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    Clinical Trial Results:
    Multicenter, open-label single arm phase II study testing the tolerability and the efficacy of Bosutinib step-in dosing in Chronic Phase CML patients intolerant or refractory to previous Imatinib, Nilotinib or Dasatinib therapy, "Bosutinib Dose Optimization Study - BODO-Study"

    Summary
    EudraCT number
    		 2014-005531-13
    Trial protocol
    		 DE  
    Global end of trial date
    23 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Mar 2022
    First version publication date
    30 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MED3-201401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Bonn
    Sponsor organisation address
    Venusberg-Campus 1, Bonn, Germany, 53127
    Public contact
    Dr. Mareille Warnken-Uhlich, Studienzentrale Studienzentrum Bonn (SZB), 49 22828716040, verena.dykstra@gmx.de
    Scientific contact
    Dr. Mareille Warnken-Uhlich, Studienzentrale Studienzentrum Bonn (SZB), 5208835336 22828716040, verena.dykstra@gmx.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
    10 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of the BODO trial is to assess the tolerability and efficacy of a step-in dosing concept of the dual SRC-ABL kinase inhibitor Bosutinib in CP-CML patients who either developed intolerance or treatment failure to previous Imatinib, Dasatinib or Nilotinib as 1st or 2nd line therapy
    Protection of trial subjects
    The study medication has already been authorized for the treatment of CP-CML. The investigator informed the patient about the study in detail and both signed the informed consent form. A patient insurance was in place. Adverse events were documented regularly and a data safety monitoring board did assess the safety status of the trial regularly.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Apr 2016
    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: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    47
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After obtaining the signed written informed consent from a potential CML patient, centers will perform screening examinations and will check inclusion/exclusion criteria. After all data is collected the BODO trial screening form will be send via fax to the Study Center Bonn (SCB). The Study Center Bonn (SCB) will get in contact to the BODO Medical

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Bosotinib
    Arm description
    		 -
    Arm type
    		 single

    Investigational medicinal product name
    Bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    step-in dosage of 300, 400 or 500 mg per day orally

    Number of subjects in period 1
    		Bosotinib
    Started
    57
    Completed
    57

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 57 57
    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)
    		 47 47
        From 65-84 years
    		 10 10
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 25 25
        Male
    		 32 32
    Subject analysis sets

    Subject analysis set title
    full analysis data
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A total of n=57 patients were eligible to participate in the study. All n=57 patients started the bosutinib therapy and were included in the full analysis data set.

    Subject analysis sets values
    		 full analysis data
    Number of subjects
    57
    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)
    47
        From 65-84 years
    10
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Bosotinib
    Reporting group description
    		 -

    Subject analysis set title
    full analysis data
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A total of n=57 patients were eligible to participate in the study. All n=57 patients started the bosutinib therapy and were included in the full analysis data set.

    Primary: Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities) within the first 6 months of treatment

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    End point title
    		 Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities) within the first 6 months of treatment
    End point description
    End point type
    Primary
    End point timeframe
    baseline to 6 month
    End point values
    		 Bosotinib full analysis data
    Number of subjects analysed
    57
    57
    Units: whole
    57
    57
    Attachments
    		 Untitled (Filename: BODO_results toxicity.docx)
    Statistical analysis title
    		 rate of GI toxicity within first 6 months
    Statistical analysis description
    The primary endpoint was to be evaluated by calculation of the incidence rate of grade 2 to 4 gastrointestinal (GI) toxicity adverse events (AEs) within 6 months after registration. The null hypothesis for the primary endpoint was given by: “The proportion of 2-4 GI toxicity will be at least P = 0.40 within the first six months of therapy.” It was to be tested against the alternative hypothesis “The proportion of 2-4 GI toxicity will be less than P = 0.40 within the first six months of therapy.”
    Comparison groups
    Bosotinib v full analysis data
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    		 Aalen-Johansen estimator
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    59.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 45.1
         upper limit
    		 70.8
    Notes
    [1] - In this non-randomized phase II study, we chose grade 2-4 GI toxicity at 6 months as the primary endpoint. This primary endpoint will be confirmatively tested. Null hypothesis H0: The proportion of 2-4 GI toxicity will be at least P = 0.40 within the first six months of therapy. Alternative hypothesis H1: The proportion of 2-4 GI toxicity will be less than P = 0.40 within the first six months of therapy.

    Secondary: Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities) at month 6, 12 and 24

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    End point title
    		 Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities) at month 6, 12 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    month 6, 12 and 24
    End point values
    		 Bosotinib
    Number of subjects analysed
    57
    Units: whole
    57
    Attachments
    		 Untitled (Filename: BODO_results toxicity.docx)
    Untitled (Filename: AE listing BODO study.docx)
    No statistical analyses for this end point

    Secondary: Efficacy parameters: CCyR, MMR, MR4 and MR4.5 rate at month 3, 6, 12, 18 and 24

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    End point title
    		 Efficacy parameters: CCyR, MMR, MR4 and MR4.5 rate at month 3, 6, 12, 18 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    month 3, 6, 12, 18, 24
    End point values
    		 Bosotinib
    Number of subjects analysed
    57
    Units: whole
    57
    Attachments
    		 Untitled (Filename: BODO_results efficacy.docx)
    No statistical analyses for this end point

    Secondary: Patient-reported outcome measures (QoL)

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    End point title
    		 Patient-reported outcome measures (QoL)
    End point description
    End point type
    Secondary
    End point timeframe
    whole study period
    End point values
    		 Bosotinib
    Number of subjects analysed
    57
    Units: whole
    57
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    End point type
    Secondary
    End point timeframe
    whole study period
    End point values
    		 Bosotinib
    Number of subjects analysed
    57
    Units: whole
    57
    Attachments
    		 Untitled (Filename: BODO_results PFS OS.docx)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    whole study period
    End point values
    		 Bosotinib
    Number of subjects analysed
    57
    Units: whole
    57
    Attachments
    		 Untitled (Filename: BODO_results PFS OS.docx)
    No statistical analyses for this end point

    Secondary: The rate of emerging mutations during Bosutinib treatment

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    End point title
    		 The rate of emerging mutations during Bosutinib treatment
    End point description
    End point type
    Secondary
    End point timeframe
    whole study period
    End point values
    		 Bosotinib
    Number of subjects analysed
    57
    Units: whole
    57
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    whole study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    bosutinib
    Reporting group description
    		 The safety analysis dataset contained all patients who received at least one dose of the investigational drug and consisted of all 57 registered patients. Time under risk for an adverse event was defined as the time while receiving study medication plus 30 days thereafter or until change of the TKI, if realized within these 30 days

    Serious adverse events
    		 bosutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 57 (28.07%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    1
    Investigations
    Catheterisation cardiac
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Coronary artery restenosis
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Embolism
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphatic fistula
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphocele
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina pectoris
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Cerebrovascular accident
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Papilloedema
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
    Additional description: MedDRA preferred Term was used,
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal artery stenosis
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Lung infection
    Additional description: MedDRA preferred Term was used, 3 such SAEs were reported
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
    Additional description: MedDRA preferred Term was used, 1 such SAE was reported
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis norovirus
    Additional description: MedDRA preferred Term was used, 1 such SAE was reported
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth abscess
    Additional description: MedDRA preferred Term was used
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 bosutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 57 (100.00%)
    Gastrointestinal disorders
    Diarrhoea
    Additional description: This AE is exemplary for all AEs. A complete listing of the AEs has been uploaded as a chart at endpoint tolerability
         subjects affected / exposed
    57 / 57 (100.00%)
         occurrences all number
    57

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2016
    Addition of pre-treatment with the first-generation TKI imatinib for inclusion Addition of follow-up visits at three-month intervals following the 24-month treatment phase until the end of the BODO study. Additional screening of patients for hepatitis B prior to initiation of treatment with tyrosine kinase inhibitors (TKIs) Bone marrow aspiration (BMP) is now only mandatory at screening/ inclusion.
    16 May 2018
    Inclusion criterion changed: pre-treated with one or two different TKIs (imatinib, dasatinib, or nilotinib) possible, i.e., bosutinib as a 2nd- or 3rd-line TKI. The definition of intolerance has been changed so that the degree of toxicity leading to treatment switch is not the sole criterion. The recruitment period has been extended by 1 year.

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

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