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    Clinical Trial Results:
    Phase 1b/2 Study of Carfilzomib in Combination With Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia

    Summary
    EudraCT number
    		 2014-001633-84
    Trial protocol
    		 IT   GB   ES   FR   AT   DK   NL   SE   GR   PL   PT   BG   NO   CZ   RO  
    Global end of trial date
    28 Jun 2024

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Apr 2025
    First version publication date
    26 Dec 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CFZ008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02303821
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, United States,
    Public contact
    Amgen (EUROPE) GmbH, IHQ Medical Info-Clinical Trials, MedInfoInternational@amgen.com
    Scientific contact
    Amgen (EUROPE) GmbH, IHQ Medical Info-Clinical Trials, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001806-PIP04-19
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study were: - Phase 1b: To assess the safety and tolerability of carfilzomib, alone and in combination with induction chemotherapy, for the treatment of children with relapsed or refractory acute lymphoblastic leukemia (ALL) and to determine the maximum tolerated dose (MTD) of carfilzomib in combination with induction chemotherapy and to recommend a phase 2 dose of carfilzomib in combination with induction chemotherapy - Phase 2: to compare the rate of complete remission (CR) of relapsed or refractory pediatric ALL to treatment with carfilzomib with vincristine, dexamethasone, PEG-asparaginase, and daunorubicin (CFZVXLD) at the end of induction therapy to an appropriate external control selected from an observational study (Amgen 20180065).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Brazil: 24
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Chile: 1
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 6
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Saudi Arabia: 1
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Türkiye: 14
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Worldwide total number of subjects
    140
    EEA total number of subjects
    45
    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)
    7
    Children (2-11 years)
    87
    Adolescents (12-17 years)
    37
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were recruited in 32 countries, including Australia, Argentina, Brazil, Canada, France, Italy, Mexico, Spain, the UK, and the US, between February 2015 and June 2024.

    Pre-assignment
    Screening details
    		 Phase 2: After a 7-day screening, participants received VXLD (vincristine, PEG-asparaginase, daunorubicin, dexamethasone) with carfilzomib during a 28-day induction. One B-cell group participant did not receive carfilzomib and was excluded from the primary analysis. Participants were followed for up to 2 years post-treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b: Dose Escalation 1 (Dose A)
    Arm description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose A in combination with dexamethasone, mitoxantrone, polyethylene glycol (PEG-asparaginase, and vincristine (R3 dose escalation) IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) infusion

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Phase 1b: Dose Escalation 1 (Dose B)
    Arm description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose B in combination with R3 IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) infusion

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Phase 1b: Dose Escalation 2 (Dose B)
    Arm description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose B in combination with vincristine, dexamethasone, PEG-asparaginase, and daunorubicin (VXLD dose escalation) IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) infusion

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Phase 1b: Dose Escalation 2 (Dose C)
    Arm description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose C in combination with VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) infusion

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Phase 1b: Dose Escalation 2 (Dose D)
    Arm description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose D in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) infusion

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Phase 1b: Dose Escalation 2 (Dose E)
    Arm description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose E in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) infusion

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Phase 2: B-cell
    Arm description
    		 Eligible participants with relapsed or refractory ALL (B-cell) were treated with VXLD plus carfilzomib for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator’s discretion, be treated with 1 28-day consolidation cycle of Children’s Oncology group-modified Berlin-Frankfurt-Munster (BFM) therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and intrathecal (IT) therapy plus carfilzomib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) infusion

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Arm title
    		 Phase 2: T-cell
    Arm description
    		 Eligible participants with relapsed or refractory ALL (T-cell) were treated with VXLD plus carfilzomib for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator’s discretion, be treated with 1 28-day consolidation cycle of BFM therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and IT therapy plus carfilzomib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    Daunorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Investigational medicinal product name
    PEG-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Infusion

    Number of subjects in period 1
    		Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E) Phase 2: B-cell Phase 2: T-cell
    Started
    5
    6
    3
    7
    4
    10
    61
    44
    Received IP in induction therapy
    5
    6
    3
    7
    4
    10
    61
    44
    Received IP in consolidation therapy
    2 [1]
    1 [2]
    1 [3]
    5 [4]
    3 [5]
    3 [6]
    25
    20
    Completed
    5
    3
    3
    7
    4
    5
    19
    13
    Not completed
    0
    3
    0
    0
    0
    5
    42
    31
         Adverse event, serious fatal
    -
    2
    -
    -
    -
    3
    41
    29
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    -
    2
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    1
    -
         Protocol-specified criteria
    -
    1
    -
    -
    -
    1
    -
    -
         Decision by sponsor
    -
    -
    -
    -
    -
    1
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone indicates how many participants moved from the induction therapy to receive the IP in the consolidation therapy.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone indicates how many participants moved from the induction therapy to receive the IP in the consolidation therapy.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone indicates how many participants moved from the induction therapy to receive the IP in the consolidation therapy.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone indicates how many participants moved from the induction therapy to receive the IP in the consolidation therapy.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone indicates how many participants moved from the induction therapy to receive the IP in the consolidation therapy.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestone indicates how many participants moved from the induction therapy to receive the IP in the consolidation therapy.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b: Dose Escalation 1 (Dose A)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose A in combination with dexamethasone, mitoxantrone, polyethylene glycol (PEG-asparaginase, and vincristine (R3 dose escalation) IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 1 (Dose B)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose B in combination with R3 IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose B)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose B in combination with vincristine, dexamethasone, PEG-asparaginase, and daunorubicin (VXLD dose escalation) IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose C)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose C in combination with VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose D)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose D in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose E)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose E in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 2: B-cell
    Reporting group description
    		 Eligible participants with relapsed or refractory ALL (B-cell) were treated with VXLD plus carfilzomib for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator’s discretion, be treated with 1 28-day consolidation cycle of Children’s Oncology group-modified Berlin-Frankfurt-Munster (BFM) therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and intrathecal (IT) therapy plus carfilzomib.

    Reporting group title
    Phase 2: T-cell
    Reporting group description
    		 Eligible participants with relapsed or refractory ALL (T-cell) were treated with VXLD plus carfilzomib for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator’s discretion, be treated with 1 28-day consolidation cycle of BFM therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and IT therapy plus carfilzomib.

    Reporting group values
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E) Phase 2: B-cell Phase 2: T-cell Total
    Number of subjects
    		 5 6 3 7 4 10 61 44 140
    Age Categorical
    Units: Subjects
        < 1 month
    		 0 0 0 0 0 0 0 0 0
        1 month - <= 17 years
    		 5 6 3 7 3 9 57 41 131
        > 17 years
    		 0 0 0 0 1 1 4 3 9
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.60 ( 4.39 ) 7.50 ( 6.57 ) 11.33 ( 3.51 ) 6.57 ( 4.20 ) 14.75 ( 3.10 ) 8.57 ( 5.36 ) 9.04 ( 5.15 ) 10.59 ( 4.42 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 3 3 0 1 1 3 19 5 35
        Male
    		 2 3 3 6 3 7 42 39 105
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1 2 0 0 28 11 43
        Not Hispanic or Latino
    		 4 6 2 5 4 10 33 33 97
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 2 2 4
        Asian
    		 0 0 0 0 0 1 9 6 16
        Black or African American
    		 0 1 0 0 0 2 2 2 7
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0 0
        White
    		 5 5 2 7 3 6 38 33 99
        Other
    		 0 0 1 0 1 1 9 1 13
        Multiple
    		 0 0 0 0 0 0 1 0 1
        Unknown
    		 0 0 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b: Dose Escalation 1 (Dose A)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose A in combination with dexamethasone, mitoxantrone, polyethylene glycol (PEG-asparaginase, and vincristine (R3 dose escalation) IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 1 (Dose B)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose B in combination with R3 IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose B)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose B in combination with vincristine, dexamethasone, PEG-asparaginase, and daunorubicin (VXLD dose escalation) IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose C)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose C in combination with VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose D)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose D in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose E)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose E in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 2: B-cell
    Reporting group description
    		 Eligible participants with relapsed or refractory ALL (B-cell) were treated with VXLD plus carfilzomib for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator’s discretion, be treated with 1 28-day consolidation cycle of Children’s Oncology group-modified Berlin-Frankfurt-Munster (BFM) therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and intrathecal (IT) therapy plus carfilzomib.

    Reporting group title
    Phase 2: T-cell
    Reporting group description
    		 Eligible participants with relapsed or refractory ALL (T-cell) were treated with VXLD plus carfilzomib for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator’s discretion, be treated with 1 28-day consolidation cycle of BFM therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and IT therapy plus carfilzomib.

    Subject analysis set title
    Carfilzomib - Day 8 Induction Cycle (PK Analysis Set)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Eligible participants with relapsed or refractory acute lymphoblastic leukemia who had PK assessments on Day 8 of the induction cycle.

    Subject analysis set title
    Carfilzomib - Day 1 Consolidation Cycle (PK Analysis Set)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Eligible participants with relapsed or refractory acute lymphoblastic leukemia who had PK assessments on Day 1 of the consolidation cycle.

    Primary: Phase 1b: Number of Participants who Experienced Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Phase 1b: Number of Participants who Experienced Treatment-emergent Adverse Events (TEAEs) [1] [2]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. Treatment-related AEs (TRAEs) were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. A serious AE (SAE) was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
    End point type
    Primary
    End point timeframe
    From first dose of study treatment up to 30 days after the last dose of study treatment; median duration of carfilzomib treatment was 16 days.
    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: No additional statistical analysis was pre-specified for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E)
    Number of subjects analysed
    5 [3]
    6 [4]
    3 [5]
    7 [6]
    4 [7]
    10 [8]
    Units: Participants
        All TEAEs
    5
    6
    3
    7
    4
    9
        All fatal TEAEs
    0
    2
    0
    0
    0
    3
        All TRAEs
    5
    4
    3
    7
    4
    8
        All fatal TRAEs
    0
    0
    0
    0
    0
    1
        All SAEs
    4
    4
    3
    6
    4
    7
    Notes
    [3] - Phase 1b Safety Analysis Set.
    [4] - Phase 1b Safety Analysis Set.
    [5] - Phase 1b Safety Analysis Set.
    [6] - Phase 1b Safety Analysis Set.
    [7] - Phase 1b Safety Analysis Set.
    [8] - Phase 1b Safety Analysis Set.
    No statistical analyses for this end point

    Primary: Phase 1b: Number of Participants who Experienced Dose Limiting Toxicities (DLTs)

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    End point title
    		 Phase 1b: Number of Participants who Experienced Dose Limiting Toxicities (DLTs) [9] [10]
    End point description
    A DLT was defined as any of the following toxicities assessed by the investigator as possibly, probably, or definitely attributable to carfilzomib, with protocol defined exclusions: Any Grade 4 nonhematologic toxicity ≥ Grade 4 neutropenia or ≥ Grade 3 thrombocytopenia. Phase 1b DLT Evaluable Analysis Set: All participants who received all planned dose of carfilzomib and the chemotherapy backbone per protocol during the lead-in window and induction cycle, or received at least one dose of carfilzomib and the chemotherapy backbone per protocol and experienced a DLT prior to completion of the lead-in window or induction cycle, or as clinically indicated.
    End point type
    Primary
    End point timeframe
    Up to approximately 35 days
    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: No additional statistical analysis was pre-specified for this endpoint.
    [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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E)
    Number of subjects analysed
    4
    4
    2
    4
    3
    8
    Units: Participants
        Haemolytic uraemic syndrome
    0
    1
    0
    0
    0
    0
        Platelet count decreased
    0
    0
    0
    0
    0
    1
        Pulmonary haemorrhage
    0
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Phase 2: Complete Remission (CR) After Induction Therapy

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    End point title
    		 Phase 2: Complete Remission (CR) After Induction Therapy [11]
    End point description
    CR was defined as: a. Attainment of M1 bone marrow status (less than 5% blasts in a bone marrow aspirate and at least 200 cells counted) with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - Absolute neutrophil count (ANC) greater than or equal to 1000/µL - Platelet count greater than or equal to 100000/µL. Data was adjusted as inverse probability of treatment weight (IPTW) for the average treatment effect of the treated (IPTW-ATT). Participants enrolled in 20140106, in the Primary Analysis Set (PAS), who received at least 1 dose of carfilzomib.
    End point type
    Primary
    End point timeframe
    Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
    Notes
    [11] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    61
    44
    Units: Percentage of Participants
        number (confidence interval 95%)
    14.8 (5.9 to 23.7)
    13.6 (3.5 to 23.8)
    Statistical analysis title
    		 Participants Achieving CR - 20140106 vs control
    Statistical analysis description
    The primary objective of this endpoint was to compare the percentage of participants achieving CR after the end of induction therapy in study 20140106 with the percentage of participants achieving CR in an external control arm selected from an observational study (Amgen 20180065).
    Comparison groups
    Phase 2: T-cell v Phase 2: B-cell
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 99999 [13]
    Method
    		 External comparison
    Confidence interval
    Notes
    [12] - In the external control arm, 7.8% of B-Cell participants (95% confidence interval [CI]: 1.0%, 14.7%) achieved CR, with a treatment difference odds ratio of 2.04 (95% CI: 0.54, 7.66). For T-Cell participants, 9.1% (95% CI: 0.7%, 17.5%) achieved CR, with an odds ratio of 1.58 (95% CI: 0.47, 5.31).
    [13] - Value of "99999" indicates no P-value.

    Secondary: Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination

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    End point title
    		 Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination [14]
    End point description
    The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval. Phase 1b PK Analysis Set: All participants who received the study treatment regimen during the lead-in cycle and induction cycles, and had available data.
    End point type
    Secondary
    End point timeframe
    Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose
    Notes
    [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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E)
    Number of subjects analysed
    5
    6
    3
    6
    3
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Dose Escalation 1 - Lead in Cycle Day 1
    927 ( 259 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Induction cycle Day 8
    771 ( 151 )
    0 ( 0 )
    445 ( 260 )
    1070 ( 359 )
    1630 ( 875 )
    11200 ( 16400 )
        Dose Escalation 2 - Induction cycle Day 8
    0 ( 0 )
    0 ( 0 )
    445 ( 260 )
    1070 ( 359 )
    1630 ( 875 )
    11200 ( 16400 )
    No statistical analyses for this end point

    Secondary: Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib

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    End point title
    		 Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib [15]
    End point description
    The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval. Phase 1b PK Analysis Set: All participants who received the study treatment regimen during the lead-in cycle and induction cycles, and had available data.
    End point type
    Secondary
    End point timeframe
    Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose
    Notes
    [15] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E)
    Number of subjects analysed
    5
    6
    3
    6
    3
    9
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Dose Escalation 1 - Lead in Cycle Day 1
    387 ( 125 )
    240 ( 113 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Induction Cycle Day 8
    361 ( 160 )
    374 ( 273 )
    214 ( 155 )
    529 ( 210 )
    829 ( 479 )
    4000 ( 6370 )
        Dose Escalation 2 - Induction Cycle Day 8
    0 ( 0 )
    0 ( 0 )
    214 ( 155 )
    529 ( 210 )
    829 ( 479 )
    4000 ( 6370 )
    No statistical analyses for this end point

    Secondary: Phase 1b: AUC From Time 0 to infinity (AUCinf) of Carfilzomib

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    End point title
    		 Phase 1b: AUC From Time 0 to infinity (AUCinf) of Carfilzomib [16]
    End point description
    The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval. Phase 1b PK Analysis Set: All participants who received the study treatment regimen during the lead-in cycle and induction cycles, and had available data.
    End point type
    Secondary
    End point timeframe
    Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E)
    Number of subjects analysed
    5
    5
    1
    5
    3
    5
    Units: hr*ng/ mL
    arithmetic mean (standard deviation)
        Dose Escalation 1 - Lead in Cycle Day 1
    387 ( 124 )
    268 ( 101 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Induction Cycle Day 8
    368 ( 184 )
    374 ( 273 )
    406 ( 0.0 )
    565 ( 243 )
    848 ( 510 )
    1300 ( 1440 )
    No statistical analyses for this end point

    Secondary: Phase 1b: Percentage of Participants who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the end of Induction Cycle

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    End point title
    		 Phase 1b: Percentage of Participants who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the end of Induction Cycle [17]
    End point description
    CR was defined as the attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC > 750 mcl and platelet count > 75,000 mcl). CRp was defined as the attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease and with recovery of ANCs (ANC > 750 mcl), but with insufficient recovery of platelets (< 75,000 mcl).
    End point type
    Secondary
    End point timeframe
    Up to approximately Day 29 of Induction Cycle (28-days cycle, assessment on Day 29)
    Notes
    [17] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E)
    Number of subjects analysed
    5
    5
    3
    7
    4
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    40.0 (5.3 to 85.3)
    20.0 (0.5 to 71.6)
    33.3 (0.8 to 90.6)
    28.6 (3.7 to 71.0)
    25.0 (0.6 to 80.6)
    20.0 (2.5 to 55.6)
    No statistical analyses for this end point

    Secondary: Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10⁻³ and <10⁻⁴ Lymphoblasts at the end of Induction Cycle

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    End point title
    		 Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10⁻³ and <10⁻⁴ Lymphoblasts at the end of Induction Cycle [18]
    End point description
    MRD was defined as the quantification of residual lymphoblast in the blood. Assessed by NGS. Phase 1b Induction SAS: All participants who received any amount of the study treatment regimen during the induction period, and achieved MRD 10^3 or 10^4 lymphoblasts. Value of "-99999" and "99999" indicate that dispersion was not estimable as 0 participants achieved MRD status.
    End point type
    Secondary
    End point timeframe
    Up to approximately Day 29 of Induction Cycle (28-days cycle, assessment on Day 29)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E)
    Number of subjects analysed
    5
    5
    3
    7
    4
    10
    Units: Percentage of Participants
    number (confidence interval 95%)
        Achieved MRD status < 10^3 lymphoblasts
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    14.3 (0.4 to 57.9)
    25.0 (0.6 to 80.6)
    0 (-99999 to 99999)
        Achieved MRD status < 10^4 lymphoblasts
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    0 (-99999 to 99999)
    14.3 (0.4 to 57.9)
    25.0 (0.6 to 80.6)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Participants who Experienced TEAEs

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    End point title
    		 Phase 2: Number of Participants who Experienced TEAEs [19]
    End point description
    An AE is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. TRAEs were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. A SAE was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
    End point type
    Secondary
    End point timeframe
    From first dose of carfilzomib up to 30 days after the last dose of study treatment; median duration of carfilzomib treatment was 16 days.
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    61 [20]
    44 [21]
    Units: Participants
        TEAEs
    61
    44
        SAEs
    44
    31
        Fatal TEAEs
    15
    3
        TRAEs
    50
    39
        Serious TRAEs
    25
    24
        Fatal TRAEs
    5
    1
    Notes
    [20] - SAS: All participants enrolled in study 20140106 who received at least 1 dose of carfilzomib.
    [21] - SAS: All participants enrolled in study 20140106 who received at least 1 dose of carfilzomib.
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Participants CR with Incomplete Hematologic Recovery (CRi) After Induction Therapy or Better Remission Status

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    End point title
    		 Phase 2: Percentage of Participants CR with Incomplete Hematologic Recovery (CRi) After Induction Therapy or Better Remission Status [22]
    End point description
    CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CR with partial hematologic recovery (CRh), CR without platelet recovery (CRp), or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 1000/µL ii. Platelet count < 100 000/µL. CRh was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 500/µL but < 1000/µL ii. Platelet count ≥ 50 000/µL but < 100 000/µL. Data was IPTW adjusted.
    End point type
    Secondary
    End point timeframe
    Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    61 [23]
    44 [24]
    Units: Percentage of Participants
        number (confidence interval 95%)
    42.6 (30.2 to 55.0)
    27.3 (14.1 to 40.4)
    Notes
    [23] - Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib.
    [24] - Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib.
    Statistical analysis title
    		 rate of CRi - 20140106 vs control
    Statistical analysis description
    The objective of this endpoint was to compare the rate of CRi or better status against an external control arm selected from an observational study (Amgen 20180065).
    Comparison groups
    Phase 2: T-cell v Phase 2: B-cell
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 99999 [26]
    Method
    		 External comparison
    Confidence interval
    Notes
    [25] - The rate of CRi or better status in the external control arm was 26.3% (95% CI: 15.1, 37.5) for B-Cell participants with treatment difference odds ratio of 2.082% (95% CI: 0.968, 4.477). For T-Cell participants the rate of CRi or better status was 18.6 (95% CI: 7.1, 30.0) with treatment difference odds ratio of 1.646 (95% CI: 0.639. 4.245).
    [26] - Value of "99999" indicates no P-value.

    Secondary: Phase 2: Event Free Survival (EFS)

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    End point title
    		 Phase 2: Event Free Survival (EFS) [27]
    End point description
    EFS was defined as time from initiation of therapy until treatment failure (defined as failure to reach at least a CRi after consolidation or after induction in participants that did not receive consolidation), relapse, or death from any cause. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp, or CR. Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib. Medians were estimated using the Kaplan-Meier (KM) method. Data was IPTW adjusted.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    61
    44
    Units: Months
        median (confidence interval 95%)
    1.18 (0.95 to 2.24)
    1.20 (0.95 to 1.48)
    Statistical analysis title
    		 EFS 20140106 vs control
    Statistical analysis description
    The objective of this endpoint was to compare EFS in study 20140106 with EFS in an external control arm selected from an observational study (Amgen 20180065).
    Comparison groups
    Phase 2: B-cell v Phase 2: T-cell
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 = 99999 [29]
    Method
    		 External comparison
    Confidence interval
    Notes
    [28] - The median duration in months in the external control arm was 3.62 (95% CI: 1.55, 5.36) for B-cell participants, with a treatment difference hazard ration of 1.435 (95% CI: 0.976, 2.111). For T-Cell participants the median in months was 2.93 (95% CI: 0.95, 5.10) with a treatment difference hazard ratio of 1.404 (95% CI: 0.869, 2.270).
    [29] - Value of "99999" indicates no P-value.

    Secondary: Phase 2: Overall Survival (OS)

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    End point title
    		 Phase 2: Overall Survival (OS) [30]
    End point description
    OS was defined as time from initiation of therapy until death from any cause. Participants enrolled in 20140106, in the PAS, who received at least 1 dose of carfilzomib. Medians were estimated using the KM method. Data was IPTW adjusted.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    Notes
    [30] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    61
    44
    Units: Months
        median (confidence interval 95%)
    5.23 (2.93 to 9.24)
    4.51 (3.49 to 9.18)
    Statistical analysis title
    		 OS 20140106 vs control
    Statistical analysis description
    The objective of this endpoint was to compare the OS in study 20140106 with OS in an external control arm selected from an observational study (Amgen 20180065).
    Comparison groups
    Phase 2: B-cell v Phase 2: T-cell
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 99999 [32]
    Method
    		 External comparison
    Confidence interval
    Notes
    [31] - The median OS in months for the B-Cell participants in the external control arm was 8.59 (95% CI: 5.26, 10.59) with a treatment difference hazard ratio of 1.245 (95% CI: 0.805, 1.927). For the T-Cell participants the median OS in months was 7.04 (95% CI: 7.04, NE) with a treatment difference hazard ratio of 1.040 (95% CI: 0.641, 1.688).
    [32] - Value of "99999" indicates no P-value.

    Secondary: Phase 2: Duration of Remission (DOR)

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    End point title
    		 Phase 2: Duration of Remission (DOR) [33]
    End point description
    DOR was defined as time from earliest of CR, CRp, CRh, or CRi to relapse or death from any cause. CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp) or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 1000/µL ii. Platelet count < 100 000/µL. CRh was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 500/µL but less than 1000/µL ii. Platelet count ≥ 50 000/µL but less than 100 000/µL.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    Notes
    [33] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    26
    14 [34]
    Units: Months
        median (confidence interval 95%)
    7.55 (3.42 to 22.20)
    9.01 (2.57 to 99999)
    Notes
    [34] - Value of "99999" indicates that no upper CI was calculated due to few observations.
    Statistical analysis title
    		 DOR 20140106 vs control
    Statistical analysis description
    The DOR in study 20140106 was estimated relative to the DOR in an external control arm selected from an observational study (Amgen 20180065).
    Comparison groups
    Phase 2: B-cell v Phase 2: T-cell
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 99999 [36]
    Method
    		 External Comparison
    Confidence interval
    Notes
    [35] - The median DOR in months in the external control arm was 8.72 (95% CI: 5.07, 32.24) in B-Cell participants. For T-Cell participants the median DOR in months was 5.82 (95% CI: 1.22, 19.80).
    [36] - Value of "99999" indicates no P-value.

    Secondary: Phase 2: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10⁻³ and <10⁻⁴ Cells in Participants With CR After Induction Therapy

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    End point title
    		 Phase 2: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10⁻³ and <10⁻⁴ Cells in Participants With CR After Induction Therapy [37]
    End point description
    MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with next generation sequencing (NGS). Induction Safety Analysis Set: All participants who started the induction cycle and received at least 1 dose of carfilzomib during the induction period.
    End point type
    Secondary
    End point timeframe
    Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
    Notes
    [37] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    61
    44
    Units: Percentage of Participants
    number (confidence interval 95%)
        Percentage of Participants Achieving MRD <10⁻³
    8.2 (2.7 to 18.1)
    4.5 (0.6 to 15.5)
        Percentage of Participants Achieving MRD <10⁻⁴
    3.3 (0.4 to 11.3)
    4.5 (0.6 to 15.5)
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Participants Achieving MRD Status of <10⁻³ and <10⁻⁴ Cells in Participants With CRi or Better Status After Induction Therapy

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    End point title
    		 Phase 2: Percentage of Participants Achieving MRD Status of <10⁻³ and <10⁻⁴ Cells in Participants With CRi or Better Status After Induction Therapy [38]
    End point description
    MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with NGS. Induction Safety Analysis Set: All participants who started the induction cycle and received at least 1 dose of carfilzomib during the induction period.
    End point type
    Secondary
    End point timeframe
    Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
    Notes
    [38] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    61
    44
    Units: Percentage of Participants
    number (confidence interval 95%)
        Percentage of Participants Achieving MRD <10⁻³
    18.0 (9.4 to 30.0)
    9.1 (2.5 to 21.7)
        Percentage of Participants Achieving MRD <10⁻⁴
    9.8 (3.7 to 20.2)
    6.8 (1.4 to 18.7)
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Participants Achieving MRD Status of <10⁻³ and <10⁻⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy

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    End point title
    		 Phase 2: Percentage of Participants Achieving MRD Status of <10⁻³ and <10⁻⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy [39]
    End point description
    MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with NGS. Consolidation Safety Analysis Set: All participants who started the consolidation cycle and received at least 1 dose of study treatment during the consolidation period.
    End point type
    Secondary
    End point timeframe
    Up to Day 100 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants] + 28-day cycle of consolidation therapy + + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
    Notes
    [39] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    25
    20
    Units: Percentage of Participants
    number (confidence interval 95%)
        Percentage of Participants Achieving MRD <10⁻³
    16.0 (4.5 to 36.1)
    20.0 (5.71 to 43.7)
        Percentage of Participants Achieving MRD <10⁻⁴
    16.0 (4.5 to 36.1)
    20.0 (5.71 to 43.7)
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Participants Who Underwent Stem Cell Transplant or Chimeric Antigen Receptor T-cell (CAR-T) Without Intervening Relapse Following Protocol-Specified Therapy

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    End point title
    		 Phase 2: Percentage of Participants Who Underwent Stem Cell Transplant or Chimeric Antigen Receptor T-cell (CAR-T) Without Intervening Relapse Following Protocol-Specified Therapy [40]
    End point description
    Percentage of participants who successfully underwent stem cell transplant or CAR-T therapy without experiencing a relapse after receiving the protocol-specified treatment. Safety analysis set: All participants who received at least 1 dose of carfilzomib.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years
    Notes
    [40] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    61
    44
    Units: Percentage of Participants
        number (confidence interval 95%)
    19.7 (10.6 to 31.8)
    27.3 (15.0 to 42.8)
    No statistical analyses for this end point

    Secondary: Phase 2: AUClast of Carfilzomib

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    End point title
    		 Phase 2: AUClast of Carfilzomib
    End point description
    AUClast refers to the total exposure of a drug in the body over time, calculated from the time of administration until the last measurable concentration in the blood. PK analysis set: All participants who received at least 1 dose of carfilzomib, had 1 PK sample collected and a quantifiable number of observations. Per SAP, analysis was not planned to compare T-cell and B-cell.
    End point type
    Secondary
    End point timeframe
    Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle)
    End point values
    		 Carfilzomib - Day 8 Induction Cycle (PK Analysis Set) Carfilzomib - Day 1 Consolidation Cycle (PK Analysis Set)
    Number of subjects analysed
    83
    34
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    4330 ( 10300 )
    9410 ( 36200 )
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Participants With CRi After Consolidation Therapy or Better Remission Status

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    End point title
    		 Phase 2: Percentage of Participants With CRi After Consolidation Therapy or Better Remission Status [41]
    End point description
    CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp, or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ to 1000/µL ii. Platelet count < 100 000/µL. CRh was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 500/µL but < 1000/µL ii. Platelet count ≥ 50 000/µL but < 100 000/µL. Data was IPTW adjusted.
    End point type
    Secondary
    End point timeframe
    Up to Day 100 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants] + 28-day cycle of consolidation therapy + + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
    Notes
    [41] - 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: No additional statistical analysis was pre-specified for this endpoint.
    End point values
    		 Phase 2: B-cell Phase 2: T-cell
    Number of subjects analysed
    25 [42]
    20 [43]
    Units: Percentage of Participants
    number (confidence interval 95%)
        Percentage of participants with CRi or better
    36.0 (18.0 to 57.5)
    50.0 (27.2 to 72.8)
    Notes
    [42] - All participants who started the consolidation cycle.
    [43] - All participants who started the consolidation cycle.
    No statistical analyses for this end point

    Secondary: Phase 2: Cmax of Carfilzomib

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    End point title
    		 Phase 2: Cmax of Carfilzomib
    End point description
    Cmax is the maximum concentration of a drug in the bloodstream after administration. PK analysis set: All participants who received at least 1 dose of carfilzomib, had 1 PK sample collected and a quantifiable number of observations. Per SAP, analysis was not planned to compare T-cell and B-cell.
    End point type
    Secondary
    End point timeframe
    Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle)
    End point values
    		 Carfilzomib - Day 8 Induction Cycle (PK Analysis Set) Carfilzomib - Day 1 Consolidation Cycle (PK Analysis Set)
    Number of subjects analysed
    83
    34
    Units: ng/mL
        arithmetic mean (standard deviation)
    9590 ( 27800 )
    13800 ( 44200 )
    No statistical analyses for this end point

    Secondary: Phase 2: AUCinf of Carfilzomib

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    End point title
    		 Phase 2: AUCinf of Carfilzomib
    End point description
    AUCinf represents the total drug exposure over time, extrapolated from the time of administration until the drug is completely eliminated from the body. PK analysis set: All participants who received at least 1 dose of carfilzomib, had 1 PK sample collected and a quantifiable number of observations. Per SAP, analysis was not planned to compare T-cell and B-cell.
    End point type
    Secondary
    End point timeframe
    Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle)
    End point values
    		 Carfilzomib - Day 8 Induction Cycle (PK Analysis Set) Carfilzomib - Day 1 Consolidation Cycle (PK Analysis Set)
    Number of subjects analysed
    46
    23
    Units: hr*ng/mL
        arithmetic mean (standard deviation)
    4070 ( 11000 )
    1200 ( 2480 )
    No statistical analyses for this end point

    Secondary: Phase 2: Terminal Half-life (t1/2,z) of Carfilzomib

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    End point title
    		 Phase 2: Terminal Half-life (t1/2,z) of Carfilzomib
    End point description
    T1/2,z refers to the time required for the plasma concentration of a drug to decrease by half during the final phase of elimination from the body. PK analysis set: All participants who received at least 1 dose of carfilzomib, had 1 PK sample collected and a quantifiable number of observations. Per SAP, analysis was not planned to compare T-cell and B-cell.
    End point type
    Secondary
    End point timeframe
    Day 8 of induction cycle (28-days cycle) and Day 1 of consolidation cycle (28-days cycle)
    End point values
    		 Carfilzomib - Day 8 Induction Cycle (PK Analysis Set) Carfilzomib - Day 1 Consolidation Cycle (PK Analysis Set)
    Number of subjects analysed
    46
    23
    Units: hour
        arithmetic mean (standard deviation)
    0.371 ( 0.162 )
    0.332 ( 0.0894 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 112 months
    Adverse event reporting additional description
    Phase 1b/2 Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1/27.0
    Reporting groups
    Reporting group title
    Phase 1b: Dose Escalation 1 (Dose A)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose A in combination with R3 IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 1 (Dose B)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose B in combination with R3 IV for approximately 9 weeks (1-week lead-in window, 28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose B)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose B in combination with vincristine, dexamethasone, PEG-asparaginase, and daunorubicin (VXLD dose escalation) IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose C)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose C in combination with VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose D)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose D in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 1b: Dose Escalation 2 (Dose E)
    Reporting group description
    		 Participants with relapsed or refractory ALL received carfilzomib Dose E in combination VXLD IV for approximately 8 weeks (28-day induction cycle, and 28-day optional consolidation cycle).

    Reporting group title
    Phase 2: B-cell
    Reporting group description
    		 Eligible participants with relapsed or refractory ALL (B-cell) were treated with VXLD plus carfilzomib for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator’s discretion, be treated with 1 28-day consolidation cycle of Children’s Oncology group-modified BFM therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and IT therapy plus carfilzomib.

    Reporting group title
    Phase 2: T-cell
    Reporting group description
    		 Eligible participants with relapsed or refractory ALL (T-cell) were treated with VXLD plus carfilzomib for 1 cycle (induction), followed by assessment of treatment response. Participants who did not show progression during induction underwent a bone marrow and extramedullary disease evaluation after completion of induction therapy. Participants without disease progression after induction could at the investigator’s discretion, be treated with 1 28-day consolidation cycle of BFM therapy (cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine), and IT therapy plus carfilzomib.

    Serious adverse events
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E) Phase 2: B-cell Phase 2: T-cell
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    4 / 6 (66.67%)
    3 / 3 (100.00%)
    6 / 7 (85.71%)
    4 / 4 (100.00%)
    7 / 10 (70.00%)
    44 / 61 (72.13%)
    31 / 44 (70.45%)
         number of deaths (all causes)
    0
    2
    0
    0
    0
    3
    41
    29
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    5 / 5
    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
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 10 (20.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Mediastinal disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pulmonary veno-occlusive disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    1 / 1
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter culture positive
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac disorders
    Cardiac dysfunction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Toxic cardiomyopathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Consciousness fluctuating
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cerebral small vessel ischaemic disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    4 / 44 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    Clonic convulsion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    8 / 61 (13.11%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
    1 / 1
    4 / 4
    1 / 1
    2 / 2
    7 / 11
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperleukocytosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    4 / 44 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    9 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 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
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatobiliary disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Alpha haemolytic streptococcal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Encephalitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    1 / 1
    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
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex reactivation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    2 / 61 (3.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    4 / 61 (6.56%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    2 / 2
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Severe acute respiratory syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    9 / 61 (14.75%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    3 / 11
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Sepsis syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    4 / 61 (6.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Bacillus bacteraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fusobacterium infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection in an immunocompromised host
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    Stomatococcal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b: Dose Escalation 1 (Dose A) Phase 1b: Dose Escalation 1 (Dose B) Phase 1b: Dose Escalation 2 (Dose B) Phase 1b: Dose Escalation 2 (Dose C) Phase 1b: Dose Escalation 2 (Dose D) Phase 1b: Dose Escalation 2 (Dose E) Phase 2: B-cell Phase 2: T-cell
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    7 / 7 (100.00%)
    4 / 4 (100.00%)
    9 / 10 (90.00%)
    61 / 61 (100.00%)
    43 / 44 (97.73%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chloroma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 4 (75.00%)
    2 / 10 (20.00%)
    3 / 61 (4.92%)
    4 / 44 (9.09%)
         occurrences all number
    1
    0
    0
    0
    8
    2
    3
    5
    Hypertension
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    6 / 7 (85.71%)
    2 / 4 (50.00%)
    7 / 10 (70.00%)
    25 / 61 (40.98%)
    13 / 44 (29.55%)
         occurrences all number
    6
    4
    5
    8
    9
    10
    28
    23
    Thrombophlebitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Flushing
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    5 / 61 (8.20%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    3
    0
    1
    2
    5
    0
    Face oedema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    4 / 44 (9.09%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    4
    Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    3 / 61 (4.92%)
    7 / 44 (15.91%)
         occurrences all number
    0
    0
    0
    2
    0
    5
    3
    9
    Pyrexia
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 6 (66.67%)
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    2 / 4 (50.00%)
    3 / 10 (30.00%)
    27 / 61 (44.26%)
    23 / 44 (52.27%)
         occurrences all number
    4
    7
    2
    4
    3
    6
    57
    52
    Oedema peripheral
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    2
    1
    Oedema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    0
    3
    0
    1
    1
    1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    2 / 4 (50.00%)
    3 / 10 (30.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    4
    1
    1
    1
    2
    4
    1
    0
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Catheter site pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    6
    Hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    1
    Immunodeficiency common variable
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    3
    0
    1
    0
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    4 / 44 (9.09%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    2
    4
    Cough
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    4 / 44 (9.09%)
         occurrences all number
    3
    2
    2
    2
    0
    0
    3
    4
    Epistaxis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    4 / 44 (9.09%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    1
    5
    Pleural effusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    5 / 61 (8.20%)
    3 / 44 (6.82%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    3
    Nasal congestion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    2
    Aspiration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Dry throat
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    8
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Pulmonary oedema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 10 (20.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    1
    2
    Rhinitis allergic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Tachypnoea
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 4 (50.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences all number
    0
    1
    0
    2
    2
    0
    1
    2
    Abnormal behaviour
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Affective disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Agitation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    Depression
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    2
    1
    Irritability
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    4
    1
    0
    0
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    2 / 4 (50.00%)
    4 / 10 (40.00%)
    11 / 61 (18.03%)
    4 / 44 (9.09%)
         occurrences all number
    36
    42
    25
    28
    58
    13
    40
    33
    Neutrophil count decreased
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    6 / 61 (9.84%)
    4 / 44 (9.09%)
         occurrences all number
    23
    4
    4
    13
    1
    1
    19
    21
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    4 / 61 (6.56%)
    0 / 44 (0.00%)
         occurrences all number
    34
    7
    0
    18
    0
    4
    9
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    3 / 44 (6.82%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    7 / 61 (11.48%)
    5 / 44 (11.36%)
         occurrences all number
    4
    1
    0
    1
    13
    0
    10
    8
    Blood bilirubin increased
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    6 / 61 (9.84%)
    4 / 44 (9.09%)
         occurrences all number
    6
    2
    5
    1
    10
    0
    12
    4
    Antithrombin III decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    5 / 44 (11.36%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    18 / 61 (29.51%)
    10 / 44 (22.73%)
         occurrences all number
    7
    2
    0
    5
    2
    0
    35
    33
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    1 / 4 (25.00%)
    2 / 10 (20.00%)
    21 / 61 (34.43%)
    14 / 44 (31.82%)
         occurrences all number
    11
    5
    1
    12
    2
    6
    46
    32
    White blood cell count decreased
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    11 / 61 (18.03%)
    5 / 44 (11.36%)
         occurrences all number
    25
    14
    4
    23
    1
    0
    36
    27
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    5
    0
    0
    2
    0
    0
    0
    0
    Ammonia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Amylase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    1
    Aspartate aminotransferase decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Bacterial test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    2 / 44 (4.55%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    4
    Blood creatinine increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    2
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    1
    3
    Blood urea increased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    1 / 44 (2.27%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    2
    1
    Breath sounds abnormal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Blood creatine increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    2
    Candida test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Immunoglobulins decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Lipase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    0
    3
    Lymphocyte count
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Staphylococcus test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    Urine protein/creatinine ratio increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    3
    2
    0
    1
    1
    1
    0
    1
    Weight increased
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences all number
    10
    0
    1
    0
    12
    1
    1
    2
    Protein total abnormal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Foreign body ingestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    1
    Procedural nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Scratch
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    2
    1
    0
    1
    1
    0
    2
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    3 / 4 (75.00%)
    0 / 10 (0.00%)
    4 / 61 (6.56%)
    0 / 44 (0.00%)
         occurrences all number
    0
    2
    0
    2
    5
    0
    5
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    2 / 44 (4.55%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    3
    2
    Cardiac failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Bradycardia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences all number
    2
    0
    0
    0
    2
    1
    1
    2
    Atrioventricular block
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    1 / 10 (10.00%)
    2 / 61 (3.28%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    2
    4
    2
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    2 / 4 (50.00%)
    2 / 10 (20.00%)
    8 / 61 (13.11%)
    10 / 44 (22.73%)
         occurrences all number
    4
    0
    1
    5
    5
    2
    10
    15
    Neuropathy peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    4 / 61 (6.56%)
    3 / 44 (6.82%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    4
    3
    Neuralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    2
    Dizziness
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    0
    0
    Epilepsy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Loss of consciousness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    0
    Seizure
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 5 (80.00%)
    5 / 6 (83.33%)
    2 / 3 (66.67%)
    4 / 7 (57.14%)
    3 / 4 (75.00%)
    3 / 10 (30.00%)
    37 / 61 (60.66%)
    23 / 44 (52.27%)
         occurrences all number
    62
    31
    20
    24
    49
    8
    145
    98
    Febrile neutropenia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    3 / 10 (30.00%)
    17 / 61 (27.87%)
    11 / 44 (25.00%)
         occurrences all number
    1
    1
    1
    0
    1
    3
    19
    19
    Neutropenia
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    24 / 61 (39.34%)
    17 / 44 (38.64%)
         occurrences all number
    7
    3
    0
    1
    8
    0
    46
    39
    Thrombocytopenia
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    23 / 61 (37.70%)
    20 / 44 (45.45%)
         occurrences all number
    43
    1
    1
    3
    0
    0
    90
    49
    Lymphopenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    6 / 61 (9.84%)
    4 / 44 (9.09%)
         occurrences all number
    11
    0
    0
    0
    0
    0
    14
    18
    Leukopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    12 / 61 (19.67%)
    10 / 44 (22.73%)
         occurrences all number
    0
    1
    0
    0
    12
    0
    19
    17
    Coagulopathy
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    0
    Myelosuppression
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Bone marrow failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Periorbital oedema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    1
    1
    0
    Periorbital swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Eye irritation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Photophobia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    4 / 44 (9.09%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    4
    4
    Abdominal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    9 / 61 (14.75%)
    7 / 44 (15.91%)
         occurrences all number
    1
    2
    2
    3
    1
    1
    11
    10
    Constipation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    1 / 10 (10.00%)
    7 / 61 (11.48%)
    9 / 44 (20.45%)
         occurrences all number
    0
    3
    2
    3
    4
    1
    7
    11
    Diarrhoea
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    0 / 4 (0.00%)
    3 / 10 (30.00%)
    13 / 61 (21.31%)
    9 / 44 (20.45%)
         occurrences all number
    6
    2
    2
    4
    0
    6
    18
    11
    Nausea
         subjects affected / exposed
    4 / 5 (80.00%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    5 / 7 (71.43%)
    2 / 4 (50.00%)
    0 / 10 (0.00%)
    8 / 61 (13.11%)
    11 / 44 (25.00%)
         occurrences all number
    5
    0
    3
    10
    6
    0
    8
    19
    Oral pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    3 / 44 (6.82%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    3
    Vomiting
         subjects affected / exposed
    4 / 5 (80.00%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    3 / 4 (75.00%)
    2 / 10 (20.00%)
    7 / 61 (11.48%)
    7 / 44 (15.91%)
         occurrences all number
    8
    2
    1
    3
    11
    4
    8
    10
    Stomatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    4 / 61 (6.56%)
    7 / 44 (15.91%)
         occurrences all number
    0
    3
    0
    3
    0
    0
    6
    7
    Dental caries
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    Colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    1
    Anal fissure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    3 / 61 (4.92%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    1
    0
    1
    3
    1
    Abdominal distension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    3 / 61 (4.92%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    0
    Dry mouth
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Oral mucosal erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Pancreatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    0
    Toothache
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    2 / 61 (3.28%)
    4 / 44 (9.09%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    3
    5
    Hepatic lesion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Cholecystitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Cholangitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    4 / 61 (6.56%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    4
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Dermatitis bullous
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    2 / 44 (4.55%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    1
    3
    Alopecia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Papule
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Petechiae
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    3 / 10 (30.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    0
    1
    3
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    1
    0
    0
    Purpura
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    3 / 44 (6.82%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    1
    3
    Acute kidney injury
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    5 / 61 (8.20%)
    2 / 44 (4.55%)
         occurrences all number
    3
    0
    0
    0
    0
    3
    6
    2
    Chromaturia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Cushingoid
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    2 / 61 (3.28%)
    3 / 44 (6.82%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    2
    4
    Back pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    4 / 44 (9.09%)
         occurrences all number
    1
    0
    2
    3
    0
    0
    1
    4
    Pain in extremity
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    4 / 7 (57.14%)
    2 / 4 (50.00%)
    1 / 10 (10.00%)
    4 / 61 (6.56%)
    3 / 44 (6.82%)
         occurrences all number
    2
    4
    0
    5
    2
    1
    5
    3
    Muscle spasms
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    2 / 61 (3.28%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    2
    1
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Pain in jaw
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    1 / 44 (2.27%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    2
    2
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    4 / 61 (6.56%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    4 / 61 (6.56%)
    3 / 44 (6.82%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    3
    COVID-19
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    4 / 61 (6.56%)
    3 / 44 (6.82%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    4
    Sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    2 / 61 (3.28%)
    3 / 44 (6.82%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    3
    Rhinovirus infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    4 / 61 (6.56%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    4
    0
    Appendicitis perforated
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Aspergillus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Bacterial infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Device related bacteraemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Device related infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    2 / 61 (3.28%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Fungal sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Infection in an immunocompromised host
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    2
    Oral herpes
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    3
    1
    Paronychia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    Septic shock
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    3
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    Stomatococcal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    1 / 44 (2.27%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    1
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    2 / 4 (50.00%)
    3 / 10 (30.00%)
    15 / 61 (24.59%)
    17 / 44 (38.64%)
         occurrences all number
    15
    7
    4
    3
    4
    6
    35
    27
    Hypomagnesaemia
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    1 / 10 (10.00%)
    5 / 61 (8.20%)
    5 / 44 (11.36%)
         occurrences all number
    6
    6
    0
    0
    2
    1
    6
    6
    Hyponatraemia
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    2 / 10 (20.00%)
    6 / 61 (9.84%)
    4 / 44 (9.09%)
         occurrences all number
    2
    6
    4
    1
    0
    3
    7
    5
    Hyperglycaemia
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    3 / 61 (4.92%)
    6 / 44 (13.64%)
         occurrences all number
    11
    4
    3
    0
    0
    1
    8
    12
    Hypoglycaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    2 / 10 (20.00%)
    3 / 61 (4.92%)
    3 / 44 (6.82%)
         occurrences all number
    3
    5
    0
    4
    0
    5
    3
    7
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    4 / 44 (9.09%)
         occurrences all number
    3
    0
    0
    0
    3
    0
    0
    14
    Hyperuricaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    8 / 61 (13.11%)
    1 / 44 (2.27%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    10
    1
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    1 / 10 (10.00%)
    18 / 61 (29.51%)
    8 / 44 (18.18%)
         occurrences all number
    20
    8
    2
    9
    8
    1
    36
    10
    Hypocalcaemia
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    11 / 61 (18.03%)
    5 / 44 (11.36%)
         occurrences all number
    9
    10
    1
    3
    0
    0
    26
    8
    Hyperkalaemia
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    5 / 61 (8.20%)
    1 / 44 (2.27%)
         occurrences all number
    2
    3
    0
    2
    0
    0
    5
    2
    Hypophosphataemia
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    3 / 10 (30.00%)
    5 / 61 (8.20%)
    5 / 44 (11.36%)
         occurrences all number
    18
    10
    0
    1
    1
    5
    17
    5
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    5 / 61 (8.20%)
    2 / 44 (4.55%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    5
    2
    Decreased appetite
         subjects affected / exposed
    4 / 5 (80.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    0 / 44 (0.00%)
         occurrences all number
    6
    0
    1
    2
    1
    0
    3
    0
    Acidosis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 10 (10.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Fluid overload
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    3
    1
    0
    2
    0
    0
    0
    0
    Hypernatraemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 10 (0.00%)
    1 / 61 (1.64%)
    0 / 44 (0.00%)
         occurrences all number
    11
    0
    0
    0
    3
    0
    2
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    0 / 61 (0.00%)
    0 / 44 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 10 (0.00%)
    3 / 61 (4.92%)
    2 / 44 (4.55%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2014
    Significant changes from the Original Protocol to Amendment 1 are: • Added PK sample collection times of 2 and 4 hours after the end of carfilzomib infusion • Germline DNA collection time moved to the end of Induction • Pharmacodynamic sample collection added on Day 29 of Induction.
    23 Jan 2015
    • Added details of MRD specimen collection, including the type of specimen to be submitted or the timing of the specimen collection • Added detailed information regarding timing of pharmacodynamics specimen collection • Corrected inconsistencies within the protocol and between the protocol and the laboratory manual regarding the proper day for collection of blood or saliva to serve as a source of normal (non-tumor) DNA from subjects who have consented to the optional genomic studies • Removed ≥ Grade 3 peripheral neuropathy or neuropathic pain from the definition of dose limiting toxicity, due to its strong association with vincristine and rare association with carfilzomib • Corrected the dose modification of vincristine in the setting of constipation, ileus, or typhlitus to reflect modification at ≥ Grade 3, rather than > Grade 3 • Added information about PRES and the required dose modification of carfilzomib when PRES is suspected • Updated the options for pregnancy testing during screening to include a urine pregnancy test, to include a urine pregnancy test, which is less invasive and more readily available at pediatric facilities • Increased the duration of required contraception to incorporate the best practices for all drugs in the treatment regimen • Modified the definition of permanent sterilization and revised the list of highly effective methods of contraception, to be consistent with recent guidance • Added language to allow for higher total bilirubin level at screening, for subjects with a diagnosis of Gilbert syndrome • Added language to clarify that the restricted use of antineoplastic agents prior to enrollment only applies to the use of agents with therapeutic intent.
    20 Oct 2016
    The protocol is amended to: • Add a second dose escalation portion to evaluate carfilzomib with a different chemotherapy backbone (VXLD) of vincristine, dexamethasone, PEG-asparaginase, and daunorubicin Rationale: Toxicity related to the R3 induction chemotherapy backbone of dexamethasone, mitoxantrone, PEG-asparaginase, and vincristine is suspected to have limited the ability to dose escalate carfilzomib. A second dose escalation using the less toxic VXLD backbone is being added to the protocol to ensure the optimal dose of carfilzomib is selected before moving on to a Phase 2 study. • Remove the Phase 2 portion of the study Rationale: The Phase 2 portion of the study will instead be conducted with a stand-alone protocol treating participants at the defined MTD. • Revise eligibility criteria to o Include enrollment of participants aged 21 years or younger at the time of initial ALL diagnosis and limiting enrollment to those aged > 1 year at the time of study treatment initiation o Include the enrollment of participants with any first relapse of T-ALL, removing the limitation to those with an early relapse o Modify definition of adequate liver function o Specify grade of pancreatitis as an exclusion criterion o Clarify evidence for bacteria or fungal infection o Clarify antineoplastic agents that are included in prior therapy restrictions.
    20 Oct 2016
    • Clarify the target number of participants to be enrolled in each age group • Change requirement for medical monitor approval with requirement to contact medical monitor • Remove the requirement for bone marrow biopsy during screening Revise Section 8.4 (Dose Modification Guidelines) to o Add text clarifying that the carfilzomib dose modification guidelines also apply to the Optional Consolidation Cycle o Add dose modification guidelines for daunorubicin • Add Section 8.6 (Product Complaints) • Revise Section 9 (Supportive Care Requirements and Guidelines) to o Clarify that fungal prophylaxis must be provided during periods of neutropenia o Correct definition for fever and neutropenia o Update Section 9.14 (Contraception) • Update Section 12.6 (Pregnancy and Lactation Reporting) • Add guidelines for taking temperature and blood pressure of participants • Add Section 15.7 (Publication Policy) • Update Section 3 (Background Information) • Make minor text clarifications, additions, and edits throughout the protocol.
    22 Feb 2017
    The protocol is amended to: • Revise inclusion criteria regarding hepatic function Rationale: Provide clarity that participants with hyperbilirubinemia due to Gilbert syndrome are only eligible if they have a direct bilirubin ≤ 1.5 x institutional upper limit of normal. • Modify carfilzomib infusion time from "approximately 30 minutes" to "30 ± 5 minutes" Rationale: Provide clarity on the infusion time ensuring all participants are exposed to the same range of IV infusion time. • Add language within the Induction Cycle describing the dose level lists with the carfilzomib dose for each dose escalation and specify that during Dose Escalation 2, participants will receive 20 mg/m2 of carfilzomib on Day 1 of the Induction Cycle. Rationale: This language was erroneously omitted during Amendment 3. • Update Study 20140106 Induction Cycle Dose Escalation 2 (VXLD) road map with actual dose administered placeholders to match the VXLD backbone. Rationale: Dexamethasone, vincristine, and PEG-asparaginase administration placeholders were not correctly placed within the appropriate study day. • Administrative updates, editorial changes, and style and formatting revisions have been made to improve clarity and consistency throughout the document. Significant changes are described in the table below. Detailed, changed text is displayed for first major occurrence only. Changes in sections of the protocol body were also made in the protocol synopsis and elsewhere in the document, as applicable. Deletions of text are presented in strikethrough format. Added text is presented in bold format.
    11 Sep 2017
    The protocol is amended to: • Modify the language for dexamethasone dose instruction in the VXLD regimen from 6 mg/m2 twice daily to 6 mg/m2 per day BID – given orally (3 mg/m2 per dose given twice daily). Rationale: Update the language describing required dexamethasone dosing instructions to ensure clarity and remove ambiguity. • Update the posterior reversible encephalopathy syndrome (PRES) language. Rationale: Update PRES language to ensure alignment between study protocol and the carfilzomib Investigator Brochure v17.1. • Update PRES management recommendation with a no “re-challenge requirement”. Rationale: Prohibit reintroduction of carfilzomib if PRES is identified in a participant at the request of the Global Safety Team (GST). • Administrative updates, editorial changes, and style and formatting revisions have been made to improve clarity and consistency throughout the document. Significant changes are described in the table below. Detailed, changed text is displayed for first major occurrence only. Changes in sections of the protocol body were also made in the protocol synopsis and elsewhere in the document, as applicable. Added text is presented in bold format.
    24 Oct 2018
    The protocol is amended to: • Modify the stopping criteria for the Bayesian algorithm Rationale: Changes to language on how the Bayesian output will be used to determine the maximum tolerated dose in order to trigger the end of the study. • Update the cohort safety review committee language. Rationale: Update increases the discretion of the cohort safety review committee to recommend the maximum tolerated dose. • Add 2 additional dose levels in dose escalation 2 Rationale: Accumulating pharmacokinetic data in children indicates drug exposure was approximately 40% lower than that of adults at the same dose and schedule; therefore, current dose escalation plan updated to include 2 higher dose levels. • Minor modifications to the definition of dose limiting toxicities that are based on biochemical adverse events without clinical manifestations • Administrative updates, editorial changes, and style and formatting revisions have been made to improve clarity and consistency throughout the document. Significant changes are described in the table below. Detailed, changed text is displayed for first major occurrence only. Changes in sections of the protocol body were also made in the protocol synopsis and elsewhere in the document, as applicable. Added text is presented in bold format.
    19 Sep 2019
    The protocol is amended to: • To add hepatitis B testing at screening for all participants and at the safety follow up for participants with positive hepatitis B serology at screening or past history of HBV infection. Participants with hepatitis B infection with positive hepatitis B DNA are excluded from the study. In addition, guidance was provided for the monitoring and management of HBV infections. • To allow enrollment of participants with first refractory bone marrow relapse occurring any time after original diagnosis after achieving a CR (ie, ≥ 1 failed attempt to induce a second remission) in the study. • To indicate that prior therapy with inotuzumab within 36 days (3 antibody half-lives), rather than 30 days, is exclusionary. • To indicate that next generation sequencing will be used to assess MRD status and lymphoblasts at the end of the Induction Cycle. • To indicate that the degree of proteasome inhibition will only be assayed in whole blood. • To clarify that participants should be in a rested and calm state before blood pressure measurements but are not required to be supine. • To clarify the reporting requirements for AEs that are laboratory findings that do not result in a clinical action or alter treatment. • To clarify that for the Cohort Safety Review Committee and the Data Monitoring Committee as-is snapshots will be used for the analyses. • To clarify that for the final analyses the database will be cleaned, processed and a locked database used in the analysis. • Editorial changes (including typographical, grammatical, and formatting) have been made throughout the document.
    13 Aug 2020
    The protocol was amended as follow: • Addition of the phase 2 part to the existing phase 1 study to allow currently participating sites to seamlessly continue to enroll participants without a break in availability of this therapy for participants that may benefit from carfilzomib combined with vincristine, dexamethasone, PEG-asparaginase, and daunorubicin (VXLD). • The primary objective of the phase 1 part of the study has been amended to clarify that in addition to determining the maximum tolerated dose, the objective is also to recommend a phase 2 dose of carfilzomib with induction therapy. • Typographical and formatting changes have been made throughout the document.
    04 Feb 2021
    The protocol was amended as follow: • The recommended phase 2 dose of 20/56 mg/m2 carfilzomib identified from phase 1 by the Cohort Safety Review Committee was added. • Protocol-approved substitutions with dose equivalents were specified for components of VXLD or intrathecal chemotherapy for regions where these components are not available to allow enrollment globally while ensuring comparability of backbone therapy. • The omission of components of VXLD treatment (eg, anthracycline) under certain conditions or steroid from intrathecal chemotherapy is allowed to be consistent with current clinical practice or local standard of care. • For participants ≥ 12 months, the dose of daunorubicin during induction was changed from 25 mg/m2 for 4 doses to 60 mg/m2 and the dosing frequency was decreased from 4 times to once per cycle (reduced total dose from 100 to 60 mg/m2). This change is intended to reduce toxicity of the VXLD backbone by both reducing the total daunorubicin dose and to move it earlier in regimen to allow bone marrow function more time to recover. The change matches the design for daunorubicin used with the VPLD backbone in similar participants in COG Study AALL01P2 and Study AALL07P1 (VPLD + bortezomib). • The rationale for changes to the VXLD regimen in the phase 2 versus phase 1 portions of the study was added. • Vindesine was removed as an acceptable replacement for vincristine because no planned country/region is expected to require this substitution. • The discontinuation of asparaginase is allowed if Erwinia asparaginase is not available or desensitization procedure for asparaginase.
    04 Feb 2021
    • Details on non-investigational products and other protocol-required therapies were added to the phase 2 portion of the study for clarity. • The recommended dosing of trimethoprim sulfamethoxazole was added along with suggested alternatives for contraindication or significant concerns of bone marrow suppression, with a requirement to include the rationale for the use of an alternative agent in the case report form. • Clarification was added that adjustment of the carfilzomib dose is required for certain toxicities. • Dose modification guidelines, including adding guidance for progressive multifocal leukoencephalopathy and resuming carfilzomib with controlled hepatitis B reactivation, were aligned with those of the carfilzomib program for consistency across studies. • Supportive care requirements and guidelines were updated and guidelines for mucositis was added based on the recommendations of the steering committee. • The most impactful difference in participant population between phase 1 and phase 2 was clarified. • A correction was made to the inclusion criterion that adequate cardiac function is defined as shortening fraction of ≥ 30% > not 30%. • A correction was made to the inclusion criterion that life expectancy must be  6 weeks not ≥ 6 weeks. • Clarification was added to the exclusion criterion that participants should be excluded for intolerance, hypersensitivity, or inability to receive any of the chemotherapy components of the VXLD regimen (or acceptable substitutes as defined in the protocol). • Corrections were made to the exclusion criteria that participants should refrain from becoming pregnant or breastfeeding and must use contraception for 6 months after the last dose of any study treatment or for 12 months after the last dose of cyclophosphamide if used. • A recommendation was added that oral hormonal contraception not be used during PEG- or Erwinia asparaginase treatment due to a potential interaction.
    04 Feb 2021
    • Collection of serious adverse events was extended through long-term follow-up for compliance with clinical trial guidance. • A requirement for cytomegalovirus (CMV) polymerase chain reaction (PCR) testing at screening was added for participants with prior transplant. CMV PCR testing at screening was added to the schedule of assessments and analyte listing to clarify the required testing for these participants and those who are CMV positive, and to further clarify that CMV testing is recommended for all participants. • Clarification was added to the schedule of assessments that participants with symptoms of congestive heart failure during or after completion of induction therapy should have an echocardiogram before optional consolidation. • The timing of hematology collection in induction and consolidation for infants was corrected to day 36 (not day 35). • Clarification was added to the schedule of assessments the clinical chemistry parameters that are required beyond a standard metabolic panel. • A correction was made to remove cholesterol, HDL, LDL, and triglycerides from the analyte listing because they are not required for any exclusion criteria or monitoring. • Clarification was added that calculated creatinine clearance or glomerular filtration rate is required at screening. • Segmented neutrophils was added to the analyte listing to allow for calculation of total neutrophils. • The requirement for unstained slides of bone marrow aspirate and peripheral blood were removed.
    04 Feb 2021
    • Clarification was added that chest imaging is only required for participants with a mass present at screening. • Pharmacodynamic blood sample collection was added at 60 minutes after the end of carfilzomib infusion on day 1 of induction to better monitor proteasome inhibition. • Pharmacodynamic and pharmacokinetic blood sample collection were added during consolidation to allow comparison between induction and consolidation • The dosing schedule of study treatments was separated from the schedule of assessments for consistency with phase 1 and other cooperative protocols. • Clarification was added that participants may be discontinued from study treatment due to death and for those determined to be ineligible for the study. • The objectives, endpoints, and analysis sets of the phase 2 portion were aligned with the statistical analysis plan (SAP). • Phase 2 endpoints were clarified (eg, removal of ‘full’ from complete response because it has no meaning). None of the edits change the endpoints themselves. • The treatment response definitions were updated per more recent United States Food and Drug Administration (US FDA) requirements and a definition for non-evaluable was added. • The definition of induction death was clarified with respect to the timing of response evaluation. • Clarification was added that assessment of response is central review of stained slides of bone marrow aspirate, peripheral blood, and minimal residual disease (MRD) by next generation sequencing (NGS) and local assessment of sites of extramedullary disease and MRD by flow cytometry and/or PCR or NGS if available • The missing baseline covariates imputation, sample size determination, and statistical analysis sections were updated to be consistent with SAP version 2.0, dated 19 November 2020 which was amended based on the feedback from the US FDA.
    04 Feb 2021
    • Statistical comparison between experimental arm and external control arm of duration of response was removed and only descriptive statistics will be summarized because it will be analyzed only on responders in the Primary Analysis Set. • Subgroup analyses for participants who had anthracycline omitted from VXLD induction were added. Relapse time from prior transplant, number of prior relapses, and duration of most immediate prior remission subgroups were aligned with SAP. • Clarification was added that a sensitivity analysis will include any covariates still imbalanced after propensity score analysis. • The planned analyses for echocardiograms were added. • Details about the role of the independent biostatisticians who will support the futility efficacy analysis for Data Monitoring Committee (DMC) were added. • The investigators on the cover page were updated to reflect the anticipated involvement in the phase 2 portion of the study. • The anticipated number of sites participating in phase 2 was added. • A reference was added in the DMC section of the phase 1 protocol to the corresponding section for phase 2 to clarify the different roles of the DMC across phases. • Typographical and formatting issues were corrected throughout the document.
    03 Aug 2021
    The protocol was amended as follow: • Remove the pharmacogenetic biomarkers from the exploratory objectives in phase 2. • Update inclusion criterion #114 to allow participants who received blinatumomab for treatment of MRD positive disease during first remission or for primary induction failure to achieve a first remission. • Update exclusion criterion #221 to require discussion with Amgen medical monitor for participants with less than 3 antibody half-lives since the last dose of monoclonal antibody. • Add exclusion criterion for known allergy to captisol in phase 2 of the study. • Add assessments for pancreatic function tests in the Schedule of Activities for phase 2. • Add assessments for echocardiograms in the Schedule of Activities for phase 2. • Update treatment of central nervous system-positive participants to allow alternatives to hydrocortisone substitutions per local standard practice. • Clarify instructions for lumbar puncture. • Clarify information collected during long-term follow-up. • Change day 29 to day 28 in the Schedule of Activities for dose regimen for consolidation therapy in participants aged less than 12 months at screening. • Update the reasons for early removal for protocol-required investigational product(s) or procedural assessments. • Update allowance for rescreening from 1 time to 3 times. • Add the use of asparaginase erwinia chrysanthemi recombinant (RYLAZE) as a replacement for polyethylene glycol asparaginase or Erwinia asparaginase in regions where approved and available for participants less than 12 months of age at screening receiving Berlin-Frankfurt-Munster consolidation therapy. • Administrative, typographical, and formatting changes were made throughout the protocol.
    04 Nov 2022
    The protocol was amended as follow: • Allow the use of routine care procedures obtained within 7 days before enrollment to satisfy screening requirements. This is added due to a lack of clinical justification for repeating procedures that have no clinical benefit to the participant but expose the participant to potential risk. This flexibility is expected to reduce post-enrollment eligibility deviations and facilitate enrollment. • Update minimum enrollment numbers of participants with relapsed T-cell acute lymphoblastic leukemia (ALL) and with relapsed B-cell ALL based on current enrollment and health authority expectations. The minimum numbers of participants in the external control arm with relapsed B-cell ALL were also updated based on the status of incoming control arm data. The respective sample size estimates and expected power have been adjusted accordingly. • Respond to site feedback regarding confusion between phase 1 and phase 2 sections of the protocol. The synopsis is revised to remove phase 1 information and expand phase 2 information. Revisions to bring focus to phase 2 of the protocol result in a re-numbering of Sections 17 and beyond (eg, former Section 17 is now Section 18). Section and table names are revised to include “Phase 2” for clarity (throughout protocol). • Add details to define analytes used in the derivation of remission status for evaluation of the primary and secondary endpoints, and clarify that hematology and bone marrow aspirate/biopsy samples must be assessed locally • Revise the description of the primary endpoint to clarify that there is a single endpoint of CR. The previous amendment language included time window definitions for infants and children that could have been misinterpreted to suggest a CR endpoint for infants and a separate CR endpoint for children. The same clarification is made to the secondary endpoint for CR, CRp, CRh, and CRi after consolidation therapy.
    04 Nov 2022
    • Allow bone marrow to be assessed by aspirate or biopsy or flow if morphology is not available, and permit bone marrows that are performed as part of routine medical care to be used for central laboratory minimal residual disease (MRD) assessment • In the schedule of activities, replace the line for adverse events, serious adverse events, and concomitant therapies review with “X” to prevent any confusion that these will be collected, at a minimum, from screening through safety follow up. No change is made to the timing of these activities. • Corrections to schedule of activities tables: added row for “other extramedullary disease assessment” and removed day 10 hematology, which was listed in error, from Table 20 (consolidation therapy for participants less than 12 months of age) • Remove exclusion criteria 212 and 213. These required a 3-month window after previous proteasome inhibitor therapy, and a 2-month window after previous VXLD (or similar). These exclusions were not present in the phase 1 portion of the protocol, their removal was requested by investigators, and is consistent with guidance to remove time-based washout periods from clinical trials eligibility (Harvey et al, 2021). • Correct inclusion criterion 113 so eligibility requires less than 5% blasts • Extend window allowed to make up missed doses from +1 day to +3 days • Allow alternate dosing or formulation of L-asparaginase in accordance with local standard of care • Allow substitution of intrathecal regimens based on local practice • Recommendation to collect medical history and surgical history 30 days prior to signing the ICF is removed to allow collection of full ALL medical history • Update treatment response definition in alignment with National Comprehensive Cancer Network guidelines (2022) and Shallis et al, 2021, consistency with Study 20180065, and Amgen endpoint guide for leukemia.
    04 Nov 2022
    • Clarify details of the independent Data Monitoring Committee and independent Biostatistics Group, and remove requirement for every 3-month Steering Committee meetings • Update the covariates for subgroup analyses, and specify the categories into the SAP • To reduce confusion, the phase 1 pregnancy and lactation notification forms are removed with references to the respective forms to use for phase 2 • Safety reporting language updated per new Amgen protocol template updates • Revisions made for internal consistency of document (eg, number of allowed screen fails in Section 24.1.1 revised to align with Section 20.4; male contraception time revised in Section 22.1.6.15.3, Male participants to align with exclusion criteria) • Update investigator list on the cover page • Typographical and formatting issues were corrected throughout the document.
    28 Aug 2023
    The protocol was amended as follow: • The approximate sizes of the external control arm datasets (Study 20180065) for the B-cell and T-cell primary analysis sets (B-PAS/T-PAS) were updated to approximately 74 B-cell acute lymphoblastic leukemia (ALL) participants and approximately 60 T-cell ALL participants from 90 and 70 participants, respectively. Previous versions of the protocol included external control sample sizes that were larger than required to support the analysis. • Language was added to the methods of interim analysis for futility to specify that the interim analysis will be done with the external control datasets that are available at time of interim. Previous versions of the protocol required the complete external control arm dataset to be available for interim analysis. • “Full” Analysis was revised to “Final” Analysis. Definition of Final Analysis Sets (T-FAS/B-FAS) was removed, as not required. A definition of a Final Analysis Set is not required due to the revisions to Interim and Primary Analyses. As revised, all external control data, as well as all 20140106 participants, will be included in the Primary Analysis (and in the Final Analysis). • Language was updated in the Primary and Interim Futility Analyses sections to align with the new approximate size of the external control arm datasets from Study 20180065. • Power estimates were adjusted based on the expected approximate number of external control arm datasets provided above. • Safety monitoring language was added in subsection 24.2.4.5.1, ‘Adverse Events of Special Interest’. • Additional changes were made for consistency and alignment throughout the protocol including, but not limited to, administrative, typographical, formatting, numbering, and abbreviation changes.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The information presented is for the Phase 2 part of study 20140106.
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