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    Clinical Trial Results:
    An Open-label, Multicenter, Single-arm, Phase 2 Study of PCI-32765 (ibrutinib) in Subjects with Refractory Follicular Lymphoma

    Summary
    EudraCT number
    2012-004097-26
    Trial protocol
    BE   GB   DE   ES   IT   FR  
    Global end of trial date
    18 May 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    27 May 2017
    First version publication date
    27 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCI-32765FLR2002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01779791
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, 2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.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
    18 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to evaluate the overall response rate (ORR) of ibrutinib, as assessed by the Independent Review Committee (IRC), in subjects with Chemoimmunotherapy (CIT)-resistant follicular lymphoma (FL).
    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 Good Clinical Practices and applicable regulatory requirements. Safety evaluations were based upon physical examinations, electrocardiograms, vital signs (temperature, heart rate, and blood pressure), and evaluation of changes to concomitant medications, and clinical laboratory parameters (hematology, serum chemistry, coagulation, hepatitis B and C screening, pregnancy test, serum immunoglobulin [IgG, IgM, IgA], and beta 2-microglobulin). Eastern Cooperative Oncology Group (ECOG) performance status grade was used to assess changes in the subject’s daily living activities. Adverse events (AEs) were assessed throughout the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Mar 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    United States: 50
    Worldwide total number of subjects
    110
    EEA total number of subjects
    43
    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)
    67
    From 65 to 84 years
    40
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 110 subjects were screened and assigned to Ibrutinib treatment group. All 110 subjects had discontinued the study by the clinical cut off date.

    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
    Arm description
    Subjects self-administered 560 milligram (mg) oral Ibrutinib capsules (4*140 mg) once daily continuously until disease progression or unacceptable toxicity until study end (2 years after last subject enrolled).
    Arm type
    Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    JNJ-54179060
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects self-administered 560 mg oral Ibrutinib capsules (4*140 mg) once daily continuously until disease progression or unacceptable toxicity until study end (2 years after last subject enrolled).

    Number of subjects in period 1
    Ibrutinib
    Started
    110
    Completed
    0
    Not completed
    110
         Consent withdrawn by subject
    3
         Physician decision
    23
         Death
    4
         Adverse event, serious non-fatal
    7
         Progressive disease
    72
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    Subjects self-administered 560 milligram (mg) oral Ibrutinib capsules (4*140 mg) once daily continuously until disease progression or unacceptable toxicity until study end (2 years after last subject enrolled).

    Reporting group values
    Ibrutinib Total
    Number of subjects
    110 110
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    67 67
        From 65 to 84 years
    40 40
        85 years and over
    3 3
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    60.9 ( 11.83 ) -
    Title for Gender
    Units: subjects
        Female
    43 43
        Male
    67 67

    End points

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    End points reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    Subjects self-administered 560 milligram (mg) oral Ibrutinib capsules (4*140 mg) once daily continuously until disease progression or unacceptable toxicity until study end (2 years after last subject enrolled).

    Primary: Overall Response Rate (ORR)

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    End point title
    Overall Response Rate (ORR) [1]
    End point description
    ORR is defined as the percentage of subjects who achieved complete response or partial response (CR or PR), as assessed by the Independent Review Committee (IRC), according to the International Working Group (IWG) revised response criteria for malignant lymphoma. The primary efficacy analysis of ORR was conducted at approximately 24 months after enrollment of the last subject. Complete Response includes complete disappearance of all detectable evidence of disease and related symptoms. Partial Response includes greater than or equal to 50 percent decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase was observed in size of nodes, liver, or spleen, 1 PET positive site of disease. The analysis was based on the all-treated population includes all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to end of study (2 years after the last subject is enrolled).
    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 is a single arm study, statistical comparison between arms is not in scope of this study.
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: Percentage of subjects
        number (confidence interval 95%)
    20.9 (13.7 to 29.7)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    Duration of Response (DOR)
    End point description
    Duration of response is defined as the interval between the date of initial documentation of a response [complete response (CR) or partial response (PR)] and the date of first documented evidence of progressive disease (PD) (or relapse for subjects who experience CR during the study) or death, whichever occurs first. Subjects who are progression-free and alive, or have unknown status were censored at the last adequate disease assessment. Progressive disease or Relapsed Disease in most cases is the worsening, growth, or spread of the disease including abnormal lymph nodes, appearance of new nodal lesions/ extra nodal lesions, 50 percent increase from the nadir in the sum of the product of the diameters (SPD) of any previously involved nodes. This may happen until death, serious debility, or organ failure occurs. DOR was analyzed for subjects who achieved a CR or PR. Here, value 99999 indicates that the data is not estimable.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks during the first 96 weeks, followed by every 24 weeks thereafter until disease progression (up to 2 years after the last subject was enrolled)
    End point values
    Ibrutinib
    Number of subjects analysed
    23
    Units: Months
        median (confidence interval 95%)
    19.4 (8.3 to 99999)
    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
    PFS is defined as the interval between the date of first dose of study drug and the date of first confirmed documented evidence of PD (or relapse for subjects who experience CR during the study) or death, whichever comes first. Subjects who were progression-free and alive, or had unknown status were censored at the last adequate disease assessment. The all-treated population included all subjects who received at least 1 dose of study drug (Ibrutinib).
    End point type
    Secondary
    End point timeframe
    Up to progressive disease, death, lost to follow-up, withdrawal of consent, or study end (up to 2 years after the last subject is enrolled)
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: Months
        median (confidence interval 95%)
    4.6 (2.8 to 5.5)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    OS is defined as the interval between the date of the first dose of study drug and the date of the subject’s death from any cause. If the subject is alive at the time of the cut-off, it was censored at the last known alive date (the last date among visit date, adverse event start and end dates, treatment date, disease assessment date, and survival follow up date, and if available, survival sweep date, etc.). The all-treated population included all subjects who received at least 1 dose of study drug (Ibrutinib). Here, value 99999 indicates that data is not estimable because more than 50 percent of subjects were censored for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to death, lost to follow-up, withdrawal of consent, or study end (up to 2 years after the last subject is enrolled)
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    Time to Response
    End point description
    Time to response (or best response) is defined as the interval between the date of first dose and the date of initial documentation of a response (or best response). Time to Response was analyzed for subjects who achieved a CR or PR.
    End point type
    Secondary
    End point timeframe
    Every 12 weeks during the first 96 weeks, followed by every 24 weeks thereafter until disease progression (up to 2 years after the last subject is enrolled)
    End point values
    Ibrutinib
    Number of subjects analysed
    23
    Units: Months
    median (full range (min-max))
        Time to Initial Response
    5.65 (2.6 to 13.8)
        Time to Best Response
    8.34 (2.7 to 19.3)
    No statistical analyses for this end point

    Secondary: Time to Progressive Diseases on Prior Last Line of Treatment

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    End point title
    Time to Progressive Diseases on Prior Last Line of Treatment
    End point description
    Time to PD on last line of treatment was defined as the interval between prior last line of treatment start date and the date of PD/relapse on prior last line of treatment. Time to PD was defined as first dose date of ibrutinib to the first documented PD or death due to PD whichever came first. The all-treated population included all subjects who received at least 1 dose of study drug (Ibrutinib).
    End point type
    Secondary
    End point timeframe
    Up to progressive disease, death, lost to follow-up, withdrawal of consent, or study end (up to 2 years after the last patient is enrolled)
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: months
        median (full range (min-max))
    7.4 (1 to 32)
    No statistical analyses for this end point

    Secondary: Time to Next Treatment on Last Prior Line of Therapy

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    End point title
    Time to Next Treatment on Last Prior Line of Therapy
    End point description
    Time to next treatment on last prior line of therapy was the time from the first dose of the previous antineoplastic therapy to the time of the first ibrutinib dose in the study. The all-treated population included all subjects who received at least 1 dose of study drug (Ibrutinib).
    End point type
    Secondary
    End point timeframe
    Time from the first dose of the previous antineoplastic therapy to the time of the first ibrutinib dose during study period (up to 2 years after the last patient is enrolled)
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: months
        median (confidence interval 95%)
    16.03 (10.71 to 19.12)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Resolution of Lymphoma-Related B Symptoms

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    End point title
    Percentage of Subjects With Resolution of Lymphoma-Related B Symptoms
    End point description
    For subjects who have reported symptoms at baseline and had at least one time point of assessment post baseline (before start of subsequent therapy), percentage of subjects who have no symptoms reported at least one post baseline time point (before start of subsequent therapy) were summarized. The All-treated population was defined as all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 of every cycle during the first 12 months, thereafter every other cycle (up to 2 years after the last patient is enrolled)
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: Percentage of Subjects
    number (not applicable)
        Postbaseline
    23.6
    No statistical analyses for this end point

    Secondary: Number of Subjects Identified With Blood Biomarkers That Alter B-Cell Receptor Signaling or Activate Alternative Signaling Pathways

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    End point title
    Number of Subjects Identified With Blood Biomarkers That Alter B-Cell Receptor Signaling or Activate Alternative Signaling Pathways
    End point description
    Number of subjects with T-cell subset and chemokine/cytokine analyses were categorized as responders (CR an PR) and non-responders (SD and PD). T-cell subsets in peripheral blood were assessed via flow cytometry for 57 subjects with available samples. Cytokine/chemokine analysis was performed on samples from 50 subjects, using Somalogic’s Somascan Assay. The analysis was based on the all treated population includes all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 1-3, and time of disease progression, or at end-of treatment visit for participants who discontinue treatment without disease progression
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: Subjects
    number (not applicable)
        T cell subsets (n=57): Responders
    14
        T cell subsets (n=57): Non Responders
    43
        Cytokine/Chemokine analysis (n=50): Responders
    21
        Cytokine/Chemokine analysis (n=50): Non Responders
    29
    No statistical analyses for this end point

    Secondary: Plasma Concentration at 24 hour (C24h) after administration of PCI- 32765

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    End point title
    Plasma Concentration at 24 hour (C24h) after administration of PCI- 32765
    End point description
    The (C24h) is the Plasma Concentration at 24 hour observed after administration of PCI-32765 at steady state. This population included all-treated subjects with at least 1 post treatment pharmacokinetic sample.
    End point type
    Secondary
    End point timeframe
    24 hours post-dose on Day 1 of Cycle 4
    End point values
    Ibrutinib
    Number of subjects analysed
    107
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    5.77 ( 3.56 )
    No statistical analyses for this end point

    Secondary: Oral Plasma Clearance of PCI-32765

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    End point title
    Oral Plasma Clearance of PCI-32765
    End point description
    The Oral plasma Clearance (CL/F) is the clearance based on oral bioavailability. This population included all-treated subjects with at least 1 post treatment pharmacokinetic sample.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 of Cycles 1-3, post-dose Day 1 of Cycles 1, 2 at 1, 2, and 4 hours
    End point values
    Ibrutinib
    Number of subjects analysed
    110 [2]
    Units: Liter per hour (L/h)
        arithmetic mean (standard deviation)
    1100 ( 99999 )
    Notes
    [2] - Here 99999 indicates that no standard deviation was reported as mean was considered fixed parameter.
    No statistical analyses for this end point

    Secondary: Oral Volume of Distribution at Steady State of PCI-32765

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    End point title
    Oral Volume of Distribution at Steady State of PCI-32765
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time. This population included all-treated subjects with at least 1 post treatment pharmacokinetic sample.
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1 of Cycles 1-3, post-dose Day 1 of Cycles 1, 2 at 1, 2, and 4 hours
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: Liter (L)
        arithmetic mean (standard deviation)
    10553 ( 3882 )
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of PCI-32765

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    End point title
    Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) of PCI-32765
    End point description
    The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours at steady state. This population included all-treated subjects with at least 1 post treatment Pharmacokinetic sample.
    End point type
    Secondary
    End point timeframe
    Predose, 1, 2, and 4 hours postdose on Day 1 of Cycle 4
    End point values
    Ibrutinib
    Number of subjects analysed
    107
    Units: nanogram* hour per milliliter (ng*h/mL)
        arithmetic mean (standard deviation)
    539 ( 360 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events

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    End point title
    Number of Subjects With Adverse Events
    End point description
    An AE is any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. The safety population included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 30 days after the last dose of study medication
    End point values
    Ibrutinib
    Number of subjects analysed
    110
    Units: Subjects
    107
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days after the last dose of study medication
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    Subjects self-administered 560 milligram (mg) oral Ibrutinib capsules (4*140 mg) once daily continuously until disease progression or unacceptable toxicity until study end (2 years after last subject enrolled).

    Serious adverse events
    Ibrutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    53 / 110 (48.18%)
         number of deaths (all causes)
    38
         number of deaths resulting from adverse events
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute Myeloid Leukaemia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to Meninges
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous Cell Carcinoma of Skin
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Inferior Vena Cava Syndrome
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Multi-Organ Failure
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 110 (6.36%)
         occurrences causally related to treatment / all
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    4 / 110 (3.64%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Alcohol Abuse
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Alcohol Withdrawal Syndrome
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Weight Decreased
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Head Injury
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral Haemorrhage
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Iron Deficiency Anaemia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Spleen Disorder
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Macular Fibrosis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Internal Hernia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Small Intestinal Obstruction
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Bile Duct Obstruction
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Hepatosplenomegaly
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Tract Obstruction
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Monarthritis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain Abscess
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Emphysematous Cystitis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia Bacteraemia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma Infection
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes Zoster Disseminated
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung Abscess
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymph Node Abscess
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis Bacterial
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    Peritonitis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 110 (6.36%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    1 / 1
    Pseudomonas Infection
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal Abscess
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lactic Acidosis
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Tumour Lysis Syndrome
         subjects affected / exposed
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ibrutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 110 (95.45%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 110 (6.36%)
         occurrences all number
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 110 (12.73%)
         occurrences all number
    14
    Chills
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    13
    Fatigue
         subjects affected / exposed
    44 / 110 (40.00%)
         occurrences all number
    77
    Oedema Peripheral
         subjects affected / exposed
    31 / 110 (28.18%)
         occurrences all number
    36
    Pyrexia
         subjects affected / exposed
    24 / 110 (21.82%)
         occurrences all number
    44
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    39 / 110 (35.45%)
         occurrences all number
    65
    Dyspnoea
         subjects affected / exposed
    13 / 110 (11.82%)
         occurrences all number
    17
    Epistaxis
         subjects affected / exposed
    8 / 110 (7.27%)
         occurrences all number
    12
    Oropharyngeal Pain
         subjects affected / exposed
    10 / 110 (9.09%)
         occurrences all number
    14
    Psychiatric disorders
    Depression
         subjects affected / exposed
    8 / 110 (7.27%)
         occurrences all number
    9
    Insomnia
         subjects affected / exposed
    14 / 110 (12.73%)
         occurrences all number
    16
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    10 / 110 (9.09%)
         occurrences all number
    17
    Platelet Count Decreased
         subjects affected / exposed
    13 / 110 (11.82%)
         occurrences all number
    26
    White Blood Cell Count Decreased
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    11
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    10 / 110 (9.09%)
         occurrences all number
    13
    Fall
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    7
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    8 / 110 (7.27%)
         occurrences all number
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 110 (10.91%)
         occurrences all number
    14
    Headache
         subjects affected / exposed
    19 / 110 (17.27%)
         occurrences all number
    26
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    24 / 110 (21.82%)
         occurrences all number
    62
    Neutropenia
         subjects affected / exposed
    16 / 110 (14.55%)
         occurrences all number
    28
    Thrombocytopenia
         subjects affected / exposed
    21 / 110 (19.09%)
         occurrences all number
    40
    Eye disorders
    Dry Eye
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    7
    Lacrimation Increased
         subjects affected / exposed
    7 / 110 (6.36%)
         occurrences all number
    7
    Vision Blurred
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    12 / 110 (10.91%)
         occurrences all number
    13
    Abdominal Pain Upper
         subjects affected / exposed
    10 / 110 (9.09%)
         occurrences all number
    10
    Constipation
         subjects affected / exposed
    14 / 110 (12.73%)
         occurrences all number
    15
    Diarrhoea
         subjects affected / exposed
    55 / 110 (50.00%)
         occurrences all number
    115
    Dry Mouth
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    14
    Dyspepsia
         subjects affected / exposed
    8 / 110 (7.27%)
         occurrences all number
    9
    Nausea
         subjects affected / exposed
    32 / 110 (29.09%)
         occurrences all number
    44
    Stomatitis
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    8
    Vomiting
         subjects affected / exposed
    15 / 110 (13.64%)
         occurrences all number
    17
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    10 / 110 (9.09%)
         occurrences all number
    11
    Pruritus
         subjects affected / exposed
    13 / 110 (11.82%)
         occurrences all number
    15
    Rash
         subjects affected / exposed
    18 / 110 (16.36%)
         occurrences all number
    24
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 110 (8.18%)
         occurrences all number
    10
    Back Pain
         subjects affected / exposed
    14 / 110 (12.73%)
         occurrences all number
    18
    Muscle Spasms
         subjects affected / exposed
    35 / 110 (31.82%)
         occurrences all number
    76
    Myalgia
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    15
    Pain in Extremity
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    14
    Conjunctivitis
         subjects affected / exposed
    9 / 110 (8.18%)
         occurrences all number
    18
    Nasopharyngitis
         subjects affected / exposed
    6 / 110 (5.45%)
         occurrences all number
    9
    Sinusitis
         subjects affected / exposed
    11 / 110 (10.00%)
         occurrences all number
    14
    Upper Respiratory Tract Infection
         subjects affected / exposed
    19 / 110 (17.27%)
         occurrences all number
    31
    Urinary Tract Infection
         subjects affected / exposed
    7 / 110 (6.36%)
         occurrences all number
    18
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    16 / 110 (14.55%)
         occurrences all number
    19
    Hypokalaemia
         subjects affected / exposed
    14 / 110 (12.73%)
         occurrences all number
    37
    Hypomagnesaemia
         subjects affected / exposed
    9 / 110 (8.18%)
         occurrences all number
    11
    Hyponatraemia
         subjects affected / exposed
    10 / 110 (9.09%)
         occurrences all number
    12

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2012
    The global amendment INT-1 included clarification to the mechanism of action of ibrutinib. Additional safety data were added. Clarification regarding collection of tissue specimen for biomarker analysis was added. Other malignant diseases were observed in subjects who were treated with ibrutinib; it was unclear whether or not these events were attributable to ibrutinib. Therefore, other malignancies occurring in subjects treated in this study were reported and collected on the electronic case report form (eCRF). Guidance and clarification for the administration of cytochrome P450 (CYP) 3A4/5 subtype inhibitors/inducers during ibrutinib administration was provided. QT prolongation was not expected with ibrutinib; the precaution for concomitant use of ibrutinib and medications known to cause QT prolongation was simplified. Instructions for concomitant use of ibrutinib and antiplatelet agents, anticoagulants, supplements such as fish oil and vitamin E preparations were updated. Actual increase for the maximum plasma concentration and the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration in ibrutinib exposure when administered in combination with ketoconazole was updated. Additional pharmacokinetic (PK) samples were requested from subjects who received a strong or moderate cytochrome P450 (CYP) 3A4/5 inhibitor while receiving treatment with ibrutinib. Additional details for the Hepatitis B and C samples collected at screening and instructions for documentation of any additional laboratory testing performed in relation to an adverse event(s) (AE) were added. Interim analysis was removed.
    31 Jan 2014
    The global amendment INT-2 addressed the novel situation of delayed responses that had been observed after progressive disease (PD). In addition, this amendment addressed the situation of subjects with borderline disease progression and the management and evaluation of subjects with radiological evidence of PD. Language was added to allow for continuation of ibrutinib in subjects with radiological evidence of PD who were clinically stable or improving or exhibiting signs of tumor flare without confirmation of PD by positron emission tomography (PET) or biopsy, had no signs of impending organ compromise, and who were not experiencing significant toxicity. In addition, resumption of ibrutinib was permitted if a delayed response was observed after ibrutinib had been discontinued for PD. Additional new safety information (rashes and infection) based on studies conducted with ibrutinib and the incidence for treatment discontinuations in the monotherapy and combination therapy safety population was added.
    18 Dec 2014
    The global amendment INT-3 included the following changes: The clinical cutoff was extended to 15 months after the last subject enrolled to ensure that response data was fully captured for the study. PET scans performed at maximal tumor reduction could include response assessments at 12 months. Instructions for PET assessment for those subjects who had been on the study more than 48 weeks without a PET scan were added. Potential risks associated with ibrutinib were updated based on the 2014 investigator’s brochure (IB) (version 8.0) and new risks (cytopenias, diarrhea) were added. The definition of a major hemorrhagic bleeding event was broadened to include any bleeding event that was grade 3 or higher (including all hemorrhagic events requiring a transfusion of red blood cells), was considered a serious AE, or any central nervous system hemorrhage/hematoma. Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Instructions were added to periodically monitor subjects clinically for atrial fibrillation. Precautions for concomitant use of ibrutinib with CYP3A inhibitors, CYP3A inducers, P-glycoprotein (P-gp) substrates, QT prolonging agents, agents and anticoagulants were revised.
    16 Nov 2015
    The global amendment INT-5 included the following changes: Subjects continued to experience a partial or complete response to treatment with ibrutinib; therefore, the clinical cutoff was further extended to 24 months to allow for maturation of the data on the duration of response (DOR). Expanded disease evaluation to include screening, every 12 weeks (+/- 7 days) for the first 96 weeks, and then every 24 weeks (+/-) 14 days) thereafter until disease progression or the clinical cutoff. For subjects who had disease evaluations greater than 3 months prior to clinical cutoff, a final disease evaluation was to be performed at the last cycle visit prior to clinical cutoff.

    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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