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    Clinical Trial Results:
    Open-Label, Multicenter Phase II Study For the Evaluation of Dasatinib (Sprycel™) Following Induction and Consolidation Therapy as well as in Maintenance Therapy in Patients With Newly Diagnosed Core-Binding Factor (CBF) Acute Myeloid Leukemia (AML)

    Summary
    EudraCT number
    		 2008-008238-35
    Trial protocol
    		 DE   AT  
    Global end of trial date
    30 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2016
    First version publication date
    16 Dec 2016
    Other versions
    Summary report(s)
    		 AMLSG 11-08 Final report

    Trial information

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    Trial identification
    Sponsor protocol code
    AMLSG11-08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00850382
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Úniversitätsklinikum Ulm
    Sponsor organisation address
    Albert-Einstein-Allee 29, Ulm, Germany, 89081
    Public contact
    AMLSG Studienzentrale, Universitätsklinikum Ulm, +49 731500 56072,
    Scientific contact
    Prof. Dr. Hartmut Döhner, Universitätsklinikum Ulm, +49 731500 45901, hartmut.doehner@uniklinik-ulm.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 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: To assess the feasibility of dasatinib 100 mg QD given after intensive induction (daunorubicin and cytarabine) and consolidation chemotherapy (high-dose cytarabine) and as single agent in maintenance therapy. The primary endpoint was a combined endpoint integrating the rates of early/hypoplastic death (Rate(ED/HD)), rate of pleural or pericardial effusion grade 3/4 (Rate(effuse)), rate of liver toxicity grade 3 or 4 that does not improve to grade 2 or less within 14 days after discontinuing responsible medication (Rate(liver)), and rate of refractory disease (Rate(RD)). Feasibility/tolerability for an individual patient was defined as a pleural or cardiac effusion level that does not exceed grade 2, as well as a liver toxicity equal to or less than grade 2 and the achievement of a complete remission after induction therapy.
    Protection of trial subjects
    In this study, safety was assessed by evaluating the following: reported adverse events, clinical laboratory test results, vital signs measurements, ECG findings, chest X-ray, echo scan, physical examination findings, monitoring of concomitant therapy. For each safety parameter, all findings (whether normal or abnormal) were recorded in the CRF.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jun 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Germany: 83
    Worldwide total number of subjects
    91
    EEA total number of subjects
    91
    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)
    75
    From 65 to 84 years
    15
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient in: 03.09.2009 Last patient last visit: 30.11.2015 (completion date) After the enrollment of initially planned 25 patients on 22.06.2010, recruitment was interrupted until approval of the amended protocol Version 3.1 (01.09.2010). Re-cruitment was restarted on 01.12.2010. Overall, n=91 patients were enrolled

    Pre-assignment
    Screening details
    		 Molecular genetic analysis (central AMLSG reference lab) of blood and bone marrow for CBF-associated gene fusions was performed at baseline within 48 hours to make an enrollment possible.

    Period 1
    Period 1 title
    Enrollment
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 All patients received induction chemotherapy (cytarabine and daunorubicin) in combination with dasatinib followed by consolidation therapy with either high-dose cytarabine in combination with dasatinib. After consolidation therapy a one-year maintenance therapy with dasatinib (continuously over 365 days) was intended in all patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Sprycel
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib was administered oral, in a daily dose of 100 mg (one a day, two tablets à 50 Patients should have taken their daily dose at approximately the same time in the morning. Each daily dose should have beene given with food and a glass of water (~240 mL). Patients should have been instructed to swallow capsules whole and not chew capsules. Induction therapy: 100 mg/day, days 8-21 Consolidation therapy: 100 mg/day, days 6-28 Maintenance therapy: 100 mg/day over 365 days

    Number of subjects in period 1
    		Treatment
    Started
    91
    Completed
    89
    Not completed
    2
         violation of inclusion/exclusion criteria
    2
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 All patients received induction chemotherapy (cytarabine and daunorubicin) in combination with dasatinib followed by consolidation therapy with either high-dose cytarabine in combination with dasatinib. After consolidation therapy a one-year maintenance therapy with dasatinib (continuously over 365 days) was intended in all patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dasatinib
    Investigational medicinal product code
    Other name
    Sprycel
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dasatinib was administered oral, in a daily dose of 100 mg (one a day, two tablets à 50 Patients should have taken their daily dose at approximately the same time in the morning. Each daily dose should have beene given with food and a glass of water (~240 mL). Patients should have been instructed to swallow capsules whole and not chew capsules. Induction therapy: 100 mg/day, days 8-21 Consolidation therapy: 100 mg/day, days 6-28 Maintenance therapy: 100 mg/day over 365 days

    Number of subjects in period 2
    		Treatment
    Started
    89
    Induction cycle I
    89
    Induction cycle II (optional)
    7 [1]
    Consolidation cycle I
    69
    Consolidation cycle II
    64
    Consolidation cycle III
    61
    Consolidation cycle IV
    55
    Maintenance therapy
    53
    Completed
    22
    Not completed
    67
         Adverse event, serious fatal
    4
         Consent withdrawn by subject
    5
         Adverse event, non-fatal
    33
         Other reasons
    2
         Lack of efficacy
    23
    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: Induction cycle II was administered only in patients not achieving a CR/CRi after Induction cycle I. Therefore, only 7 patients started this Milestone. 69 patients started consolidation cycle I, either directly after induction cycle I or after induction cycle II.

    Baseline characteristics

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

    Reporting group values
    		 Enrollment Total
    Number of subjects
    		 91 91
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 49.6 (19 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 43 43
        Male
    		 48 48
    ECOG Performance status
    Units: Subjects
        Score 0
    		 38 38
        Score 1
    		 40 40
        Score 2
    		 9 9
        Not recorded
    		 4 4
    Type of AML
    Units: Subjects
        De Novo
    		 78 78
        sAML
    		 2 2
        tAML
    		 10 10
        not recorded
    		 1 1
    NPM1 mutation status
    Units: Subjects
        Mutated
    		 0 0
        Wildtype
    		 88 88
        Not recorded
    		 3 3
    FLT3 TKD status
    Units: Subjects
        negative
    		 82 82
        positive
    		 8 8
        not recorded
    		 1 1
    FLT3 ITD status
    Units: Subjects
        positive
    		 4 4
        negative
    		 86 86
        not recorded
    		 1 1
    KIT mutation status
    Units: Subjects
        Mutation
    		 19 19
        Wildtype
    		 66 66
        not recorded
    		 6 6
    NRAS mutation status
    Units: Subjects
        Mutation
    		 27 27
        Wildtype
    		 61 61
        not recorded
    		 3 3
    Type CBF
    Units: Subjects
        t(8;21)
    		 37 37
        inv(16)
    		 53 53
        not recorded
    		 1 1
    Hemoglobin
    Units: g/dl
        median (full range (min-max))
    		 9.2 (4.6 to 14.8) -
    Platelets
    Units: G/l
        median (full range (min-max))
    		 37 (2 to 279) -
    White blood count
    Units: G/l
        median (full range (min-max))
    		 19.4 (1.2 to 192.2) -
    Bone marrow blasts
    Units: per cent
        median (full range (min-max))
    		 70 (11 to 95) -
    Peripheral blood blasts
    Units: per cent
        median (full range (min-max))
    		 38 (0 to 94) -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients scheduled for study Treatment and started with induction cycle I were included into the full Analysis set which is used for efficacy and safety Analysis.

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    89
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    49.5 (19 to 73)
    Gender categorical
    Units: Subjects
        Female
    42
        Male
    47
    ECOG Performance status
    Units: Subjects
        Score 0
    38
        Score 1
    39
        Score 2
    9
        Not recorded
    3
    Type of AML
    Units: Subjects
        De Novo
    77
        sAML
    2
        tAML
    10
        not recorded
    0
    NPM1 mutation status
    Units: Subjects
        Mutated
    0
        Wildtype
    86
        Not recorded
    3
    FLT3 TKD status
    Units: Subjects
        negative
    81
        positive
    7
        not recorded
    1
    FLT3 ITD status
    Units: Subjects
        positive
    4
        negative
    84
        not recorded
    1
    KIT mutation status
    Units: Subjects
        Mutation
    19
        Wildtype
    65
        not recorded
    5
    NRAS mutation status
    Units: Subjects
        Mutation
    27
        Wildtype
    60
        not recorded
    2
    Type CBF
    Units: Subjects
        t(8;21)
    37
        inv(16)
    52
        not recorded
    0
    Hemoglobin
    Units: g/dl
        median (full range (min-max))
    9.2 (4.6 to 14.8)
    Platelets
    Units: G/l
        median (full range (min-max))
    37 (2 to 279)
    White blood count
    Units: G/l
        median (full range (min-max))
    19.4 (1.2 to 192.2)
    Bone marrow blasts
    Units: per cent
        median (full range (min-max))
    70 (11 to 95)
    Peripheral blood blasts
    Units: per cent
        median (full range (min-max))
    40 (0 to 94)

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 All patients received induction chemotherapy (cytarabine and daunorubicin) in combination with dasatinib followed by consolidation therapy with either high-dose cytarabine in combination with dasatinib. After consolidation therapy a one-year maintenance therapy with dasatinib (continuously over 365 days) was intended in all patients.
    Reporting group title
    Treatment
    Reporting group description
    		 All patients received induction chemotherapy (cytarabine and daunorubicin) in combination with dasatinib followed by consolidation therapy with either high-dose cytarabine in combination with dasatinib. After consolidation therapy a one-year maintenance therapy with dasatinib (continuously over 365 days) was intended in all patients.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients scheduled for study Treatment and started with induction cycle I were included into the full Analysis set which is used for efficacy and safety Analysis.

    Primary: Feasibility

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    End point title
    		 Feasibility [1]
    End point description
    The primary endpoint was a combined endpoint integrating the rates of early/hypoplastic death (Rate(ED/HD)), rate of pleural or pericardial effusion grade 3/4 (Rate(effuse)), rate of liver toxicity grade 3 or 4 that does not improve to grade 2 or less within 14 days after discontinuing responsible medication (Rate(liver)), and rate of refractory disease (Rate(RD)). Feasibility/tolerability for an individual patient was defined as a pleural or cardiac effusion level that does not exceed grade 2, as well as a liver toxicity equal to or less than grade 2 and the achievement of a complete remission after induction therapy.
    End point type
    Primary
    End point timeframe
    Whole Treatment period of patients (maximally 19 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was done for Primary endpoint. Everytime an event of one of the four single endpoints occured, the cumulative number of Events of the specific endpoint was compared to the predefined critial number of Events at this enrollment stage (current number of enrolled patients). At every sequential testing time point during the study and for all single primary endpoints, the cum. number of events was below the critical value. Thus, primary endpoint was met, feasibility was shown.
    End point values
    		 Treatment Full analysis set
    Number of subjects analysed
    89
    89
    Units: subject
        Refractory Disease
    2
    2
        Early Death/Hypoplastic Death
    4
    4
        Pleural/pericardial effusion
    6
    6
        Liver toxicities
    6
    6
    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
    4 years after inclusion into the study
    End point values
    		 Treatment Full analysis set
    Number of subjects analysed
    89
    89
    Units: per cent
        number (confidence interval 95%)
    74.7 (66.1 to 84.5)
    74.7 (66.1 to 84.5)
    No statistical analyses for this end point

    Secondary: Cumulative incidence of relapse

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    End point title
    		 Cumulative incidence of relapse
    End point description
    End point type
    Secondary
    End point timeframe
    4 years after inclusion into the trial
    End point values
    		 Treatment Full analysis set
    Number of subjects analysed
    73
    73
    Units: per cent
        number (not applicable)
    35.2
    35.2
    No statistical analyses for this end point

    Secondary: Cumulative incidence of death

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    End point title
    		 Cumulative incidence of death
    End point description
    End point type
    Secondary
    End point timeframe
    after 4 years after inclusion into the trial
    End point values
    		 Treatment Full analysis set
    Number of subjects analysed
    73
    73
    Units: per cent
        number (not applicable)
    4.2
    4.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse event reporting period for this trial began upon signing of informed consent and ended 28 days after the last treatment administration or until all drug-related toxicities were resolved, whichever was later or until the Investigators assessed
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Safety data set
    Reporting group description
    		 The safety analysis set included 89 patients scheduled for study Treatment.

    Serious adverse events
    		 Safety data set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    56 / 89 (62.92%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary malingancy (possibly related to cancer treatment)
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Thrombosis/embolism
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Other vascular disorder
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    Rigor/chills
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death not associated with CTCAE term
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Other haemorrhage
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Other disorders
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Other pulmonary disorder
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Airway obstruction
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Dyspnea
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 89 (4.49%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    CRP increase
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Supraventricular arrhythmia
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Other cardiac disorders
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac ischemia/infarction
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    cTnT
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular systolic dysfunction
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    CNS hemorrhage
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuropathy sensory
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychosis
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Blood - Other disorders
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hemoglobin
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukocytes
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Neutrophils
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Platelets
         subjects affected / exposed
    4 / 89 (4.49%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Splenic function
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Blurred vision
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    6 / 7
         deaths causally related to treatment / all
    1 / 1
    Constipation
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhea
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Other gastrointestinal disorders
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hemorrhage gastrointestinal
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain abdomen
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Other hepatobiliary disorders
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Petechiae
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Other renal disorder
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Trismus
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Colitis, infectious
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences causally related to treatment / all
    6 / 13
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    18 / 89 (20.22%)
         occurrences causally related to treatment / all
    11 / 20
         deaths causally related to treatment / all
    1 / 2
    Other infection
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection abdomen
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection anal/perianal
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection colon
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection peritoneal cavity
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung (pneumonia)
         subjects affected / exposed
    17 / 89 (19.10%)
         occurrences causally related to treatment / all
    9 / 18
         deaths causally related to treatment / all
    0 / 0
    Infection pleura (empyema)
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection upper airway
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection urinary tract
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety data set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    89 / 89 (100.00%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    8 / 89 (8.99%)
         occurrences all number
    10
    Thrombosis/Embolism
         subjects affected / exposed
    6 / 89 (6.74%)
         occurrences all number
    6
    General disorders and administration site conditions
    Other constitutional symptom
         subjects affected / exposed
    7 / 89 (7.87%)
         occurrences all number
    11
    Fatigue
         subjects affected / exposed
    34 / 89 (38.20%)
         occurrences all number
    108
    Fever
         subjects affected / exposed
    58 / 89 (65.17%)
         occurrences all number
    183
    Insomnia
         subjects affected / exposed
    35 / 89 (39.33%)
         occurrences all number
    83
    rigor/chills
         subjects affected / exposed
    12 / 89 (13.48%)
         occurrences all number
    19
    sweating
         subjects affected / exposed
    7 / 89 (7.87%)
         occurrences all number
    9
    Weight gain
         subjects affected / exposed
    16 / 89 (17.98%)
         occurrences all number
    24
    Hemorrhage - other
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    14
    Pain - other
         subjects affected / exposed
    20 / 89 (22.47%)
         occurrences all number
    46
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    25 / 89 (28.09%)
         occurrences all number
    34
    Reproductive system and breast disorders
    Hemorrhage genitourinary
         subjects affected / exposed
    8 / 89 (8.99%)
         occurrences all number
    10
    Respiratory, thoracic and mediastinal disorders
    Hemorrhage pulmonary
         subjects affected / exposed
    18 / 89 (20.22%)
         occurrences all number
    26
    Pain - Chest/thorax
         subjects affected / exposed
    11 / 89 (12.36%)
         occurrences all number
    17
    Pain - Throat/pharynx/larynx
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    11
    Cough
         subjects affected / exposed
    25 / 89 (28.09%)
         occurrences all number
    39
    Dyspnea
         subjects affected / exposed
    19 / 89 (21.35%)
         occurrences all number
    32
    Pleural effusion
         subjects affected / exposed
    16 / 89 (17.98%)
         occurrences all number
    46
    Pneumonitis
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    13
    Investigations
    Alanine aminotransferase
         subjects affected / exposed
    17 / 89 (19.10%)
         occurrences all number
    44
    Aspartate aminotransferase
         subjects affected / exposed
    15 / 89 (16.85%)
         occurrences all number
    33
    Bilirubin
         subjects affected / exposed
    7 / 89 (7.87%)
         occurrences all number
    12
    Gamma-glutamyltransferase
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    17
    Hyperuricemia
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    6
    Hypoalbuminemia
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    6
    Hypocalcemia
         subjects affected / exposed
    14 / 89 (15.73%)
         occurrences all number
    34
    Hypokalemia
         subjects affected / exposed
    40 / 89 (44.94%)
         occurrences all number
    129
    Hypomagnesemia
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    23
    CRP increase
         subjects affected / exposed
    17 / 89 (19.10%)
         occurrences all number
    61
    Other lab disorders
         subjects affected / exposed
    18 / 89 (20.22%)
         occurrences all number
    36
    Cardiac disorders
    Cardiac arrhythmia - other
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    14
    Supraventricular arrhythmia
         subjects affected / exposed
    9 / 89 (10.11%)
         occurrences all number
    19
    Hypertension
         subjects affected / exposed
    17 / 89 (19.10%)
         occurrences all number
    47
    Hypotension
         subjects affected / exposed
    14 / 89 (15.73%)
         occurrences all number
    23
    Pericardial effusion
         subjects affected / exposed
    6 / 89 (6.74%)
         occurrences all number
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    20 / 89 (22.47%)
         occurrences all number
    43
    Mood alteration - agitation
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    8
    Mood alteration - anxiety
         subjects affected / exposed
    11 / 89 (12.36%)
         occurrences all number
    20
    Mood alteration - depression
         subjects affected / exposed
    12 / 89 (13.48%)
         occurrences all number
    24
    Neuropathy sensory
         subjects affected / exposed
    9 / 89 (10.11%)
         occurrences all number
    16
    Pain head/Headache
         subjects affected / exposed
    39 / 89 (43.82%)
         occurrences all number
    105
    Blood and lymphatic system disorders
    Hemoglobin
         subjects affected / exposed
    72 / 89 (80.90%)
         occurrences all number
    358
    Leukocytes
         subjects affected / exposed
    53 / 89 (59.55%)
         occurrences all number
    238
    Neutrophils
         subjects affected / exposed
    27 / 89 (30.34%)
         occurrences all number
    79
    Platelets
         subjects affected / exposed
    72 / 89 (80.90%)
         occurrences all number
    364
    Edema head and neck
         subjects affected / exposed
    8 / 89 (8.99%)
         occurrences all number
    25
    Edema limb
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    17
    Eye disorders
    Dry eye
         subjects affected / exposed
    13 / 89 (14.61%)
         occurrences all number
    25
    Other ocular disorder
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    13
    Gastrointestinal disorders
    Anorexia
         subjects affected / exposed
    16 / 89 (17.98%)
         occurrences all number
    30
    Colitis
         subjects affected / exposed
    7 / 89 (7.87%)
         occurrences all number
    10
    Constipation
         subjects affected / exposed
    39 / 89 (43.82%)
         occurrences all number
    100
    Diarrhea
         subjects affected / exposed
    61 / 89 (68.54%)
         occurrences all number
    162
    Enteritis
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    9
    Flatulence
         subjects affected / exposed
    11 / 89 (12.36%)
         occurrences all number
    28
    Gastritis
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    5
    Other gastrointestinal disorder
         subjects affected / exposed
    13 / 89 (14.61%)
         occurrences all number
    19
    Heartburn
         subjects affected / exposed
    9 / 89 (10.11%)
         occurrences all number
    19
    Mucositis
         subjects affected / exposed
    37 / 89 (41.57%)
         occurrences all number
    49
    Nausea
         subjects affected / exposed
    74 / 89 (83.15%)
         occurrences all number
    248
    Taste alteration
         subjects affected / exposed
    9 / 89 (10.11%)
         occurrences all number
    15
    Vomiting
         subjects affected / exposed
    45 / 89 (50.56%)
         occurrences all number
    106
    Hemorrhage gastrointestinal
         subjects affected / exposed
    6 / 89 (6.74%)
         occurrences all number
    7
    Pain - abdomen
         subjects affected / exposed
    29 / 89 (32.58%)
         occurrences all number
    77
    Pain - anus
         subjects affected / exposed
    7 / 89 (7.87%)
         occurrences all number
    9
    Pain - Dental / teeth
         subjects affected / exposed
    8 / 89 (8.99%)
         occurrences all number
    10
    Pain - Stomach
         subjects affected / exposed
    19 / 89 (21.35%)
         occurrences all number
    35
    Skin and subcutaneous tissue disorders
    Dermatology - other disorder
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    14
    Dry skin
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    5
    Hand - foot syndrom
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    6
    Injection site reaction
         subjects affected / exposed
    13 / 89 (14.61%)
         occurrences all number
    21
    Pruritus
         subjects affected / exposed
    16 / 89 (17.98%)
         occurrences all number
    18
    Rash
         subjects affected / exposed
    53 / 89 (59.55%)
         occurrences all number
    113
    Hematoma
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    12
    Petechiae
         subjects affected / exposed
    16 / 89 (17.98%)
         occurrences all number
    27
    Renal and urinary disorders
    Fluid retention
         subjects affected / exposed
    36 / 89 (40.45%)
         occurrences all number
    95
    Other renal disorders
         subjects affected / exposed
    7 / 89 (7.87%)
         occurrences all number
    9
    Renal failure
         subjects affected / exposed
    7 / 89 (7.87%)
         occurrences all number
    8
    Musculoskeletal and connective tissue disorders
    Other musculoskeletal disorders
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    5
    Pain - Back
         subjects affected / exposed
    28 / 89 (31.46%)
         occurrences all number
    56
    Pain - Bone
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    16
    Pain - Extremity
         subjects affected / exposed
    9 / 89 (10.11%)
         occurrences all number
    12
    Pain - Joint
         subjects affected / exposed
    23 / 89 (25.84%)
         occurrences all number
    39
    Pain - Neck
         subjects affected / exposed
    6 / 89 (6.74%)
         occurrences all number
    9
    Infections and infestations
    Colitis, Infectious
         subjects affected / exposed
    6 / 89 (6.74%)
         occurrences all number
    7
    Febrile neutropenia
         subjects affected / exposed
    39 / 89 (43.82%)
         occurrences all number
    81
    Sepsis
         subjects affected / exposed
    24 / 89 (26.97%)
         occurrences all number
    56
    Other infection
         subjects affected / exposed
    43 / 89 (48.31%)
         occurrences all number
    96
    Lip/perioral infection
         subjects affected / exposed
    14 / 89 (15.73%)
         occurrences all number
    23
    Infection anal/perianal
         subjects affected / exposed
    6 / 89 (6.74%)
         occurrences all number
    8
    Infection oral cavity/gums (gingivitis)
         subjects affected / exposed
    8 / 89 (8.99%)
         occurrences all number
    8
    Infection catheter-related
         subjects affected / exposed
    12 / 89 (13.48%)
         occurrences all number
    26
    Lung (pneumonia)
         subjects affected / exposed
    31 / 89 (34.83%)
         occurrences all number
    53
    Infection upper airways
         subjects affected / exposed
    22 / 89 (24.72%)
         occurrences all number
    40
    Infection urinary tract
         subjects affected / exposed
    13 / 89 (14.61%)
         occurrences all number
    33

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Aug 2009
    Amendment 1 (dated 17 August 2009) was issued before start of patient enrollment. There were no changes made to the protocol, but new investigational sites and investigators introduced to the study.
    04 Feb 2010
    Amendment 2 (dated 04 February 2010) to the protocol was issued after 11 patients were enrolled into the study. The major changes made to the protocol were due to integration of Austria as new country with four new investigational sites.
    01 Sep 2010
    Amendment 3 (dated 01 September 2010) to the protocol was issued after 25 patients were enrolled and intial planned study cohort was completed. The following major procedural changes (not all-inclusive) were made to the protocol: • Increase of sample size to additional 57 patients (overall sample size = 82 patients). • Implementation of an optional second induction cycle for patients not achieving complete remission after the first induction cycle.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Jun 2010
    After the enrollment of initially planned 25 patients on 22.06.2010, recruitment was interrupted until approval of the amended protocol Version 3.1 (01.09.2010). Re-cruitment was restarted on 01.12.2010.
    01 Dec 2010

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

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