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    Clinical Trial Results:
    PHASE IB STUDY OF IBRUTINIB COMBINED WITH R-DHAP OR R-DHAOX IN PATIENTS WITH B-CELL LYMPHOMAS

    Summary
    EudraCT number
    		 2013-000771-33
    Trial protocol
    		 BE  
    Global end of trial date
    22 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jan 2021
    First version publication date
    02 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BIBLOS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02055924
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LYSARC
    Sponsor organisation address
    Centre Hospitalier Lyon-Sud Secteur Sainte Eugénie - Pavillon 6D , PIERRE-BENITE, France, 69495
    Public contact
    Julie ASSEMAT, LYSARC, 0033 472669333,
    Scientific contact
    Gilles SALLES, LYSA, 0033 472669333,
    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
    29 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to determine the recommended dose of ibrutinib when administered in combination with R-DHAP (rituximab + dexamethasone + cytarabine + cisplatin) or with R-DHAOx (rituximab + dexametasone + cytarabine + oxaliplatin) in patients with relapsed or refractory B-cell malignancies eligible for autologous stem cell transplantation (ASCT) by assessing the maximum tolerated dose (MTD) observed during the dose escalation part of the study. Assessment of the MTD will be performed by the analysis of the dose-limiting toxicities (DLTs).
    Protection of trial subjects
    Salvage therapy planned if patients withdraw from protocol and study treatment.
    Background therapy
    		 R-DHAOx R-DHAP
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 May 2014
    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
    Belgium: 10
    Country: Number of subjects enrolled
    France: 71
    Worldwide total number of subjects
    81
    EEA total number of subjects
    81
    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)
    53
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 France: from 26-MAY-2014 to 23-MAR-2018 Belgium: from 13-OCT-2014 to 12-MAR-2018

    Pre-assignment
    Screening details
    		 Demographics/Medical History: age, gender, height, relevant medical history, concomitant treatments, history of the NHL, Physical exam, Weight, BSA, Vital signs, ECOG PS, Presence of B symptoms,Tumor and Bone Marrow biopsies, cardiac exam, biochemistry & haematology lab tests, CT/PET scans Nb of screened pts: 94 Nb of included pts: 85 Rando: NA

    Period 1
    Period 1 title
    overall-trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 R-DHAOx
    Arm description
    		 R-DHAOx + ibrutinib
    Arm type
    		 Experimental

    Investigational medicinal product name
    R-DHAOx + Ibrutinib
    Investigational medicinal product code
    R-DHAOx + Ibrutinib
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    rituximab, oxaliplatin, cytosine arabinoside, dexamethasone IV + ibrutininb PO

    Investigational medicinal product name
    R-DHAP + Ibrutinib
    Investigational medicinal product code
    R-DHAP
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    rituximab, cisplatin, cytosine arabinoside, dexamethasone IV + ibrutininb PO

    Arm title
    		 R-DHAP
    Arm description
    		 R-DHAP + ibrutinib
    Arm type
    		 Experimental

    Investigational medicinal product name
    R-DHAP + Ibrutinib
    Investigational medicinal product code
    R-DHAP
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    rituximab, cisplatin, cytosine arabinoside, dexamethasone IV + ibrutininb PO

    Number of subjects in period 1
    		R-DHAOx R-DHAP
    Started
    56
    25
    Completed
    43
    14
    Not completed
    13
    11
         Consent withdrawn by subject
    2
    1
         Following to security alert
    5
    -
         Adverse event, non-fatal
    2
    6
         Progression
    4
    3
         Concurrent illness
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    R-DHAOx
    Reporting group description
    		 R-DHAOx + ibrutinib

    Reporting group title
    R-DHAP
    Reporting group description
    		 R-DHAP + ibrutinib

    Reporting group values
    		 R-DHAOx R-DHAP Total
    Number of subjects
    		 56 25 81
    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
        geometric mean (full range (min-max))
    		 57.2 (25 to 70) 59.3 (25 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 19 8 27
        Male
    		 37 17 54
    Subject analysis sets

    Subject analysis set title
    Safety analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set includes all patients who took at least one dose of ibrutinib.

    Subject analysis sets values
    		 Safety analysis
    Number of subjects
    81
    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
        geometric mean (full range (min-max))
    58.4 (25 to 70)
    Gender categorical
    Units: Subjects
        Female
    27
        Male
    54

    End points

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    End points reporting groups
    Reporting group title
    R-DHAOx
    Reporting group description
    		 R-DHAOx + ibrutinib

    Reporting group title
    R-DHAP
    Reporting group description
    		 R-DHAP + ibrutinib

    Subject analysis set title
    Safety analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set includes all patients who took at least one dose of ibrutinib.

    Primary: Overall response

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    End point title
    		 Overall response [1]
    End point description
    End point type
    Primary
    End point timeframe
    3 or 4 cycles of chemotherapy + ibrutinib = 9 or 12 weeks
    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 analyses since there is no comparison between cohorts
    End point values
    		 R-DHAOx R-DHAP
    Number of subjects analysed
    56
    25
    Units: OR
        Escalation
    24
    25
        Expansion
    32
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AE of grade ≥ 2 for cardiac, renal, neuropathic and hemorrhagic toxicities regardless relationship to investigational product occurring from the date of informed consent form signature to end of treatment evaluation (30 days after last drug adm.)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    total population
    Reporting group description
    		 -

    Serious adverse events
    		 total population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 81 (53.09%)
         number of deaths (all causes)
    26
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    7 / 81 (8.64%)
         occurrences causally related to treatment / all
    5 / 8
         deaths causally related to treatment / all
    1 / 1
    Immune system disorders
    Iodine allergy
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    drug administration error
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 81 (4.94%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    15 / 81 (18.52%)
         occurrences causally related to treatment / all
    18 / 24
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    11 / 81 (13.58%)
         occurrences causally related to treatment / all
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Venoocclusive liver disease
         subjects affected / exposed
    6 / 81 (7.41%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    12 / 81 (14.81%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    14 / 81 (17.28%)
         occurrences causally related to treatment / all
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    hyponatremia
         subjects affected / exposed
    4 / 81 (4.94%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 total population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 81 (92.59%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences all number
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 81 (7.41%)
         occurrences all number
    6
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    11 / 81 (13.58%)
         occurrences all number
    12
    Immune system disorders
    Iodine allergy
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences all number
    2
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences all number
    2
    Investigations
    Blood phosphorus decreased
         subjects affected / exposed
    3 / 81 (3.70%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    drug administration error
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences all number
    2
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    2 / 81 (2.47%)
         occurrences all number
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    9 / 81 (11.11%)
         occurrences all number
    12
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    12 / 81 (14.81%)
         occurrences all number
    14
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    75 / 81 (92.59%)
         occurrences all number
    336
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 81 (23.46%)
         occurrences all number
    27
    Hepatobiliary disorders
    Venoocclusive liver disease
         subjects affected / exposed
    8 / 81 (9.88%)
         occurrences all number
    10
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 81 (4.94%)
         occurrences all number
    4
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    16 / 81 (19.75%)
         occurrences all number
    17
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    19 / 81 (23.46%)
         occurrences all number
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2014
    Update of protocol with modifications on end of treatment evaluation, abnormal lab ranges declaration and description of IMP + new IB of Ibrutinib v8.0
    05 Oct 2015
    New design of escalation phase, updated protocol and new IB of ibrutinib v9.0
    14 Feb 2017
    Adding of antiviral prophylaxis, update of protocol and new IB of ibrutinib v10.0
    29 Jun 2017
    Slight changes in the design of expansion phase and update of protocol
    19 Oct 2017
    Update of protocol Following observation of HBV reactivation, update of dexamethasone administration, and update of SAE reporting rules
    10 Apr 2018
    Update of protocol with adding of an exclusion criterion: history of liver chronic disease or venoocclusive syndrome, and new IB of ibrutinib v11.0

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Mar 2018
    Following to 3 cases of venoocclusive syndrome in the trial, ANSM and LYSARC decided to stop recruitment prematurely.
    -

    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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