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    Clinical Trial Results:
    Age-adjusted high-dose chemotherapy and autologous stem cell transplant in elderly and fit primary CNS lymphoma patients

    Summary
    EudraCT number
    		 2016-001628-72
    Trial protocol
    		 DE  
    Global end of trial date
    27 Dec 2021

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

    Trial information

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    Trial identification
    Sponsor protocol code
    P001317
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS: DRKS00011932
    Sponsors
    Sponsor organisation name
    Medical Center - University of Freiburg
    Sponsor organisation address
    Hugstetter Straße 55, Freiburg, Germany, 79106
    Public contact
    PD Dr. med. Elisabeth Schorb, Universitätsklinikum Freiburg, Klinik für Innere Medizin I, 0049 761270-35361, elisabeth.schorb@uniklinik-freiburg.de
    Scientific contact
    PD Dr. med. Elisabeth Schorb, Universitätsklinikum Freiburg, Klinik für Innere Medizin I, 0049 761270-35361, elisabeth.schorb@uniklinik-freiburg.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to investigate the efficacy of age-adapted induction treatment followed by high-dose chemotherapy and autologous stem cell transplantation regarding 1-year PFS in elderly and fit patients with primary CNS lymphoma.
    Protection of trial subjects
    The patient was free to withdraw from the study for any reason and at any time without giving reason for doing so and without penalty or prejudice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 54
    Number of subjects completed
    		 54

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Single arm trial, not blinded

    Arms
    Arm title
    		 Induction treatment followed by high-dose chemo
    Arm description
    		 Induction treatment: 2 cycles, stem-cell harvest after first cycle: rituximab 375 mg/m²/d i.v. (days 0, 4), MTX 3.5 g/m² i.v. (day 1), and Ara-C 2 x 2 g/m²/d i.v. (days 2-3) followed by Consolidation treatment: High-dose chemotherapy: rituximab 375 mg/m² i.v. (days -8), busulfan 3.2 mg/kg/d i.v. (days -7 and -6), thiotepa 5 mg/kg/d i.v. (days -5 and -4), ASCT (day 0)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Concentrate for solution for infusion
    Dosage and administration details
    Strength: 10 mg/mL (referred to concentrate) Dose: 1875 mg/m2 (total), for induction and consolidation treatment

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Busilvex®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Concentrate for solution for infusion
    Dosage and administration details
    Strength: 6 mg/ml (refers to concentrate) Dose: 6.4 mg/kg (total)

    Investigational medicinal product name
    Thiotepa
    Investigational medicinal product code
    Other name
    TEPADINA® 100 mg
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Concentrate for solution for infusion
    Dosage and administration details
    Strength: 10 mg/mL (refers to concentrate) Dose: 10 mg/kg (total), for high-dose consolidation

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Methotrexat medac 100 mg/mL Injektionslösung
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Strength: 100 mg/mL MTX Dose: 7 g/m2 (total), for induction treatment

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    ARA-cell® 4000 mg Infusionslösung
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Strength: 50 mg/mL Dose: 16 g/m2 (total), for induction treatment

    Number of subjects in period 1
    		Induction treatment followed by high-dose chemo
    Started
    54
    Completed
    37
    Not completed
    17
         Multiple reasons
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Reporting group values
    		 Overall Total
    Number of subjects
    		 54 54
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 54 54
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 28 28
        Male
    		 26 26
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS analysis is based on the data of 51 registered patients who received at least one administration of IMP and who had no major protocol deviations.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis was performed in the safety analysis set (SAF), comprising all patients for whom treatment was started. In case the SAF was restricted to those patients who received HD-ASCT, it was denoted as SAF-PP.

    Subject analysis sets values
    		 Full analysis set (FAS) Safety analysis set (SAF)
    Number of subjects
    51
    54
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    0
    0
        From 65-84 years
    51
    54
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    27
    28
        Male
    24
    26

    End points

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    End points reporting groups
    Reporting group title
    Induction treatment followed by high-dose chemo
    Reporting group description
    		 Induction treatment: 2 cycles, stem-cell harvest after first cycle: rituximab 375 mg/m²/d i.v. (days 0, 4), MTX 3.5 g/m² i.v. (day 1), and Ara-C 2 x 2 g/m²/d i.v. (days 2-3) followed by Consolidation treatment: High-dose chemotherapy: rituximab 375 mg/m² i.v. (days -8), busulfan 3.2 mg/kg/d i.v. (days -7 and -6), thiotepa 5 mg/kg/d i.v. (days -5 and -4), ASCT (day 0)

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS analysis is based on the data of 51 registered patients who received at least one administration of IMP and who had no major protocol deviations.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis was performed in the safety analysis set (SAF), comprising all patients for whom treatment was started. In case the SAF was restricted to those patients who received HD-ASCT, it was denoted as SAF-PP.

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival [1]
    End point description
    End point type
    Primary
    End point timeframe
    1 year from start of the induction treatment until disease progression or death, whichever occurred first.
    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: Single arm trial. The primary endpoint of the trial was PFS at 1 year, where PFS was defined as the time from start of treatment until disease progression or death, whichever occurred first. As no censored observations before 1 year occurred, the 1 year PFS rate was estimated based on the Binomial distribution, and exact CIs were derived.
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: % of patients
    number (confidence interval 80%)
        PFS at 1 year
    58.8 (48.9 to 68.2)
    No statistical analyses for this end point

    Secondary: Complete Remission after induction treatment

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    End point title
    		 Complete Remission after induction treatment
    End point description
    End point type
    Secondary
    End point timeframe
    after induction treatment
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: Number of patients
        Complete remission
    3
        Unconfirmed complete remission
    3
        Partial Remission
    36
        Stable disease
    2
        Progressive disease
    1
        Missing evaluation and death before day 43
    5
        Missing evaluation
    1
    No statistical analyses for this end point

    Secondary: Complete Remission on day 30 after HDT-ASCT

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    End point title
    		 Complete Remission on day 30 after HDT-ASCT
    End point description
    End point type
    Secondary
    End point timeframe
    30 after HDT-ASCT
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: Number of patients
        Complete Remission
    11
        Unconfirmed complete remission
    12
        Partial remission
    12
        Missing eval. and death/progr. before day 120
    12
        Mission evaluation
    4
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    End point type
    Secondary
    End point timeframe
    from start of induction treatment
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: % of patients
    number (confidence interval 80%)
        3 months
    86.3 (78.7 to 91.3)
        6 months
    68.6 (59.5 to 76.1)
        12 months
    58.8 (49.5 to 67.0)
        18 months
    55.9 (46.2 to 64.5)
        24 months
    55.9 (46.2 to 64.5)
        36 months
    55.9 (46.2 to 64.5)
        48 months
    37.3 (17.9 to 56.7)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    from start of induction treatment
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: % of patients
    number (confidence interval 95%)
        3 months
    88.2 (75.7 to 94.5)
        6 months
    72.5 (58.1 to 82.7)
        12 months
    62.7 (48.0 to 74.4)
        18 months
    60.1 (45.1 to 72.2)
        24 months
    60.1 (45.1 to 72.2)
        36 months
    60.1 (45.1 to 72.2)
        48 months
    34.4 (8.7 to 62.7)
    No statistical analyses for this end point

    Secondary: Non Relapse Mortality

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    End point title
    		 Non Relapse Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    from start of induction treatment
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: Cumulative incidence
    number (confidence interval 95%)
        3 months
    0.1176 (0.0473 to 0.2230)
        6 months
    0.2353 (0.1294 to 0.3592)
        12 months
    0.2745 (0.1599 to 0.4019)
        18 months
    0.2745 (0.1599 to 0.4019)
        24 months
    0.2745 (0.1599 to 0.4019)
        36 months
    0.2745 (0.1599 to 0.4019)
        48 months
    0.4608 (0.1070 to 0.7644)
    No statistical analyses for this end point

    Secondary: Relapse rate

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    End point title
    		 Relapse rate
    End point description
    End point type
    Secondary
    End point timeframe
    from start of induction treatment
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: Cumulative incidence
    number (confidence interval 95%)
        3 months
    0.0196 (0.0015 to 0.0919)
        6 months
    0.0784 (0.0247 to 0.1737)
        12 months
    0.1373 (0.0595 to 0.2472)
        18 months
    0.1667 (0.0756 to 0.2885)
        24 months
    0.1667 (0.0756 to 0.2885)
        36 months
    0.1667 (0.0756 to 0.2885)
        48 months
    0.1667 (0.0756 to 0.2885)
    No statistical analyses for this end point

    Secondary: EORTC QLQ-30 - Global health status

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    End point title
    		 EORTC QLQ-30 - Global health status
    End point description
    End point type
    Secondary
    End point timeframe
    During trial
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: Points (QLQ-30)
    arithmetic mean (standard deviation)
        Screening
    51.5 ( 26.4 )
        Response assessment I
    58.1 ( 21.0 )
        Response assessment II (EOT)
    56.5 ( 24.9 )
        Change from screening to EOT
    -0.4 ( 25.7 )
        1 year follow-up
    70.2 ( 22.9 )
        1 year FU: change from screening
    14.8 ( 30.1 )
    No statistical analyses for this end point

    Secondary: Activities of Daily Life

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    End point title
    		 Activities of Daily Life
    End point description
    End point type
    Secondary
    End point timeframe
    during trial
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: Points (ADL)
    arithmetic mean (standard deviation)
        Screening
    14.9 ( 6.0 )
        Response assessment I
    15.0 ( 5.7 )
        Response assessment II (EOT)
    15.6 ( 5.9 )
        Change from screening to EOT
    -0.7 ( 4.6 )
        1 year follow-up
    17.2 ( 5.3 )
    No statistical analyses for this end point

    Secondary: Mini-Mental Status Examination

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    End point title
    		 Mini-Mental Status Examination
    End point description
    End point type
    Secondary
    End point timeframe
    during trial
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: Points
    arithmetic mean (standard deviation)
        Screening
    23.4 ( 6.4 )
        Response assessment I
    24.9 ( 5.2 )
        Response assessment II (EOT)
    25.6 ( 5.8 )
        Change from screening to EOT
    2.5 ( 3.9 )
        1 year follow-up
    26.3 ( 5.4 )
    No statistical analyses for this end point

    Secondary: Neuro-psychological assessment

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    End point title
    		 Neuro-psychological assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Day 30 after EOT/ASCT
    End point values
    		 Full analysis set (FAS)
    Number of subjects analysed
    51
    Units: Points / sec
    median (full range (min-max))
        Digit span forward [points]
    9.5 (6 to 16)
        Digit span backward [points]
    5 (2 to 11)
        Digit span total [points]
    15 (9 to 24)
        Short-term recall total [points]
    16.5 (3 to 28)
        Short-term recall delayed [points]
    5 (0 to 12)
        Brief test of attention: digits [points]
    7 (1 to 10)
        Brief test of attention: letters [points]
    6 (0 to 10)
        Brief test of attention total [points]
    13 (1 to 19)
        Trail making test A [sec]
    57 (24 to 180)
        Trail making test B [sec]
    122 (66 to 300)
        Grooved pegboard right [sec]
    104 (0 to 280)
        Grooved Pegboard left [sec]
    104 (64 to 517)
        Total of correct positive answers [points]
    12 (0 to 12)
        Semantically related false positive answers [point
    0 (0 to 6)
        Semantically not related false positive answers [p
    0 (0 to 6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Complete study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Induction treatment followed by high-dose chemo
    Reporting group description
    		 Induction treatment: Rituximab 375 mg/m²/d i.v. (d0,4)+MTX 3,5 g/m² i.v. (d1)+AraC 2x2 g/m²/d i.v. (d2-3) Consolidation: Rituximab 375 mg/m² i.v. (d-8)+Busulfan 3,2 mg/kg/d i.v. (d-7 and d-6)+Thiotepa 5 mg/kg/d i.v. (d-5 and d-4)+ASCT (d0)

    Serious adverse events
    		 Induction treatment followed by high-dose chemo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 54 (51.85%)
         number of deaths (all causes)
    22
         number of deaths resulting from adverse events
    10
    General disorders and administration site conditions
    Injection site necrosis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Dysarthria
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Neurotoxicity
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Haematotoxicity
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Thrombocytopenia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Neutropenic infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 54 (11.11%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    1 / 2
    Urinary tract infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    Septic shock
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Induction treatment followed by high-dose chemo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 54 (100.00%)
    Vascular disorders
    Embolism
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Haematoma
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    4
    Hypertension
         subjects affected / exposed
    26 / 54 (48.15%)
         occurrences all number
    29
    Hypotension
         subjects affected / exposed
    20 / 54 (37.04%)
         occurrences all number
    23
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    26 / 54 (48.15%)
         occurrences all number
    33
    Gait disturbance
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Generalised oedema
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    23 / 54 (42.59%)
         occurrences all number
    28
    Pain
         subjects affected / exposed
    16 / 54 (29.63%)
         occurrences all number
    17
    Pyrexia
         subjects affected / exposed
    18 / 54 (33.33%)
         occurrences all number
    21
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hypersensitivity
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Vulvovaginal erythema
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    5
    Dysphonia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    2
    Dyspnoea
         subjects affected / exposed
    11 / 54 (20.37%)
         occurrences all number
    12
    Epistaxis
         subjects affected / exposed
    12 / 54 (22.22%)
         occurrences all number
    12
    Hypoxia
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    4
    Rhinorrhoea
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Pleural effusion
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Respiratory failure
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    4
    Confusional state
         subjects affected / exposed
    22 / 54 (40.74%)
         occurrences all number
    28
    Delirium
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Depression
         subjects affected / exposed
    5 / 54 (9.26%)
         occurrences all number
    7
    Disorientation
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hallucination
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    4
    Insomnia
         subjects affected / exposed
    9 / 54 (16.67%)
         occurrences all number
    11
    Restlessness
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    51 / 54 (94.44%)
         occurrences all number
    77
    Aspartate aminotransferase increased
         subjects affected / exposed
    30 / 54 (55.56%)
         occurrences all number
    44
    Blood creatinine increased
         subjects affected / exposed
    22 / 54 (40.74%)
         occurrences all number
    28
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Blood bilirubin increased
         subjects affected / exposed
    17 / 54 (31.48%)
         occurrences all number
    20
    Blood fibrinogen decreased
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    C-reactive protein increased
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    4
    Blood lactate dehydrogenase
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Forced expiratory volume decreased
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    43 / 54 (79.63%)
         occurrences all number
    61
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Pancreatic enzymes increased
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Neutrophil count decreased
         subjects affected / exposed
    43 / 54 (79.63%)
         occurrences all number
    63
    White blood cell count decreased
         subjects affected / exposed
    52 / 54 (96.30%)
         occurrences all number
    89
    Weight increased
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 54 (11.11%)
         occurrences all number
    8
    Fracture
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Infusion related reaction
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Thermal burn
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Arrhythmia
         subjects affected / exposed
    5 / 54 (9.26%)
         occurrences all number
    5
    Atrial fibrillation
         subjects affected / exposed
    6 / 54 (11.11%)
         occurrences all number
    6
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Bradycardia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Diastolic dysfunction
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    6 / 54 (11.11%)
         occurrences all number
    8
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    9 / 54 (16.67%)
         occurrences all number
    10
    Dysarthria
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Dysdiadochokinesis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Facial paresis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    11 / 54 (20.37%)
         occurrences all number
    14
    Hemiparesis
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    4
    Hypoaesthesia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Leukoencephalopathy
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    2
    Memory impairment
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Monoparesis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    8 / 54 (14.81%)
         occurrences all number
    8
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Presyncope
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Sciatica
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    8 / 54 (14.81%)
         occurrences all number
    9
    Syncope
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    4
    Transient ischaemic attack
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Seizure
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    54 / 54 (100.00%)
         occurrences all number
    91
    Febrile neutropenia
         subjects affected / exposed
    32 / 54 (59.26%)
         occurrences all number
    41
    Leukocytosis
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Lymphopenia
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Thrombocytopenia
         subjects affected / exposed
    54 / 54 (100.00%)
         occurrences all number
    91
    Thrombocytopenic purpura
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Ulcerative keratitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Visual impairment
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 54 (24.07%)
         occurrences all number
    14
    Anal erythema
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Anal haemorrhage
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Diverticulum intestinal
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Constipation
         subjects affected / exposed
    21 / 54 (38.89%)
         occurrences all number
    23
    Diarrhoea
         subjects affected / exposed
    22 / 54 (40.74%)
         occurrences all number
    25
    Diverticulum
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Dysphagia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Neutropenic colitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Mouth haemorrhage
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    25 / 54 (46.30%)
         occurrences all number
    32
    Oesophagitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Pancreatitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    36 / 54 (66.67%)
         occurrences all number
    39
    Vomiting
         subjects affected / exposed
    16 / 54 (29.63%)
         occurrences all number
    17
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hepatic cyst
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hepatic pain
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    4
    Erythema
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Drug eruption
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Intertrigo
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    5 / 54 (9.26%)
         occurrences all number
    5
    Rash
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Skin fissures
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Skin ulcer
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Urticaria
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Chronic kidney disease
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    4
    Haematuria
         subjects affected / exposed
    5 / 54 (9.26%)
         occurrences all number
    5
    Incontinence
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Polyuria
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Renal cyst
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Urinary tract obstruction
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Urinary incontinence
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    4
    Urinary retention
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Urinary tract pain
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Hypothyroidism
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Bone pain
         subjects affected / exposed
    11 / 54 (20.37%)
         occurrences all number
    12
    Muscle spasms
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Muscular weakness
         subjects affected / exposed
    5 / 54 (9.26%)
         occurrences all number
    5
    Myalgia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Anorectal infection bacterial
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Bacteraemia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Bacterial tracheitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Bronchitis
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Clostridium difficile infection
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Device related infection
         subjects affected / exposed
    5 / 54 (9.26%)
         occurrences all number
    6
    Escherichia infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Eye infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Febrile infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Injection site abscess
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Laryngitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Mucosal infection
         subjects affected / exposed
    9 / 54 (16.67%)
         occurrences all number
    11
    Neutropenic sepsis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Paronychia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    4
    Rash pustular
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Respiratory moniliasis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Sepsis
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    4
    Septic encephalopathy
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Septic shock
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Skin infection
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Soft tissue infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Staphylococcal infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    7 / 54 (12.96%)
         occurrences all number
    8
    Vascular device infection
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    5
    Dehydration
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Hyperglycaemia
         subjects affected / exposed
    18 / 54 (33.33%)
         occurrences all number
    27
    Hyperkalaemia
         subjects affected / exposed
    9 / 54 (16.67%)
         occurrences all number
    9
    Hypernatraemia
         subjects affected / exposed
    7 / 54 (12.96%)
         occurrences all number
    10
    Hyperphosphataemia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Hyperuricaemia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    4
    Hypocalcaemia
         subjects affected / exposed
    4 / 54 (7.41%)
         occurrences all number
    4
    Hypokalaemia
         subjects affected / exposed
    27 / 54 (50.00%)
         occurrences all number
    37
    Hypomagnesaemia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hyponatraemia
         subjects affected / exposed
    17 / 54 (31.48%)
         occurrences all number
    22
    Hypophosphataemia
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Steroid diabetes
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30925912
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