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    Clinical Trial Results:
    A Safety and Pharmacokinetic Study of Single Agent REGN2810 in Pediatric Patients with Relapsed or Refractory Solid or Central Nervous System (CNS) Tumors and a Safety and Efficacy Trial of REGN2810 in Combination with Radiotherapy in Pediatric Patients with Newly Diagnosed Diffuse Intrinsic Pontine Glioma, Newly Diagnosed High-Grade Glioma, or Recurrent High-Grade Glioma

    Summary
    EudraCT number
    		 2023-000604-19
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    10 May 2023

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    R2810-ONC-1690
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03690869
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Pacific Pediatric Neuro-Oncology Consortium (PNOC): PNOC 013 (CC#160825)
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals Inc.
    Sponsor organisation address
    777 Old Saw Mill River Road, Tarrytown, United States, NY 10591
    Public contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals Inc., 001 844-734-6643, clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals Inc., 001 844-734-6643, clinicaltrials@regeneron.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002007-PIP02-17
    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
    10 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To confirm the safety, characterize the pharmacokinetics (PK) and anticipate recommended phase 2 dose (RP2D) of REGN2810 for children with recurrent or refractory solid or CNS tumors To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with conventionally fractionated or hypofractionated radiation among participants with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG) and with re-irradiation in participants with recurrent HGG To assess PK of REGN2810 in pediatric participants with newly diagnosed DIPG, newly diagnosed HGG, or recurrent HGG when given in combination with radiation To assess anti-tumor activity of REGN2810 in combination with radiation in improving overall survival at 12 months (OS12) among participants with newly diagnosed DIPG and recurrent HGG and in improving progression-free survival at 12 months (PFS12) among participants with newly diagnosed HGG
    Protection of trial subjects
    It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 57
    Worldwide total number of subjects
    57
    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)
    21
    Adolescents (12-17 years)
    27
    Adults (18-64 years)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 65 participants had been screened and 57 participants had been enrolled and had received at least 1 dose of REGN2810 at time of study termination (Sponsor decision)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Solid Tumors (Phase 1)
    Arm description
    		 Participants with recurrent or refractory solid tumors received REGN2810 intravenous (IV) infusion every 2 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    cemiplimab (monotherapy)
    Investigational medicinal product code
    REGN2810
    Other name
    Libtayo
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously as monotherapy in Phase 1

    Arm title
    		 CNS Tumors (Phase 1)
    Arm description
    		 Participants with recurrent or refractory Central Nervous System (CNS) tumors received REGN2810 IV infusion every 2 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    cemiplimab (monotherapy)
    Investigational medicinal product code
    REGN2810
    Other name
    Libtayo
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously as monotherapy in Phase 1

    Arm title
    		 Newly Diagnosed DIPG (ndDIPG) (Efficacy Phase)
    Arm description
    		 Participants with newly diagnosed Diffuse Intrinsic Pontine Glioma (ndDIPG) received combination REGN2810 IV infusion + radiation therapy (conventionally fractionated radiation therapy [CRT] or hypofractionated radiation therapy [HYRT])
    Arm type
    		 Experimental

    Investigational medicinal product name
    cemiplimab (maintenance)
    Investigational medicinal product code
    REGN2810
    Other name
    Libtayo
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously in combination with radiation and then used as maintenance therapy

    Arm title
    		 Newly Diagnosed HGG (ndHGG) (Efficacy Phase)
    Arm description
    		 Participants with newly diagnosed High-grade Glioma (ndHGG) received combination REGN2810 IV infusion + radiation therapy (CRT or HYRT)
    Arm type
    		 Experimental

    Investigational medicinal product name
    cemiplimab (maintenance)
    Investigational medicinal product code
    REGN2810
    Other name
    Libtayo
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously in combination with radiation and then used as maintenance therapy

    Arm title
    		 Recurrent HGG (rHGG) (Efficacy Phase)
    Arm description
    		 Participants with rHGG received combination REGN2810 IV infusion + radiation therapy (CRT or HYRT)
    Arm type
    		 Experimental

    Investigational medicinal product name
    cemiplimab (maintenance)
    Investigational medicinal product code
    REGN2810
    Other name
    Libtayo
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously in combination with radiation and then used as maintenance therapy

    Number of subjects in period 1
    		Solid Tumors (Phase 1) CNS Tumors (Phase 1) Newly Diagnosed DIPG (ndDIPG) (Efficacy Phase) Newly Diagnosed HGG (ndHGG) (Efficacy Phase) Recurrent HGG (rHGG) (Efficacy Phase)
    Started
    8
    17
    11
    12
    9
    Completed
    0
    0
    0
    1
    0
    Not completed
    8
    17
    11
    11
    9
         Physician decision
    1
    -
    -
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    1
    1
         Subject decision
    -
    1
    -
    1
    -
         Death
    2
    7
    8
    2
    3
         Other
    2
    6
    3
    7
    3
         Progressive Disease
    3
    1
    -
    -
    2
         Lost to follow-up
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Solid Tumors (Phase 1)
    Reporting group description
    		 Participants with recurrent or refractory solid tumors received REGN2810 intravenous (IV) infusion every 2 weeks

    Reporting group title
    CNS Tumors (Phase 1)
    Reporting group description
    		 Participants with recurrent or refractory Central Nervous System (CNS) tumors received REGN2810 IV infusion every 2 weeks

    Reporting group title
    Newly Diagnosed DIPG (ndDIPG) (Efficacy Phase)
    Reporting group description
    		 Participants with newly diagnosed Diffuse Intrinsic Pontine Glioma (ndDIPG) received combination REGN2810 IV infusion + radiation therapy (conventionally fractionated radiation therapy [CRT] or hypofractionated radiation therapy [HYRT])

    Reporting group title
    Newly Diagnosed HGG (ndHGG) (Efficacy Phase)
    Reporting group description
    		 Participants with newly diagnosed High-grade Glioma (ndHGG) received combination REGN2810 IV infusion + radiation therapy (CRT or HYRT)

    Reporting group title
    Recurrent HGG (rHGG) (Efficacy Phase)
    Reporting group description
    		 Participants with rHGG received combination REGN2810 IV infusion + radiation therapy (CRT or HYRT)

    Reporting group values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) Newly Diagnosed DIPG (ndDIPG) (Efficacy Phase) Newly Diagnosed HGG (ndHGG) (Efficacy Phase) Recurrent HGG (rHGG) (Efficacy Phase) Total
    Number of subjects
    		 8 17 11 12 9 57
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 3 12 6 0 1 22
        Adolescents (12-17 years)
    		 5 5 3 9 5 27
        Adults (18-64 years)
    		 0 0 2 3 3 8
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.0 ( 4.60 ) 9.5 ( 4.05 ) 9.6 ( 5.87 ) 16.4 ( 3.63 ) 15.3 ( 3.94 ) -
    Gender Categorical
    Units: Subjects
        Male
    		 5 10 3 8 6 32
        Female
    		 3 7 8 4 3 25

    End points

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    End points reporting groups
    Reporting group title
    Solid Tumors (Phase 1)
    Reporting group description
    		 Participants with recurrent or refractory solid tumors received REGN2810 intravenous (IV) infusion every 2 weeks

    Reporting group title
    CNS Tumors (Phase 1)
    Reporting group description
    		 Participants with recurrent or refractory Central Nervous System (CNS) tumors received REGN2810 IV infusion every 2 weeks

    Reporting group title
    Newly Diagnosed DIPG (ndDIPG) (Efficacy Phase)
    Reporting group description
    		 Participants with newly diagnosed Diffuse Intrinsic Pontine Glioma (ndDIPG) received combination REGN2810 IV infusion + radiation therapy (conventionally fractionated radiation therapy [CRT] or hypofractionated radiation therapy [HYRT])

    Reporting group title
    Newly Diagnosed HGG (ndHGG) (Efficacy Phase)
    Reporting group description
    		 Participants with newly diagnosed High-grade Glioma (ndHGG) received combination REGN2810 IV infusion + radiation therapy (CRT or HYRT)

    Reporting group title
    Recurrent HGG (rHGG) (Efficacy Phase)
    Reporting group description
    		 Participants with rHGG received combination REGN2810 IV infusion + radiation therapy (CRT or HYRT)

    Subject analysis set title
    ndDIPG: REGN2810 + HYRT (Efficacy Phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with ndDIPG received combination REGN2810 IV infusion + hypofractionated radiation therapy (HYRT)

    Subject analysis set title
    ndDIPG: REGN2810 + CRT (Efficacy Phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with newly diagnosed diffuse Intrinsic pontine glioma (ndDIPG) received combination REGN2810 IV infusion + conventionally fractionated radiation therapy (CRT)

    Subject analysis set title
    ndHGG: REGN2810 + HYRT (Efficacy Phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with ndHGG received combination REGN2810 IV infusion + HYRT

    Subject analysis set title
    ndHGG: REGN2810 + CRT (Efficacy Phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with newly diagnosed high-grade glioma (ndHGG) received combination REGN2810 IV infusion + CRT

    Subject analysis set title
    rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with rHGG received combination REGN2810 IV infusion + radiation therapy (CRT or HYRT)

    Subject analysis set title
    Cohort A Phase 1 ST (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (0 to <12 years) with recurrent or refractory solid tumors (ST); Dose limiting toxicity analysis set (DLT AS)

    Subject analysis set title
    Cohort B Phase 1 ST (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to <18 years) with recurrent or refractory ST; DLT analysis set

    Subject analysis set title
    Cohort C Phase 1 CNS (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (0 to <12 years) with recurrent or refractory Central Nervous System (CNS) tumors; DLT analysis set

    Subject analysis set title
    Cohort D Phase 1 CNS (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to <18 years) with recurrent or refractory CNS tumors; DLT analysis set

    Subject analysis set title
    Cohort E Efficacy Phase ndDIPG (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (3 to <12 years) with ndDIPG; DLT analysis set

    Subject analysis set title
    Cohort F Efficacy Phase ndDIPG (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to 25 years) with ndDIPG; DLT analysis set

    Subject analysis set title
    Cohort H Efficacy Phase ndHGG (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to 25 years) with ndHGG; DLT analysis set

    Subject analysis set title
    Cohort I Efficacy Phase rHGG (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (3 to <12 years) with rHGG; DLT analysis set

    Subject analysis set title
    Cohort J Efficacy Phase rHGG (DLT AS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to 25 years) with rHGG; DLT analysis set

    Subject analysis set title
    Phase 1: 3mg/kg Q2W (AAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received REGN2810 3 milligrams/kilogram (mg/kg) once every 2 weeks (Q2W); anti-drug antibody analysis set (AAS)

    Subject analysis set title
    Phase 1: 4.5mg/kg Q2W (AAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received REGN2810 4.5mg/kg Q2W; AAS

    Subject analysis set title
    Efficacy Phase: 3mg/kg Q2W (AAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received REGN2810 3mg/kg Q2W + radiation therapy (CRT or HYRT); AAS

    Subject analysis set title
    Efficacy Phase: 4.5mg/kg Q2W (AAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received REGN2810 4.5mg/kg Q2W + radiation therapy (CRT or HYRT); AAS

    Subject analysis set title
    Cohort A Phase 1 ST 3mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (0 to <12 years) with recurrent or refractory ST received REGN2810 3mg/kg Q2W; Pharmacokinetic Analysis Set (PKAS)

    Subject analysis set title
    Cohort B Phase 1 ST 3mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to <18 years) with recurrent or refractory ST received REGN2810 3mg/kg Q2W; PKAS

    Subject analysis set title
    Cohort C Phase 1 CNS 3mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (0 to <12 years) with recurrent or refractory CNS tumors received REGN2810 3mg/kg Q2W; PKAS

    Subject analysis set title
    Cohort D Phase 1 CNS 3mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to <18 years) with recurrent or refractory CNS received REGN2810 3mg/kg Q2W; PKAS

    Subject analysis set title
    Cohort C Phase 1 CNS 4.5mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (0 to <12 years) with recurrent or refractory CNS tumors received REGN2810 4.5mg/kg Q2W; PKAS

    Subject analysis set title
    Cohort F Efficacy Phase ndDIPG 3mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to 25 years) with ndDIPG received REGN2810 3mg/kg Q2W; PKAS

    Subject analysis set title
    Cohort H Efficacy Phase ndHGG 3mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to 25 years) with ndHGG received REGN2810 3mg/kg Q2W; PKAS

    Subject analysis set title
    Cohort J Efficacy Phase rHGG 3mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (12 to 25 years) with rHGG received REGN2810 3mg/kg Q2W; PKAS

    Subject analysis set title
    Cohort E Efficacy Phase ndDIPG 4.5mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (3 to <12 years) with ndDIPG received REGN2810 4.5mg/kg Q2W; PKAS

    Subject analysis set title
    Cohort I Efficacy Phase rHGG 4.5mg/kg Q2W (PKAS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants (3 to <12 years) with rHGG received REGN2810 4.5mg/kg Q2W; PKAS

    Primary: Number of treatment-emergent adverse events (TEAEs)

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    End point title
    		 Number of treatment-emergent adverse events (TEAEs) [1] [2]
    End point description
    Safety analysis set (SAF): All enrolled participants who have received any study treatment (at least one dose of any component of study treatment in a combination therapy) in each study phase. Participants analyzed according to the study treatment received (as treated).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 90 days after the last dose of study treatment (up to 36 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    [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: Reporting includes subject analysis sets
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    8
    17
    6
    5
    5
    7
    9
    Units: Events
    61
    129
    148
    62
    94
    128
    203
    No statistical analyses for this end point

    Primary: Number of severe (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Grade 3/4/5) TEAEs

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    End point title
    		 Number of severe (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Grade 3/4/5) TEAEs [3] [4]
    End point description
    NCI CTCAE version 4.0 was utilized for AE grading of severity: Grade 1 (Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Safety analysis set (SAF): All enrolled participants who have received any study treatment (at least one dose of any component of study treatment in a combination therapy) in each study phase. Participants analyzed according to the study treatment received (as treated). Number of NCI grade 3/4/5 Treatment-Emergent Adverse Events (AEs) reported
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 90 days after the last dose of study treatment (up to 36 months)
    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: Descriptive statistics only
    [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: Reporting includes subject analysis sets
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    8
    17
    6
    5
    5
    7
    9
    Units: Events
    8
    13
    20
    13
    6
    13
    20
    No statistical analyses for this end point

    Primary: Number of treatment-emergent sponsor identified immune-related adverse events (irAEs)

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    End point title
    		 Number of treatment-emergent sponsor identified immune-related adverse events (irAEs) [5] [6]
    End point description
    SAF: All enrolled participants who have received any study treatment (at least one dose of any component of study treatment in a combination therapy) in each study phase. Participants analyzed according to the study treatment received (as treated).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 90 days after the last dose of study treatment (up to 36 months)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting includes subject analysis sets
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    8
    17
    6
    5
    5
    7
    9
    Units: Events
    1
    0
    3
    4
    5
    4
    9
    No statistical analyses for this end point

    Primary: Number of severe (NCI CTCAE Grade 3/4/5) treatment-emergent sponsor identified irAEs

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    End point title
    		 Number of severe (NCI CTCAE Grade 3/4/5) treatment-emergent sponsor identified irAEs [7] [8]
    End point description
    NCI CTCAE v. 4.0 was utilized for AE grading of severity: Grade 1 (Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). SAF: All enrolled participants who have received any study treatment (at least one dose of any component of study treatment in a combination therapy) in each study phase. Participants analyzed according to the study treatment received (as treated).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 90 days after the last dose of study treatment (up to 36 months)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting includes subject analysis sets
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    8
    17
    6
    5
    5
    7
    9
    Units: Events
    0
    0
    1
    2
    0
    2
    1
    No statistical analyses for this end point

    Primary: Number of adverse events of special interest (AESIs)

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    End point title
    		 Number of adverse events of special interest (AESIs) [9] [10]
    End point description
    AESIs for this study include any AE (NCI CTCAE v.4.0) that meets dose-limiting toxicity (DLT) criteria, Grade 2 ≤ infusion-related reactions, Grade 2 ≤ allergic/hypersensitivity reactions, Grade 3 ≤ immune-related AE (irAE) (or grade 2 ≤ Uveitis). (NCI CTCAE v. 4.0 AE grading of severity: Grade 1 [Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated]; Grade 2 [Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL]; Grade 3 [Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL]; Grade 4 [Life-threatening consequences; urgent intervention indicated]; Grade 5 [Death related to AE]). SAF: All enrolled participants who received any study treatment in each study phase. Participants analyzed according to treatment received (as treated).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 90 days after the last dose of study treatment (up to 36 months)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting includes subject analysis sets
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    8
    17
    6
    5
    5
    7
    9
    Units: Events
    0
    1
    2
    5
    2
    2
    8
    No statistical analyses for this end point

    Primary: Number of severe (NCI CTCAE Grade 3/4/5) AESIs

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    End point title
    		 Number of severe (NCI CTCAE Grade 3/4/5) AESIs [11] [12]
    End point description
    AESIs for this study include any AE (NCI CTCAE v.4.0) that meets dose-limiting toxicity (DLT) criteria, Grade 2 ≤ infusion-related reactions, Grade 2 ≤ allergic/hypersensitivity reactions, Grade 3 ≤ immune-related AE (irAE) (or grade 2 ≤ Uveitis). (NCI CTCAE v. 4.0 AE grading of severity: Grade 1 [Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated]; Grade 2 [Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL]; Grade 3 [Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL]; Grade 4 [Life-threatening consequences; urgent intervention indicated]; Grade 5 [Death related to AE]). SAF: All enrolled participants who received any study treatment in each study phase. Participants analyzed according to treatment received (as treated).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 90 days after the last dose of study treatment (up to 36 months)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting includes subject analysis sets
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    8
    17
    6
    5
    5
    7
    9
    Units: Events
    0
    1
    1
    3
    2
    2
    6
    No statistical analyses for this end point

    Primary: Number of deaths

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    End point title
    		 Number of deaths [13] [14]
    End point description
    SAF: All enrolled participants who have received any study treatment (at least one dose of any component of study treatment in a combination therapy) in each study phase. Participants analyzed according to the study treatment received (as treated).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 90 days after the last dose of study treatment (up to 36 months)
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting includes subject analysis sets
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    8
    17
    6
    5
    5
    7
    9
    Units: Deaths
    6
    13
    5
    5
    3
    4
    6
    No statistical analyses for this end point

    Primary: Number of participants with at least one lab abnormality (NCI-CTCAE All Grades) in Hematology, Electrolytes, Liver, Chemistry

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    End point title
    		 Number of participants with at least one lab abnormality (NCI-CTCAE All Grades) in Hematology, Electrolytes, Liver, Chemistry [15] [16]
    End point description
    Number of participants with New or Worsened laboratory abnormalities (NCI-CTCAE All Grades) reported in Hematology, Electrolytes, Liver, Chemistry; NCI CTAE v. 4.0: Grade 1 (Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). SAF: All enrolled participants who have received any study treatment (at least one dose of any component of study treatment in a combination therapy) in each study phase. Participants analyzed according to the study treatment received (as treated).
    End point type
    Primary
    End point timeframe
    Up to 36 months
    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: Descriptive statistics only
    [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: Reporting includes subject analysis sets
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    8
    17
    6
    5
    5
    6
    9
    Units: Participants
        ≥ 1 lab abnormality (All Grades) Hematology
    7
    13
    5
    5
    5
    6
    9
        ≥ 1 lab abnormality (All Grades) Electrolytes
    6
    7
    6
    4
    3
    6
    8
        ≥ 1 lab abnormality (All Grades) Liver
    3
    8
    6
    3
    1
    6
    6
        ≥ 1 lab abnormality (All Grades) Chemistry
    8
    13
    5
    5
    5
    5
    8
    No statistical analyses for this end point

    Primary: Number of participants who developed dose limiting toxicities (DLTs) (Phase 1)

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    End point title
    		 Number of participants who developed dose limiting toxicities (DLTs) (Phase 1) [17]
    End point description
    Dose limiting toxicity analysis set, Phase 1: All DLT-evaluable participants treated with monotherapy cemiplimab. DLT evaluable participants are defined as those participants who have completed the corresponding DLT observation period and those participants who discontinued early due to the development of a DLT.
    End point type
    Primary
    End point timeframe
    Baseline to 28 days
    Notes
    [17] - 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: Descriptive statistics only
    End point values
    		 Cohort A Phase 1 ST (DLT AS) Cohort B Phase 1 ST (DLT AS) Cohort C Phase 1 CNS (DLT AS) Cohort D Phase 1 CNS (DLT AS)
    Number of subjects analysed
    2
    5
    9
    5
    Units: Participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of participants who developed DLTs (Efficacy Phase)

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    End point title
    		 Number of participants who developed DLTs (Efficacy Phase) [18]
    End point description
    Efficacy Phase: The first 6 DLT-evaluable participants of each disease cohort by age group who are treated with cemiplimab + radiotherapy during 3+3 safety run-in. DLT evaluable participants are defined as those who have completed the corresponding DLT observation period and those participants who discontinued early due to the development of a DLT.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks post radiation therapy
    Notes
    [18] - 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: Descriptive statistics only
    End point values
    		 Cohort E Efficacy Phase ndDIPG (DLT AS) Cohort F Efficacy Phase ndDIPG (DLT AS) Cohort H Efficacy Phase ndHGG (DLT AS) Cohort I Efficacy Phase rHGG (DLT AS) Cohort J Efficacy Phase rHGG (DLT AS)
    Number of subjects analysed
    6
    5
    6
    1
    6
    Units: Participants
    1
    1
    0
    0
    1
    No statistical analyses for this end point

    Primary: Elimination half-life (t1/2) of functional cemiplimab (REGN2810) in serum

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    End point title
    		 Elimination half-life (t1/2) of functional cemiplimab (REGN2810) in serum [19]
    End point description
    Pharmacokinetic Analysis Set (PKAS): All treated participants who received any amount of study drug (Safety Analysis Set [SAF]) and had at least 1 non-missing functional cemiplimab measurement following the first dose of cemiplimab up to the end of study. PKAS: Based on the actual treatment received (as treated)
    End point type
    Primary
    End point timeframe
    Up to 24 months
    Notes
    [19] - 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: Descriptive statistics only
    End point values
    		 Cohort A Phase 1 ST 3mg/kg Q2W (PKAS) Cohort B Phase 1 ST 3mg/kg Q2W (PKAS) Cohort C Phase 1 CNS 3mg/kg Q2W (PKAS) Cohort D Phase 1 CNS 3mg/kg Q2W (PKAS) Cohort C Phase 1 CNS 4.5mg/kg Q2W (PKAS) Cohort F Efficacy Phase ndDIPG 3mg/kg Q2W (PKAS) Cohort H Efficacy Phase ndHGG 3mg/kg Q2W (PKAS) Cohort J Efficacy Phase rHGG 3mg/kg Q2W (PKAS) Cohort E Efficacy Phase ndDIPG 4.5mg/kg Q2W (PKAS) Cohort I Efficacy Phase rHGG 4.5mg/kg Q2W (PKAS)
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    0 [26]
    0 [27]
    0 [28]
    0 [29]
    Units: milligrams/Liter (mg/L)
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [20] - t1/2 will be later estimated by population PK analysis (PopPK)
    [21] - t1/2 will be later estimated by population PK analysis (PopPK)
    [22] - t1/2 will be later estimated by population PK analysis (PopPK)
    [23] - t1/2 will be later estimated by population PK analysis (PopPK)
    [24] - t1/2 will be later estimated by population PK analysis (PopPK)
    [25] - t1/2 will be later estimated by population PK analysis (PopPK)
    [26] - t1/2 will be later estimated by population PK analysis (PopPK)
    [27] - t1/2 will be later estimated by population PK analysis (PopPK)
    [28] - t1/2 will be later estimated by population PK analysis (PopPK)
    [29] - t1/2 will be later estimated by population PK analysis (PopPK)
    No statistical analyses for this end point

    Primary: Trough concentration (Ctrough) of functional cemiplimab (REGN2810) in serum

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    End point title
    		 Trough concentration (Ctrough) of functional cemiplimab (REGN2810) in serum [30]
    End point description
    Ctrough (trough concentration) of functional cemiplimab in serum; Pharmacokinetic analysis set (PKAS): All treated participants who received any amount of study drug (SAF) and had at least 1 non-missing functional cemiplimab measurement following the first dose of cemiplimab up to the end of study (based on actual treatment received [as treated]).
    End point type
    Primary
    End point timeframe
    Up to 24 months
    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: Descriptive statistics only
    End point values
    		 Cohort A Phase 1 ST 3mg/kg Q2W (PKAS) Cohort B Phase 1 ST 3mg/kg Q2W (PKAS) Cohort C Phase 1 CNS 3mg/kg Q2W (PKAS) Cohort D Phase 1 CNS 3mg/kg Q2W (PKAS) Cohort C Phase 1 CNS 4.5mg/kg Q2W (PKAS) Cohort F Efficacy Phase ndDIPG 3mg/kg Q2W (PKAS) Cohort H Efficacy Phase ndHGG 3mg/kg Q2W (PKAS) Cohort J Efficacy Phase rHGG 3mg/kg Q2W (PKAS) Cohort E Efficacy Phase ndDIPG 4.5mg/kg Q2W (PKAS) Cohort I Efficacy Phase rHGG 4.5mg/kg Q2W (PKAS)
    Number of subjects analysed
    3 [31]
    5 [32]
    3 [33]
    5 [34]
    8 [35]
    4 [36]
    11 [37]
    5 [38]
    6 [39]
    1 [40]
    Units: mg/L
    median (full range (min-max))
        Ctrough - after 1st dose
    16.7 (14.0 to 16.8)
    23.9 (21.1 to 27.2)
    33.8 (27.9 to 36.5)
    28.5 (19.6 to 42.2)
    48.3 (32.9 to 63.8)
    39.7 (33.9 to 41.9)
    26.0 (17.4 to 36.3)
    36.3 (25.2 to 178)
    35.8 (32.4 to 49.6)
    38.5 (38.5 to 38.5)
        Ctrough - week 16
    39.4 (39.4 to 39.4)
    78.6 (78.6 to 78.6)
    99999 (99999 to 99999)
    66.1 (66.1 to 66.1)
    113 (113 to 113)
    82.4 (65.7 to 104)
    94.3 (84.5 to 247)
    78.5 (57.0 to 134)
    122 (13.1 to 159)
    70.0 (70.0 to 70.0)
    Notes
    [31] - week 16 n = 1, Median value = Full Range (min-max) value
    [32] - week 16 n = 1, Median value = Full Range (min-max) value
    [33] - week 16 n = 0
    [34] - week 16 n = 1
    [35] - week 16 n = 1
    [36] - week 16 n = 4
    [37] - week 16 n = 7
    [38] - week 16 n = 5
    [39] - week 16 n = 5
    [40] - n = 1; Median value = Full Range (min-max) value
    No statistical analyses for this end point

    Primary: Peak concentration (Cmax) of functional cemiplimab (REGN2810) in serum

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    End point title
    		 Peak concentration (Cmax) of functional cemiplimab (REGN2810) in serum [41]
    End point description
    Cmax (peak concentration) of functional cemiplimab in serum; Pharmacokinetic Analysis Set (PKAS): All treated participants who received any amount of study drug (SAF) and had at least 1 non-missing functional cemiplimab measurement following the first dose of cemiplimab up to the end of study (based on actual treatment received [as treated]).
    End point type
    Primary
    End point timeframe
    Up to 24 months
    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: Descriptive statistics only
    End point values
    		 Cohort A Phase 1 ST 3mg/kg Q2W (PKAS) Cohort B Phase 1 ST 3mg/kg Q2W (PKAS) Cohort C Phase 1 CNS 3mg/kg Q2W (PKAS) Cohort D Phase 1 CNS 3mg/kg Q2W (PKAS) Cohort C Phase 1 CNS 4.5mg/kg Q2W (PKAS) Cohort F Efficacy Phase ndDIPG 3mg/kg Q2W (PKAS) Cohort H Efficacy Phase ndHGG 3mg/kg Q2W (PKAS) Cohort J Efficacy Phase rHGG 3mg/kg Q2W (PKAS) Cohort E Efficacy Phase ndDIPG 4.5mg/kg Q2W (PKAS) Cohort I Efficacy Phase rHGG 4.5mg/kg Q2W (PKAS)
    Number of subjects analysed
    3 [42]
    5 [43]
    3 [44]
    5 [45]
    9 [46]
    4 [47]
    11 [48]
    5 [49]
    6 [50]
    1 [51]
    Units: mg/L
    median (full range (min-max))
        Cmax - after 1st dose
    58.2 (52.0 to 86.9)
    73.5 (63.4 to 87.9)
    92.2 (87.9 to 101)
    68.3 (60.9 to 101)
    152 (76.0 to 202)
    95.1 (65.5 to 106)
    71.8 (6.41 to 88.0)
    88.8 (69.5 to 124)
    105 (93.7 to 130)
    123 (123 to 123)
        Cmax - week 16
    122 (122 to 122)
    136 (136 to 136)
    144 (144 to 144)
    112 (112 to 112)
    236 (236 to 236)
    221 (164 to 256)
    165 (143 to 200)
    179 (119 to 234)
    209 (99.2 to 297)
    225 (225 to 225)
    Notes
    [42] - week 16 n = 1, Median value = Full Range (min-max) value
    [43] - week 16 n = 1, Median value = Full Range (min-max) value
    [44] - week 16 n = 1, Median value = Full Range (min-max) value
    [45] - week 16 n = 1, Median value = Full Range (min-max) value
    [46] - week 16 n = 1, Median value = Full Range (min-max) value
    [47] - week 16 n = 4
    [48] - week 16 n = 8
    [49] - week 16 n = 5
    [50] - week 16 n = 5
    [51] - n =1, Median value = Full Range (min-max) value
    No statistical analyses for this end point

    Primary: Area under the concentration-time curve (AUC) of functional cemiplimab (REGN2810) in serum

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    End point title
    		 Area under the concentration-time curve (AUC) of functional cemiplimab (REGN2810) in serum [52]
    End point description
    Pharmacokinetic Analysis Set (PKAS): All treated participants who received any amount of study drug (SAF) and had at least 1 non-missing functional cemiplimab measurement following the first dose of cemiplimab up to the end of study. PKAS: Based on the actual treatment received (as treated)
    End point type
    Primary
    End point timeframe
    Up to 24 months
    Notes
    [52] - 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: Descriptive statistics only
    End point values
    		 Cohort A Phase 1 ST 3mg/kg Q2W (PKAS) Cohort B Phase 1 ST 3mg/kg Q2W (PKAS) Cohort C Phase 1 CNS 3mg/kg Q2W (PKAS) Cohort D Phase 1 CNS 3mg/kg Q2W (PKAS) Cohort C Phase 1 CNS 4.5mg/kg Q2W (PKAS) Cohort F Efficacy Phase ndDIPG 3mg/kg Q2W (PKAS) Cohort H Efficacy Phase ndHGG 3mg/kg Q2W (PKAS) Cohort J Efficacy Phase rHGG 3mg/kg Q2W (PKAS) Cohort E Efficacy Phase ndDIPG 4.5mg/kg Q2W (PKAS) Cohort I Efficacy Phase rHGG 4.5mg/kg Q2W (PKAS)
    Number of subjects analysed
    0 [53]
    0 [54]
    0 [55]
    0 [56]
    0 [57]
    0 [58]
    0 [59]
    0 [60]
    0 [61]
    0 [62]
    Units: mg/L
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [53] - AUC will be later estimated by population PK analysis (PopPK)
    [54] - AUC will be later estimated by PopPK
    [55] - AUC will be later estimated by PopPK
    [56] - AUC will be later estimated by PopPK
    [57] - AUC will be later estimated by PopPK
    [58] - AUC will be later estimated by PopPK
    [59] - AUC will be later estimated by PopPK
    [60] - AUC will be later estimated by PopPK
    [61] - AUC will be later estimated by PopPK
    [62] - AUC will be later estimated by PopPK
    No statistical analyses for this end point

    Primary: Overall survival (OS) rate at 12 months for participants with newly diagnosed DIPG and recurrent HGG

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    End point title
    		 Overall survival (OS) rate at 12 months for participants with newly diagnosed DIPG and recurrent HGG [63]
    End point description
    OS is defined as the time from randomization to the date of death due to any cause. A participant who has not died will be censored at the last date that participant is documented to be alive; Full analysis set (FAS) (Efficacy Phase): All ndDIPG and ndHGG participants assigned to radiation treatment by Interactive web response system (IWRS) at randomization. Participants analyzed according to treatment assigned during randomization. Includes all screen-pass and eligible participants with rHGG; All deaths due to any cause occurring on/before cut-off date in the FAS were used in the OS analysis. A participant who had not died/was lost to follow up at time of analysis cut-off date was censored at last date participant was documented to be alive
    End point type
    Primary
    End point timeframe
    Up to 12 months
    Notes
    [63] - 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: Descriptive statistics only
    End point values
    		 ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndDIPG: REGN2810 + CRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Number of subjects analysed
    6
    5 [64]
    9
    Units: Percent of survival at 12 months
        number (confidence interval 95%)
    33.3 (4.6 to 67.6)
    0.0 (0 to 0)
    31.3 (4.8 to 64.1)
    Notes
    [64] - 0 to 0 Confidence Interval (95%) = Not evaluable
    No statistical analyses for this end point

    Primary: Progression-free survival (PFS) rate at 12 months for participants with newly diagnosed HGG

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    End point title
    		 Progression-free survival (PFS) rate at 12 months for participants with newly diagnosed HGG [65]
    End point description
    PFS at 12 months; FAS includes two parts: All ndDIPG and ndHGG participants to whom the radiation treatment has been assigned by the IWRS at randomization. This is the intent to treat (ITT) population for these two disease cohorts. Per ITT principle, these patients will be analyzed according to the treatment they have been assigned to during the randomization. All recurrent HGG patients who have pass screening and are deemed to be eligible for this study.
    End point type
    Primary
    End point timeframe
    At 12 months
    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: Descriptive statistics only
    End point values
    		 ndHGG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase)
    Number of subjects analysed
    5 [66]
    7
    Units: Percent of PFS at 12 months
        number (confidence interval 95%)
    99999 (99999 to 99999)
    20.0 (0.8 to 58.2)
    Notes
    [66] - 99999 = not evaluable
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    ORR is defined as the percentage of participants who have a confirmed complete response (CR) or partial response (PR), as determined per standard criteria between the date of first study treatment and the date of the first objectively documented progression or the date of receiving another anti-cancer systemic therapy, whichever came first.
    End point type
    Secondary
    End point timeframe
    Approximately 24 months
    End point values
    		 Solid Tumors (Phase 1) CNS Tumors (Phase 1) Newly Diagnosed DIPG (ndDIPG) (Efficacy Phase) Newly Diagnosed HGG (ndHGG) (Efficacy Phase) Recurrent HGG (rHGG) (Efficacy Phase)
    Number of subjects analysed
    8
    17
    11
    12
    9
    Units: Percentage of participants
        number (confidence interval 95%)
    0 (0.0 to 36.9)
    0 (0.0 to 19.5)
    0 (0.0 to 28.5)
    8.3 (0.2 to 38.5)
    0 (0.0 to 33.6)
    No statistical analyses for this end point

    Secondary: Number of participants with anti-REGN2810 antibodies (ADA)

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    End point title
    		 Number of participants with anti-REGN2810 antibodies (ADA)
    End point description
    ADA status classified as: Positive; Pre-existing (baseline [BL] sample positive & all post BL ADA titers reported as < 9-fold BL titer value); Negative (all samples negative); ADA positive: Treatment-boosted (positive result at BL with ≥1 post BL titer result ≥9-fold BL titer value); Treatment-emergent (TE) (negative result or missing result at BL with ≥1 positive post BL result); TE: Persistent (positive result detected in ≥2 consecutive post BL samples separated by ≥ a 12/16-week post BL period with no ADA-negative results in-between, regardless of any missing samples; Indeterminate (positive result in last collection, regardless of any missing samples); Transient (not persistent or indeterminate, regardless of any missing samples); ADA analysis set (AAS): all treated participants who received any amount of cemiplimab (SAF) & had ≥1 non-missing ADA result following first dose of cemiplimab (based on actual treatment received [as treated]).
    End point type
    Secondary
    End point timeframe
    1st follow-up visit, approximately 25 months
    End point values
    		 Phase 1: 3mg/kg Q2W (AAS) Phase 1: 4.5mg/kg Q2W (AAS) Efficacy Phase: 3mg/kg Q2W (AAS) Efficacy Phase: 4.5mg/kg Q2W (AAS)
    Number of subjects analysed
    16
    5
    19
    7
    Units: Participants
        Negative
    16
    5
    17
    6
        Pre-existing immunoreactivity
    0
    0
    1
    0
        Treatment-boosted response
    0
    0
    0
    0
        Treatment-emergent (TE) response
    0
    0
    1
    1
        - persistent TE response
    0
    0
    0
    0
        - transient TE response
    0
    0
    1
    1
        - indeterminate TE response
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 90 days after the last dose of study treatment (up to 36 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Solid Tumors: REGN2810 monotherapy (Phase 1)
    Reporting group description
    		 Participants with recurrent or refractory solid tumors received REGN2810 intravenous (IV) infusion every 2 weeks

    Reporting group title
    CNS Tumors: REGN2810 monotherapy (Phase 1)
    Reporting group description
    		 Participants with recurrent or refractory Central Nervous System (CNS) tumors received REGN2810 IV infusion every 2 weeks

    Reporting group title
    ndDIPG: REGN2810 + CRT (Efficacy Phase)
    Reporting group description
    		 Participants with newly diagnosed Diffuse Intrinsic Pontine Glioma (ndDIPG) received combination REGN2810 IV infusion + conventionally fractionated radiation therapy (CRT)

    Reporting group title
    ndDIPG: REGN2810 + HYRT (Efficacy Phase)
    Reporting group description
    		 Participants with ndDIPG received combination REGN2810 IV infusion + hypofractionated radiation therapy (HYRT)

    Reporting group title
    ndHGG: REGN2810 + CRT (Efficacy Phase)
    Reporting group description
    		 Participants with newly diagnosed High-grade Glioma (ndHGG) received combination REGN2810 IV infusion + CRT

    Reporting group title
    ndHGG: REGN2810 + HYRT (Efficacy Phase)
    Reporting group description
    		 Participants with ndHGG received combination REGN2810 IV infusion + HYRT

    Reporting group title
    rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Reporting group description
    		 Participants with rHGG received combination REGN2810 IV infusion + radiation therapy (CRT or HYRT)

    Serious adverse events
    		 Solid Tumors: REGN2810 monotherapy (Phase 1) CNS Tumors: REGN2810 monotherapy (Phase 1) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    2 / 5 (40.00%)
    4 / 6 (66.67%)
    5 / 7 (71.43%)
    2 / 5 (40.00%)
    5 / 9 (55.56%)
         number of deaths (all causes)
    6
    13
    5
    5
    4
    3
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pseudoprogression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Family stress
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Foreign body ingestion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    IIIrd nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Encephalitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    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
    		 Solid Tumors: REGN2810 monotherapy (Phase 1) CNS Tumors: REGN2810 monotherapy (Phase 1) ndDIPG: REGN2810 + CRT (Efficacy Phase) ndDIPG: REGN2810 + HYRT (Efficacy Phase) ndHGG: REGN2810 + CRT (Efficacy Phase) ndHGG: REGN2810 + HYRT (Efficacy Phase) rHGG: REGN2810 + CRT/HYRT (Efficacy Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    14 / 17 (82.35%)
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    5 / 5 (100.00%)
    9 / 9 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tumour pseudoprogression
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    3 / 5 (60.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    1
    4
    0
    2
    0
    3
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    1
    Hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    Pyrexia
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    2
    2
    0
    3
    3
    1
    3
    Catheter site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Face oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 8 (25.00%)
    7 / 17 (41.18%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    3 / 7 (42.86%)
    3 / 5 (60.00%)
    7 / 9 (77.78%)
         occurrences all number
    2
    9
    2
    1
    3
    5
    10
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gait disturbance
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Social circumstances
    Family stress
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 17 (11.76%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    1
    2
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    4
    0
    2
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Tachypnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Apnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Aspiration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Haemoptysis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Laryngeal inflammation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    1
    Respiratory tract congestion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Respiration abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pharyngeal ulceration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Laryngeal oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Libido decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Irritability
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    1
    Restlessness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Personality change
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Investigations
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    1
    Lipase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 17 (17.65%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    1
    2
    3
    5
    2
    0
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    2
    2
    3
    1
    0
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    0
    0
    4
    0
    4
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    4 / 9 (44.44%)
         occurrences all number
    4
    3
    1
    5
    6
    2
    7
    Weight decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    0
    2
    1
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    1
    0
    Amylase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    4
    0
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    4
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    5
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Haemoglobin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    2
    0
    1
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    3
    Protein total decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    4 / 7 (57.14%)
    0 / 5 (0.00%)
    4 / 9 (44.44%)
         occurrences all number
    2
    0
    0
    3
    7
    0
    5
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    3
    0
    0
    0
    Wound dehiscence
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    0
    Stoma site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Radiation skin injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    3
    1
    0
    0
    2
    Procedural site reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Incision site erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Pseudomeningocele
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    1
    0
    1
    1
    1
    Tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    Palpitations
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Diastolic dysfunction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    1
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 17 (23.53%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    4 / 7 (57.14%)
    1 / 5 (20.00%)
    4 / 9 (44.44%)
         occurrences all number
    0
    5
    4
    5
    7
    3
    4
    Seizure
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    4
    0
    0
    2
    1
    3
    Accessory nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    Facial nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 17 (23.53%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    6
    1
    1
    0
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    2
    Tremor
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    2
    Aphasia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Ataxia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    1
    Auditory nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hypoglossal nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Dysmetria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Glossopharyngeal nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hemiparesis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    Hydrocephalus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    Central nervous system necrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    IIIrd nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    1
    1
    1
    1
    Memory impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Muscle spasticity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Neuralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nystagmus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    VIth nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Trigeminal nerve disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    0
    Eosinophilia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Neutrophilia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Anaemia
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    5
    2
    0
    1
    2
    1
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    External ear pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Optic atrophy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    2
    Pupillary reflex impaired
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Photophobia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Papilloedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Eyelid function disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Visual impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 17 (23.53%)
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    5 / 5 (100.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    6
    5
    5
    1
    6
    1
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    5 / 9 (55.56%)
         occurrences all number
    0
    2
    2
    3
    0
    1
    6
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 17 (11.76%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    4 / 5 (80.00%)
    4 / 9 (44.44%)
         occurrences all number
    2
    3
    1
    2
    2
    8
    6
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    1
    2
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    2
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Anal incontinence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Colitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    1
    Dermatitis acneiform
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    2
    0
    1
    1
    1
    Alopecia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    5 / 7 (71.43%)
    3 / 5 (60.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    0
    6
    3
    1
    Urticaria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 5 (40.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Skin atrophy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    1
    2
    1
    1
    Rash macular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    Rash erythematous
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    Proteinuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Adrenal insufficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hyperthyroidism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    3 / 9 (33.33%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    5
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 17 (17.65%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    3
    0
    0
    3
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    0
    1
    0
    4
    2
    Back pain
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    2
    Muscle spasms
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    1
    0
    2
    0
    0
    Arthritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Costochondritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Muscle tightness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Vaginal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Skin candida
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Mucosal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    1
    2
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 17 (23.53%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    5
    0
    3
    1
    3
    2
    Decreased appetite
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 17 (17.65%)
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    3 / 9 (33.33%)
         occurrences all number
    2
    4
    3
    2
    0
    2
    4
    Hypomagnesaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    3
    Hypophosphataemia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 17 (11.76%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    3 / 7 (42.86%)
    1 / 5 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    3
    0
    1
    4
    2
    4
    Hypermagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 17 (11.76%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    0
    0
    Increased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 17 (5.88%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Alkalosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    4
    0
    2
    Hyperphosphataemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    2
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    0
    0
    3
    1
    0
    5
    Hypocalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    6
    Hypoglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 17 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2018
    Amendment 1: Revised study design; Added assessments; Added randomization to rHGG cohort; Updated safety information/oversight; Added a global stopping rule; Clarified how disease response will be determined in patients with neuroblastoma with both Metaiodobenzylguanidine (MIBG) avid disease and bone marrow involvement; Added International Neuroblastoma Response Criteria; Excluded urinary catecholamine levels from response assessment for participants with neuroblastoma; Clarified Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria; Corrected definition of progressive disease per RANO; Added treatment criteria; Added replacement criteria for non-evaluable participants
    04 Jun 2018
    Amendment 2: The primary objective of this amendment was to improve the applicability of our adverse event management guidelines to a pediatric population.
    19 Mar 2020
    Amendment 3: The aim of this amendment was to streamline the structure and language of the protocol, to improve the clarity of the study design, and consistency of study conduct. Additionally, changes that impact the design of the study have been made.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 May 2023
    As all efficacy cohorts for this study have now been closed due to the futility criteria, Regeneron as Sponsor in collaboration PNOC have made a decision to close the study to further enrollment.
    -

    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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    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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