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    Clinical Trial Results:
    An Open-label study of Ibrutinib in Combination with Bortezomib and Dexamethasone in Subjects with Relapsed or Relapsed and Refractory Multiple Myeloma

    Summary
    EudraCT number
    2015-005105-36
    Trial protocol
    CZ   DE   ES   GR   PL   IT  
    Global end of trial date
    25 Oct 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Nov 2019
    First version publication date
    08 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1139-CA
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01744691
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharmacyclics Switzerland GmbH
    Sponsor organisation address
    Mühlentalstrasse 36, Schaffhausen, Switzerland, 8200
    Public contact
    Clinical Trial information, Pharmacyclics LLC, 140 87740330, info@pcyc.com
    Scientific contact
    Clinical Trial information, Pharmacyclics LLC, 140 87740330, info@pcyc.com
    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
    26 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate Progression-Free Survival (PFS) according to International Myeloma Working Group (IMWG) response criteria (Rajkumar 2011) in subjects with relapsed or relapsed and refractory MM.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation Harmonized Tripartite Guidelines for Good Clinical Practices and applicable local regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Sep 2016
    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
    Czech Republic: 23
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Turkey: 13
    Worldwide total number of subjects
    74
    EEA total number of subjects
    61
    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)
    29
    From 65 to 84 years
    43
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    Key Inclusion Criteria: - Subjects may have received prior bortezomib treatment but must not be refractory or non-responsive - Serum monoclonal protein (SPEP) >= 1 g/dL - Urine monoclonal protein (UPEP) >= 200 mg by 24 hour urine electrophoresis

    Pre-assignment
    Screening details
    Seventy four subjects were enrolled and 74 subjects received at least 1 dose of PCI-32765 and constitute the all treated population and the safety analysis set.

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

    Arms
    Arm title
    Ibrutinib + Bortezomib + Dexamethasone
    Arm description
    Ibrutinib 840 mg + Bortezomib 1.3 mg/sqm + Dexamethasone
    Arm type
    Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    All subjects received ibrutnib 840 mg (6 x 140 mg capsules) orally once daily in combination with 1.3 mg/sqm Bortezomib s.c. on Days 1, 4, 8, 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, and 29 on each 42-day cycle (Cycles 9-12) and 20 mg dexamethasone (10 mg in subjects 75 years and older) on Days 1, 2, 4, 5, 8, 9, 11, and 12 during each 21-day cycle (Cycles 1-8) and on Days 1, 2, 8, 9, 22, 23, 29, and 30 on each 42-day cycle (Cycles 9-12) and 40 mg once weekly (20 mg in subjects 75 years and older) during Cycle 13 and beyond. Following implementation of Amendment 4, the dexamethasone dose was reduced to on Days 1, 4, 8, and 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, and 29 on each 42-day cycle (Cycles 9-12) and unchanged thereafter.

    Number of subjects in period 1
    Ibrutinib + Bortezomib + Dexamethasone
    Started
    74
    Completed
    64
    Not completed
    10
         Consent withdrawn by subject
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall study
    Reporting group description
    All subjects received ibrutnib 840 mg (6 x 140 mg capsules) orally once daily in combination with 1.3 mg/sqm Bortezomib s.c. on Days 1, 4, 8, 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, and 29 on each 42-day cycle (Cycles 9-12) and 20 mg dexamethasone (10 mg in subjects 75 years and older) on Days 1, 2, 4, 5, 8, 9, 11, and 12 during each 21-day cycle (Cycles 1-8) and on Days 1, 2, 8, 9, 22, 23, 29, and 30 on each 42-day cycle (Cycles 9-12) and 40 mg once weekly (20 mg in subjects 75 years and older) during Cycle 13 and beyond. Following implementation of Amendment 4, the dexamethasone dose was reduced to on Days 1, 4, 8, and 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, and 30 on each 42-day cycle (Cycles 9-12) and unchanged thereafter.

    Reporting group values
    overall study Total
    Number of subjects
    74 74
    Age categorical
    Count of Participants
    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)
    29 29
        From 65-84 years
    43 43
        85 years and over
    2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.9 ± 10.14 -
    Gender categorical
    Units: Subjects
        Female
    39 39
        Male
    35 35

    End points

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    End points reporting groups
    Reporting group title
    Ibrutinib + Bortezomib + Dexamethasone
    Reporting group description
    Ibrutinib 840 mg + Bortezomib 1.3 mg/sqm + Dexamethasone

    Primary: Progression free survival

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    End point title
    Progression free survival [1]
    End point description
    The primary efficacy endpoint of this study was mPFS. Progression free survival was defined as the time from the date of first dose of study treatment to confirmed disease progression or death from any cause, whichever occurs first.
    End point type
    Primary
    End point timeframe
    The median time on study for all treated participants was 19.6 (range 0.16+, 24.64) 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: This has been a single-arm, open-label study and it is not possible to enter a statistical analysis for a single-arm study in EudraCT.
    End point values
    Ibrutinib + Bortezomib + Dexamethasone
    Number of subjects analysed
    74
    Units: Month number (confidence interval 95%)
        number (confidence interval 95%)
    8.5 (6.2 to 10.8)
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    Overall Response Rate
    End point description
    Overall Response Reate is the proportion of subjects who achieve a PR or better over the course of the study but prior to initiation of subsequent anti-cancer therapy.
    End point type
    Secondary
    End point timeframe
    The median time on study for all treated participants was 19.6 (range 0.16+, 24.64) months
    End point values
    Ibrutinib + Bortezomib + Dexamethasone
    Number of subjects analysed
    74
    Units: number (confidence interval 95%)
        number (confidence interval 95%)
    56.8 (44.7 to 68.2)
    No statistical analyses for this end point

    Secondary: Overall Survival at 24 months

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    End point title
    Overall Survival at 24 months
    End point description
    As the median overall survival has not been reached, the data for the landmark analysis at 24 months are provided.
    End point type
    Secondary
    End point timeframe
    The median time on study for all treated participants was 19.6 (range 0.16+, 24.64) months
    End point values
    Ibrutinib + Bortezomib + Dexamethasone
    Number of subjects analysed
    74
    Units: percent
        number (confidence interval 95%)
    53.6 (38.0 to 67.0)
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    End point type
    Secondary
    End point timeframe
    The median time on study for all treated participants was 19.6 (range 0.16+, 24.64) months
    End point values
    Ibrutinib + Bortezomib + Dexamethasone
    Number of subjects analysed
    74
    Units: months
        number (confidence interval 95%)
    9.5 (6.9 to 10.6)
    No statistical analyses for this end point

    Secondary: Time to Progression

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    End point title
    Time to Progression
    End point description
    End point type
    Secondary
    End point timeframe
    The median time on study for all treated participants was 19.6 (range 0.16+, 24.64) months
    End point values
    Ibrutinib + Bortezomib + Dexamethasone
    Number of subjects analysed
    74
    Units: months
        number (confidence interval 95%)
    10.6 (7.8 to 12.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of PCI-32765 to within 30 days of last dose for each participant or until study closure
    Adverse event reporting additional description
    Number of participants who had experienced at least one treatment emergent AE
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    IBRUTINIB (PCI-32765) + BORTEZOMIB + DEXAMETHASONE
    Reporting group description
    All subjects received ibrutnib 840 mg (6 x 140 mg capsules) orally once daily in combination with 1.3 mg/sqm Bortezomib s.c. on Days 1, 4, 8, 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, and 29 on each 42-day cycle (Cycles 9-12) and 20 mg dexamethasone (10 mg in subjects 75 years and older) on Days 1, 2, 4, 5, 8, 9, 11, and 12 during each 21-day cycle (Cycles 1-8) and on Days 1, 2, 8, 9, 22, 23, 29, and 30 on each 42-day cycle (Cycles 9-12) and 40 mg once weekly (20 mg in subjects 75 years and older) during Cycle 13 and beyond. Following implementation of Amendment 4, the dexamethasone dose was reduced to on Days 1, 4, 8, and 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, and 30 on each 42-day cycle (Cycles 9-12) and unchanged thereafter.

    Serious adverse events
    IBRUTINIB (PCI-32765) + BORTEZOMIB + DEXAMETHASONE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 74 (63.51%)
         number of deaths (all causes)
    27
         number of deaths resulting from adverse events
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Death
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Sudden death
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary toxicity
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Spinal compression fracture
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 3
    Atrial flutter
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Sinus bradycardia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Polyneuropathy
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 7
    Spontaneous haematoma
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Mouth ulceration
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Renal impairment
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Bacteraemia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Brain abscess
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Bronchitis
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    Bronchitis viral
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Erysipelas
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Haemophilus bacteraemia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Haemophilus infection
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Herpes simplex
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Infection
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Influenza
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Lung infection
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 2
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    11 / 74 (14.86%)
         occurrences causally related to treatment / all
    4 / 12
         deaths causally related to treatment / all
    1 / 2
    Pneumonia bacterial
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 2
    Pneumonia escherichia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumonia haemophilus
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    Pneumonia pneumococcal
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Salmonellosis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sepsis
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    1 / 3
    Staphylococcal infection
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypoglycaemia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hyponatraemia
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    IBRUTINIB (PCI-32765) + BORTEZOMIB + DEXAMETHASONE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 74 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    14
    Hypotension
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    22 / 74 (29.73%)
         occurrences all number
    60
    Fatigue
         subjects affected / exposed
    21 / 74 (28.38%)
         occurrences all number
    40
    Oedema peripheral
         subjects affected / exposed
    21 / 74 (28.38%)
         occurrences all number
    29
    Pain
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Peripheral swelling
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    6
    Pyrexia
         subjects affected / exposed
    13 / 74 (17.57%)
         occurrences all number
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 74 (20.27%)
         occurrences all number
    20
    Dyspnoea
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    11
    Epistaxis
         subjects affected / exposed
    7 / 74 (9.46%)
         occurrences all number
    8
    Oropharyngeal pain
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    6
    Productive cough
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    4
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Insomnia
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    6
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    6
    Platelet count decreased
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    16
    Weight decreased
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    5
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    6
    Headache
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    6
    Neuropathy peripheral
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    6
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    14
    Peripheral sensory neuropathy
         subjects affected / exposed
    18 / 74 (24.32%)
         occurrences all number
    19
    Polyneuropathy
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    10
    Somnolence
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    6
    Syncope
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 74 (37.84%)
         occurrences all number
    66
    Lymphopenia
         subjects affected / exposed
    11 / 74 (14.86%)
         occurrences all number
    50
    Thrombocytopenia
         subjects affected / exposed
    45 / 74 (60.81%)
         occurrences all number
    293
    Neutropenia
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    20
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    4
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    5
    Vision blurred
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    8
    Abdominal pain upper
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    7
    Constipation
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    17
    Diarrhoea
         subjects affected / exposed
    40 / 74 (54.05%)
         occurrences all number
    119
    Dyspepsia
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    5
    Mouth haemorrhage
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    18 / 74 (24.32%)
         occurrences all number
    24
    Stomatitis
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    11 / 74 (14.86%)
         occurrences all number
    13
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    22
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    6
    Rash maculo-papular
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    15
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    6
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 74 (20.27%)
         occurrences all number
    19
    Bone pain
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    5
    Muscle spasms
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    7
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    4
    Musculoskeletal pain
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    6
    Pain in extremity
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    8
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 74 (12.16%)
         occurrences all number
    11
    Conjunctivitis
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    11
    Herpes zoster
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    4
    Infection
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Influenza
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Nasopharyngitis
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    17
    Oral candidiasis
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    4
    Pharyngitis
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Pneumonia
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    5
    Respiratory tract infection
         subjects affected / exposed
    7 / 74 (9.46%)
         occurrences all number
    11
    Tonsillitis
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 74 (25.68%)
         occurrences all number
    29
    Urinary tract infection
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    11
    Hyperuricaemia
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences all number
    3
    Hypocalcaemia
         subjects affected / exposed
    11 / 74 (14.86%)
         occurrences all number
    16
    Hypomagnesaemia
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    4
    Hypokalaemia
         subjects affected / exposed
    13 / 74 (17.57%)
         occurrences all number
    22
    Hyponatraemia
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    10
    Hypophosphataemia
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Feb 2016
    • Modify inclusion criteria to allow subjects with IgA, IgD, IgE or IgM multiple myeloma to enroll in the study with SPEP ≥ 0.5 g/dL. • Removal of local analysis of FISH at Screening and clarification of biomarker testing. • Added option for low-dose whole-body CT scan to be performed instead of skeletal survey based upon methods that could be used to clarify presence of bone disease for the diagnosis of multiple myeloma. • Provided updated text regarding risks associated with ibrutinib for second primary malignancies. • Provided updated information regarding hepatic impairment. • Provided updated results on safety and efficacy for the Phase 1 part of PCYC-1119-CA (Study 1119). • Clarification added for dose reductions due to toxicity for dexamethasone for subjects >75 years of age. • Modified timing of collection of bone marrow aspirate samples at time of CR from every 3 months after confirmed CR to every 12 months after confirmed CR as MRD assessment more often than once a year is not needed.
    08 Dec 2016
    • Include changes to clarify requirements for mid-cycle visits in the case of bortezomib discontinuation prior to protocol-scheduled completion • Include changes to clarify cycles and some test requirements for efficacy assessments • Update safety language per ibrutinib Investigator’s Brochure Version 10
    18 Jan 2017
    • Update of risk and dose modification language for ibrutinib • Update the exclusion criteria regarding treatment free interval for recent prior monoclonal antibody use from <6 weeks to <2 weeks (exclusion criteria #3). • Update reporting instructions for special reporting situations, adverse events and pregnancies and clarification regarding safety analysis.
    12 May 2017
    • Provide an update on the current safety status of the study and outcome of recent Sponsor Safety review • Modify inclusion criteria to only enroll subjects with 2 or 3 prior lines of therapy • Update inclusion criteria for absolute neutrophil count • Modify the treatment schedule of dexamethasone to only administer dexamethasone on the day of bortezomib administration • Modify dose reduction guidelines of bortezomib to be in line with current clinical practice • Include clarification that interim analysis will include analysis of the enrollment distribution to reassess the initial hypothesis based on the actual subject population enrolled. • Implement a formal internal safety review committee to review safety data • Update protocol language per the current ibrutinib protocol template.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 May 2017
    On this date, enrollment of subjects was put on hold for the implementation of safety measures based on the observation of an increased incidence of serious and fatal infections in treated subjects. Risk minimization mainly included a reduction of the dexamethasone dose (effectively halving the dose in treatment cycles 1-12) and strengthening of infection prophylaxis. Subjects already enrolled were allowed to continue treatment with the reduced dose of dexamethasone. As significantly reduced number of serious and no fatal infections were observed in the following 6 months leading to approval of restarting enrollment by regulatory authorities and ethics committees. However, an evaluation of the efficacy data performed at the same time indicated that the primary endpoint of achieving a mPFS of >12 months was unlikely to be achieved following inclusion of additional subjects. As a result, the study was terminated and enrolment was not restarted.
    -

    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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