2 / 6 (33.33%)
         occurrences all number
    10
    49
    8
    6
    21
    2
    Gait disturbance
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    1
    1
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    1
    1
    1
    0
    Localised oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    4 / 28 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    0
    0
    4
    3
    Face oedema
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    5
    2
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    8 / 68 (11.76%)
    4 / 8 (50.00%)
    2 / 12 (16.67%)
    6 / 28 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    0
    8
    6
    2
    6
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 12 (8.33%)
    8 / 68 (11.76%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    6 / 28 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    2
    8
    2
    0
    6
    0
    Pain
         subjects affected / exposed
    4 / 12 (33.33%)
    16 / 68 (23.53%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    4 / 28 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    5
    17
    2
    2
    5
    0
    Pyrexia
         subjects affected / exposed
    3 / 12 (25.00%)
    26 / 68 (38.24%)
    3 / 8 (37.50%)
    4 / 12 (33.33%)
    12 / 28 (42.86%)
    2 / 6 (33.33%)
         occurrences all number
    5
    34
    4
    8
    16
    2
    Swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Oedema genital
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    0
    Pelvic pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    2
    0
    Penile pain
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    4 / 12 (33.33%)
    9 / 68 (13.24%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    4
    9
    2
    1
    2
    0
    Dyspnoea
         subjects affected / exposed
    3 / 12 (25.00%)
    13 / 68 (19.12%)
    4 / 8 (50.00%)
    1 / 12 (8.33%)
    7 / 28 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    17
    6
    1
    7
    0
    Dysphonia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    1
    0
    1
    0
    Cough
         subjects affected / exposed
    8 / 12 (66.67%)
    26 / 68 (38.24%)
    4 / 8 (50.00%)
    4 / 12 (33.33%)
    15 / 28 (53.57%)
    2 / 6 (33.33%)
         occurrences all number
    11
    36
    5
    4
    18
    3
    Atelectasis
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    1
    3
    0
    Pneumothorax
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 12 (8.33%)
    6 / 68 (8.82%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    7
    1
    0
    3
    0
    Nasal congestion
         subjects affected / exposed
    3 / 12 (25.00%)
    15 / 68 (22.06%)
    3 / 8 (37.50%)
    1 / 12 (8.33%)
    7 / 28 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    20
    3
    1
    7
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    7 / 68 (10.29%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
    5 / 28 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    2
    7
    3
    2
    7
    0
    Oropharyngeal plaque
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 68 (5.88%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    6 / 28 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    2
    1
    6
    0
    Pneumonitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Hiccups
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    Tachypnoea
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 68 (7.35%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    6
    0
    0
    3
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Sinus pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    1
    1
    3
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 68 (7.35%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    2 / 6 (33.33%)
         occurrences all number
    2
    6
    0
    0
    2
    2
    Productive cough
         subjects affected / exposed
    0 / 12 (0.00%)
    6 / 68 (8.82%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    0
    6
    0
    0
    3
    0
    Throat irritation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 68 (7.35%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    1
    16
    0
    1
    4
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 12 (0.00%)
    12 / 68 (17.65%)
    3 / 8 (37.50%)
    1 / 12 (8.33%)
    6 / 28 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    0
    12
    3
    1
    6
    0
    Hallucination
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    Depression
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 68 (7.35%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    2
    5
    0
    1
    2
    0
    Delirium
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    Confusional state
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 68 (4.41%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    1
    2
    2
    0
    Personality change
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Agitation
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 68 (1.47%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    2
    0
    2
    0
    Irritability
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 68 (7.35%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    1 / 6 (16.67%)
         occurrences all number
    1
    7
    0
    1
    3
    1
    Anxiety
         subjects affected / exposed
    4 / 12 (33.33%)
    12 / 68 (17.65%)
    0 / 8 (0.00%)
    3 / 12 (25.00%)
    9 / 28 (32.14%)
    1 / 6 (16.67%)
         occurrences all number
    5
    12
    0
    5
    9
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 12 (8.33%)
    9 / 68 (13.24%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    5 / 28 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    1
    10
    1
    0
    5
    0
    Activated partial thromboplastin time shortened
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    6 / 68 (8.82%)
    3 / 8 (37.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    7
    3
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 12 (41.67%)
    29 / 68 (42.65%)
    4 / 8 (50.00%)
    4 / 12 (33.33%)
    10 / 28 (35.71%)
    3 / 6 (50.00%)
         occurrences all number
    6
    39
    4
    5
    10
    4
    Amylase decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Amylase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    1 / 8 (12.50%)
    5 / 12 (41.67%)
    2 / 28 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    1
    5
    2
    1
    Anion gap increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 12 (50.00%)
    30 / 68 (44.12%)
    7 / 8 (87.50%)
    5 / 12 (41.67%)
    7 / 28 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    50
    7
    7
    7
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 12 (16.67%)
    15 / 68 (22.06%)
    2 / 8 (25.00%)
    3 / 12 (25.00%)
    6 / 28 (21.43%)
    2 / 6 (33.33%)
         occurrences all number
    3
    19
    2
    4
    6
    2
    Alanine aminotransferase decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood bicarbonate increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 12 (8.33%)
    11 / 68 (16.18%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    1
    12
    2
    2
    4
    0
    Blood chloride decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    3
    0
    0
    0
    2
    Blood cholesterol increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    3 / 12 (25.00%)
    20 / 68 (29.41%)
    3 / 8 (37.50%)
    3 / 12 (25.00%)
    9 / 28 (32.14%)
    3 / 6 (50.00%)
         occurrences all number
    7
    31
    3
    5
    10
    4
    Carbon dioxide decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 68 (4.41%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    1
    1
    1
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    2 / 12 (16.67%)
    4 / 68 (5.88%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    5
    2
    1
    0
    1
    Blood urea decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    0
    0
    0
    0
    C-reactive protein
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    9
    0
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    2 / 12 (16.67%)
    17 / 68 (25.00%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    8 / 28 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    2
    22
    0
    2
    9
    1
    Blood fibrinogen decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 68 (5.88%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    0
    2
    0
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    4
    1
    1
    0
    1
    Haemoglobin increased
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    2
    11
    0
    0
    4
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 12 (0.00%)
    6 / 68 (8.82%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    6
    1
    1
    2
    0
    Lipase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 68 (7.35%)
    2 / 8 (25.00%)
    3 / 12 (25.00%)
    7 / 28 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    15
    2
    4
    8
    0
    Lymphocyte count decreased
         subjects affected / exposed
    9 / 12 (75.00%)
    40 / 68 (58.82%)
    7 / 8 (87.50%)
    5 / 12 (41.67%)
    20 / 28 (71.43%)
    3 / 6 (50.00%)
         occurrences all number
    13
    88
    9
    6
    39
    3
    Lymphocyte count increased
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    7 / 12 (58.33%)
    36 / 68 (52.94%)
    3 / 8 (37.50%)
    4 / 12 (33.33%)
    6 / 28 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    11
    103
    4
    7
    15
    2
    Platelet count decreased
         subjects affected / exposed
    7 / 12 (58.33%)
    40 / 68 (58.82%)
    3 / 8 (37.50%)
    6 / 12 (50.00%)
    8 / 28 (28.57%)
    3 / 6 (50.00%)
         occurrences all number
    11
    90
    3
    6
    15
    3
    Protein total decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    Thyroxine free decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Urine output decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Weight decreased
         subjects affected / exposed
    4 / 12 (33.33%)
    15 / 68 (22.06%)
    3 / 8 (37.50%)
    4 / 12 (33.33%)
    10 / 28 (35.71%)
    3 / 6 (50.00%)
         occurrences all number
    4
    17
    3
    4
    10
    3
    Weight increased
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 68 (7.35%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    1 / 6 (16.67%)
         occurrences all number
    2
    5
    2
    2
    1
    1
    White blood cell count decreased
         subjects affected / exposed
    7 / 12 (58.33%)
    41 / 68 (60.29%)
    4 / 8 (50.00%)
    5 / 12 (41.67%)
    8 / 28 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    17
    113
    5
    9
    21
    2
    White blood cell count increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    0
    0
    0
    Arthropod bite
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 12 (8.33%)
    6 / 68 (8.82%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    1
    6
    0
    1
    3
    0
    Fall
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    2
    0
    1
    0
    Fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 68 (5.88%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    1
    1
    1
    0
    Seroma
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    Vascular access complication
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Wound complication
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    0
    0
    3
    1
    Sinus tachycardia
         subjects affected / exposed
    6 / 12 (50.00%)
    26 / 68 (38.24%)
    3 / 8 (37.50%)
    4 / 12 (33.33%)
    16 / 28 (57.14%)
    2 / 6 (33.33%)
         occurrences all number
    13
    31
    5
    4
    25
    2
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pericardial effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    1
    2
    0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Amnesia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 12 (8.33%)
    8 / 68 (11.76%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    8
    2
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    0
    1
    0
    Seizure
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Radiculopathy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Phantom limb syndrome
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 68 (7.35%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    5
    1
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 12 (0.00%)
    6 / 68 (8.82%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    6
    0
    1
    2
    1
    Lethargy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Hypersomnia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hemiparesis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    4 / 12 (33.33%)
    21 / 68 (30.88%)
    3 / 8 (37.50%)
    5 / 12 (41.67%)
    10 / 28 (35.71%)
    3 / 6 (50.00%)
         occurrences all number
    6
    25
    3
    5
    10
    3
    Encephalopathy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Dyskinesia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Trigeminal nerve disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    Somnolence
         subjects affected / exposed
    2 / 12 (16.67%)
    6 / 68 (8.82%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    1 / 6 (16.67%)
         occurrences all number
    2
    6
    0
    1
    4
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 12 (91.67%)
    51 / 68 (75.00%)
    4 / 8 (50.00%)
    12 / 12 (100.00%)
    17 / 28 (60.71%)
    3 / 6 (50.00%)
         occurrences all number
    21
    81
    7
    17
    22
    4
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eosinophilia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    3 / 8 (37.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    0
    Febrile neutropenia
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    0
    1
    1
    0
    Ear and labyrinth disorders
    External ear pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hypoacusis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Eye disorders
    Anisocoria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Photopsia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eye pain
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    1
    3
    0
    0
    3
    1
    Eyelid function disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eyelid margin crusting
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Periorbital oedema
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    Photophobia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Eye disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Uveitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    5 / 28 (17.86%)
    1 / 6 (16.67%)
         occurrences all number
    0
    4
    1
    1
    5
    1
    Visual impairment
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    4 / 28 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    6
    2
    0
    4
    0
    Abdominal pain
         subjects affected / exposed
    3 / 12 (25.00%)
    21 / 68 (30.88%)
    5 / 8 (62.50%)
    3 / 12 (25.00%)
    8 / 28 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    3
    27
    7
    3
    8
    2
    Duodenal ulcer
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Anal incontinence
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Ascites
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    Colitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Constipation
         subjects affected / exposed
    6 / 12 (50.00%)
    24 / 68 (35.29%)
    3 / 8 (37.50%)
    2 / 12 (16.67%)
    8 / 28 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    6
    28
    3
    2
    8
    2
    Diarrhoea
         subjects affected / exposed
    3 / 12 (25.00%)
    17 / 68 (25.00%)
    4 / 8 (50.00%)
    1 / 12 (8.33%)
    8 / 28 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    7
    26
    4
    1
    13
    1
    Dry mouth
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    6 / 28 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    6
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 68 (7.35%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    5 / 28 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    1
    6
    0
    2
    5
    0
    Dysphagia
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    1
    0
    Eructation
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    3
    0
    Gastritis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    4
    0
    Oral pain
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 68 (4.41%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    1
    0
    2
    0
    Lip disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    6 / 12 (50.00%)
    32 / 68 (47.06%)
    3 / 8 (37.50%)
    3 / 12 (25.00%)
    12 / 28 (42.86%)
    1 / 6 (16.67%)
         occurrences all number
    8
    43
    3
    3
    14
    2
    Oesophageal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oesophagitis
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    Gingival pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pancreatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    1
    0
    1
    0
    Toothache
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    4 / 12 (33.33%)
    32 / 68 (47.06%)
    4 / 8 (50.00%)
    2 / 12 (16.67%)
    14 / 28 (50.00%)
    2 / 6 (33.33%)
         occurrences all number
    5
    50
    4
    2
    15
    2
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 12 (16.67%)
    6 / 68 (8.82%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    5 / 28 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    2
    7
    1
    0
    6
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    5
    2
    1
    0
    2
    Blister
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 68 (7.35%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    1
    5
    1
    1
    2
    1
    Erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    6 / 68 (8.82%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    6
    0
    0
    0
    1
    Pain of skin
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    5 / 12 (41.67%)
    12 / 68 (17.65%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    4 / 28 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    5
    13
    3
    0
    4
    0
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Rash erythematous
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin ulcer
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    5 / 12 (41.67%)
    11 / 68 (16.18%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    3 / 28 (10.71%)
    3 / 6 (50.00%)
         occurrences all number
    5
    14
    1
    2
    3
    4
    Renal and urinary disorders
    Urinary tract pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 68 (5.88%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    1
    2
    0
    Chromaturia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Glycosuria
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Haematuria
         subjects affected / exposed
    4 / 12 (33.33%)
    13 / 68 (19.12%)
    3 / 8 (37.50%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    6
    16
    4
    1
    5
    0
    Haemoglobinuria
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Ketonuria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    2
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 12 (8.33%)
    14 / 68 (20.59%)
    4 / 8 (50.00%)
    6 / 12 (50.00%)
    7 / 28 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    15
    5
    7
    7
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 12 (8.33%)
    4 / 68 (5.88%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    1
    0
    3
    0
    Urinary retention
         subjects affected / exposed
    0 / 12 (0.00%)
    9 / 68 (13.24%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    10
    0
    1
    2
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    Endocrine disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hyperthyroidism
         subjects affected / exposed
    0 / 12 (0.00%)
    7 / 68 (10.29%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    8
    2
    0
    2
    0
    Hypothyroidism
         subjects affected / exposed
    2 / 12 (16.67%)
    10 / 68 (14.71%)
    2 / 8 (25.00%)
    4 / 12 (33.33%)
    5 / 28 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    2
    10
    2
    4
    5
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    18 / 68 (26.47%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
    9 / 28 (32.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    19
    1
    2
    11
    1
    Arthralgia
         subjects affected / exposed
    1 / 12 (8.33%)
    6 / 68 (8.82%)
    3 / 8 (37.50%)
    4 / 12 (33.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    6
    3
    4
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    23 / 68 (33.82%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    10 / 28 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    2
    29
    1
    2
    13
    2
    Neck pain
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 68 (4.41%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    1
    1
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    2 / 8 (25.00%)
    3 / 12 (25.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    2
    3
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    2 / 12 (16.67%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 12 (0.00%)
    11 / 68 (16.18%)
    2 / 8 (25.00%)
    1 / 12 (8.33%)
    7 / 28 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    11
    2
    1
    7
    0
    Muscle spasms
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    2
    0
    Joint range of motion decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    0
    0
    3
    1
    Flank pain
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    6
    1
    2
    0
    0
    Chest wall mass
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 68 (7.35%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    1
    0
    1
    1
    Infections and infestations
    Otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    2
    2
    0
    Device related infection
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Mucosal infection
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    1
    2
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 12 (0.00%)
    6 / 68 (8.82%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    0
    8
    0
    0
    3
    0
    Rash pustular
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    2
    0
    Skin infection
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    8 / 68 (11.76%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    5 / 28 (17.86%)
    1 / 6 (16.67%)
         occurrences all number
    1
    16
    1
    0
    5
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 68 (5.88%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    6
    3
    2
    1
    0
    Wound infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 68 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Alkalosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 12 (8.33%)
    8 / 68 (11.76%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    7 / 28 (25.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    9
    1
    0
    8
    2
    Hypercalcaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    7 / 68 (10.29%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    1
    7
    0
    0
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    5 / 12 (41.67%)
    27 / 68 (39.71%)
    7 / 8 (87.50%)
    5 / 12 (41.67%)
    9 / 28 (32.14%)
    3 / 6 (50.00%)
         occurrences all number
    8
    36
    9
    6
    11
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    15 / 68 (22.06%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    4 / 28 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    15
    1
    0
    7
    0
    Hypermagnesaemia
         subjects affected / exposed
    2 / 12 (16.67%)
    13 / 68 (19.12%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    5 / 28 (17.86%)
    1 / 6 (16.67%)
         occurrences all number
    2
    21
    0
    1
    5
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    7 / 68 (10.29%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
    3 / 28 (10.71%)
    0 / 6 (0.00%)
         occurrences all number
    0
    11
    0
    3
    3
    0
    Decreased appetite
         subjects affected / exposed
    4 / 12 (33.33%)
    25 / 68 (36.76%)
    4 / 8 (50.00%)
    4 / 12 (33.33%)
    13 / 28 (46.43%)
    0 / 6 (0.00%)
         occurrences all number
    4
    29
    5
    4
    14
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 68 (1.47%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    4 / 12 (33.33%)
    28 / 68 (41.18%)
    3 / 8 (37.50%)
    3 / 12 (25.00%)
    8 / 28 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    6
    34
    4
    4
    12
    2
    Hyponatraemia
         subjects affected / exposed
    7 / 12 (58.33%)
    37 / 68 (54.41%)
    4 / 8 (50.00%)
    6 / 12 (50.00%)
    13 / 28 (46.43%)
    4 / 6 (66.67%)
         occurrences all number
    8
    54
    6
    8
    15
    4
    Hypomagnesaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    22 / 68 (32.35%)
    3 / 8 (37.50%)
    2 / 12 (16.67%)
    5 / 28 (17.86%)
    0 / 6 (0.00%)
         occurrences all number
    0
    29
    3
    3
    6
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 68 (1.47%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
    1 / 28 (3.57%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    1
    0
    1
    2
    Hypoglycaemia
         subjects affected / exposed
    2 / 12 (16.67%)
    9 / 68 (13.24%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
    2 / 28 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    4
    9
    2
    0
    3
    0
    Hypochloraemia
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 68 (4.41%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    6 / 12 (50.00%)
    34 / 68 (50.00%)
    6 / 8 (75.00%)
    4 / 12 (33.33%)
    9 / 28 (32.14%)
    2 / 6 (33.33%)
         occurrences all number
    6
    53
    8
    4
    12
    2
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 12 (50.00%)
    36 / 68 (52.94%)
    6 / 8 (75.00%)
    6 / 12 (50.00%)
    11 / 28 (39.29%)
    2 / 6 (33.33%)
         occurrences all number
    6
    45
    7
    7
    14
    2
    Hyperuricaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 68 (2.94%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
    0 / 28 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    1
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    6 / 12 (50.00%)
    26 / 68 (38.24%)
    3 / 8 (37.50%)
    3 / 12 (25.00%)
    9 / 28 (32.14%)
    3 / 6 (50.00%)
         occurrences all number
    8
    39
    5
    3
    13
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2015
    Clarified the correlative sample processing instructions and Endocrine and Autoimmune observations have been modified and the total required blood volumes have been significantly reduced.
    30 Oct 2015
    Added guidelines for management of pleural effusion as well as to add an additional cohort to Part B for enrollment of patients with relapsed or refractory neuroblastoma who are evaluable only for MIBG response. Also, a non-statistical cohort for melanoma patients was added.
    07 Jul 2016
    Added Part D. Additionally, the eligibility criteria have been modified to permit enrollment of patients with lymphoma who have previously received an allogeneic stem cell transplant.
    17 Jan 2017
    Updated the versions of the Comprehensive Adverse Events and Potential Risks (CAEPR) list.
    24 Feb 2017
    Stopping rules were added for the incidence of GVHD in lymphoma patients who enrolled following allogeneic stem cell transplant. Also, assessment of cardiac function, was added given the occurrence of myocarditis in patients using combination Ipi/Nivo in other studies.
    09 Aug 2018
    The revised toxicity profile (CAEPR) has been inserted in the protocol, and the associated risk information in the informed consent document has been revised accordingly. This amendment also reflected the conversion of the protocol to CTCAE version 5.0.
    02 Apr 2019
    Added a new arm (Part E) to explore a different combination of nivolumab and ipilimumab in patients with rhabdomyosarcoma or Ewing Sarcoma/Peripheral PNET.
    23 May 2019
    Revised CAEPR for ipilimumab has been inserted in the protocol, and the associated risk information in the informed consent documents has been revised accordingly.
    31 Jul 2019
    This protocol has been amended to update the infusion time of nivolumab from 60 min to 30 min. Ipilimumab was infused over 90 min.
    20 Feb 2020
    Nivolumab drug information has been updated also included the addition of preclinical biomarker study information.
    30 Mar 2020
    Included the addition of off-study criteria for Part E patients.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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