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    Clinical Trial Results:
    A Phase I/IIa trial of VTD-panobinostat treatment and panobinostat maintenance in relapsed and relapsed/refractory multiple myeloma patients

    Summary
    EudraCT number
    2012-000842-36
    Trial protocol
    GB  
    Global end of trial date
    15 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    16 May 2018
    First version publication date
    16 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HM12/10174
    Additional study identifiers
    ISRCTN number
    ISRCTN59395590
    US NCT number
    NCT02145715
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Leeds
    Sponsor organisation address
    Leeds, Leeds, United Kingdom,
    Public contact
    CTRU, University of Leeds CTRU, 0044 01133431478, l.m.flanagan@leeds.ac.uk
    Scientific contact
    CTRU, University of Leeds CTRU, 0044 01133431478, medctco@leeds.ac.uk
    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
    15 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    During the dose escalation phase, the purpose of the study is to determine the maximum tolerated dose (MTD) of panobinostat, administered in combination with VTD, in subjects with relapsed and relapsed/refractory multiple myeloma. In the dose expansion phase the purpose of the study is to estimate the response rate (partial response or better) within 16 cycles of VTD-pano at the RD identified in the dose escalation phase.
    Protection of trial subjects
    N/A
    Background therapy
    There are no comparators for this trial all participants received the trial drug.
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    37
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were recruited to the trial from January 2013 until October 2014 from NHS hospitals across the UK

    Pre-assignment
    Screening details
    Relapsed/refractory myeloma with 1-4 prior lines of treatment. Adults.

    Pre-assignment period milestones
    Number of subjects started
    57
    Number of subjects completed

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

    Arms
    Arm title
    Safety Population
    Arm description
    The safety population includes all participants who have received at least one dose of any trial treatment. Only patients for whom written informed consent was not received are excluded.
    Arm type
    Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    20mg/15mg/10mg Days 1, 3, 5, 8, 10 and 12

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/m2 Days 1 and 8

    Investigational medicinal product name
    Thalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg od. days 1-21 50mg given to patients with peripheral neuropathy at baseline

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20mg Days 1, 2, 8 and 9

    Number of subjects in period 1
    Safety Population
    Started
    57
    Completed
    57

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Reporting group values
    Overall Trial Total
    Number of subjects
    57 57
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.8 ± 9.19 -
    Gender categorical
    Units: Subjects
        Female
    23 23
        Male
    34 34
    ECOG perfomance Status
    Units: Subjects
        Zero
    26 26
        One
    26 26
        Two
    3 3
        Missing
    2 2
    ISS
    Units: Subjects
        One
    32 32
        Two
    16 16
        Three
    6 6
        Missing
    3 3
    Number of previous lines of Treatment
    Units: Subjects
        One
    43 43
        Two
    6 6
        Three
    5 5
        Four
    3 3
    Previous Velcade
    Units: Subjects
        No
    19 19
        Yes
    38 38
    Previous Treatment with IMiD
    Units: Subjects
        Yes
    34 34
        No
    23 23
    Previous autologous stem cell transplantation
    Whether a patient has received a ASCT prior to entry to the trial
    Units: Subjects
        Yes
    36 36
        No
    21 21
    Time from diagnosis to registration
    Calculation includes partial dates, missing day and months were set to 15 and 06 respectively
    Units: months
        median (inter-quartile range (Q1-Q3))
    33 (26 to 59) -
    Subject analysis sets

    Subject analysis set title
    RD ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population is defined by participants registered to receive to the 20mg recommended Panobinostat dose, (RD) , who receive at least one cycle of experimental treatment defined as 1 dose of panobinostat.

    Subject analysis sets values
    RD ITT
    Number of subjects
    46
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.3 ± 9.19
    Gender categorical
    Units: Subjects
        Female
    19
        Male
    27
    ECOG perfomance Status
    Units: Subjects
        Zero
    22
        One
    21
        Two
    2
        Missing
    1
    ISS
    Units: Subjects
        One
    28
        Two
    13
        Three
    3
        Missing
    2
    Number of previous lines of Treatment
    Units: Subjects
        One
    37
        Two
    5
        Three
    1
        Four
    3
    Previous Velcade
    Units: Subjects
        No
    13
        Yes
    33
    Previous Treatment with IMiD
    Units: Subjects
        Yes
    24
        No
    22
    Previous autologous stem cell transplantation
    Whether a patient has received a ASCT prior to entry to the trial
    Units: Subjects
        Yes
    27
        No
    19
    Time from diagnosis to registration
    Calculation includes partial dates, missing day and months were set to 15 and 06 respectively
    Units: months
        median (inter-quartile range (Q1-Q3))
    31 (26 to 54)

    End points

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    End points reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    The safety population includes all participants who have received at least one dose of any trial treatment. Only patients for whom written informed consent was not received are excluded.

    Subject analysis set title
    RD ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population is defined by participants registered to receive to the 20mg recommended Panobinostat dose, (RD) , who receive at least one cycle of experimental treatment defined as 1 dose of panobinostat.

    Primary: DLT

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    End point title
    DLT [1]
    End point description
    DLT was defined as any of the following events: • Total bilirubin ≥ Grade 3 according to NCI CTCAE Version 4 which fails to return to Grade 1 within 7 days. In participants with Gilbert’s Syndrome with grade 1-2 hyperbilirubinemia at screening, total bilirubin need only return to ≤ Grade 2 (within 7 days). • Any other non haematological toxicity ≥ Grade 3 according to NCI CTCAE Version 4 which fails to return to ≤ Grade 1 or baseline within 7 days. Nausea, vomiting, diarrhoea and electrolyte imbalances will be considered DLTs only if they remain ≥ Grade 3 severity despite adequate supportive care measures. • Grade 4 neutropenia lasting 7 days or Grade 4 neutropenia with sepsis. • Any grade 4 thrombocytopenia which fails to return to Grade 2 within 7 days. • Prolongation of QTc ≥ Grade 3 according to NCI CTCAE Version 4.0 • Treatment Related Death
    End point type
    Primary
    End point timeframe
    Dose limiting toxicity (DLT) was assessed during the first treatment cycle up to the administration of cycle 2 day 1.
    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: Single arm trial; endpoint used to make escalation decisions with no formal analysis conducted
    End point values
    Safety Population
    Number of subjects analysed
    15 [2]
    Units: Subjects
        10mg DLT
    0
        10mg No DLT
    6
        15mg DLT
    0
        15mg No DLT
    3
        20mg DLT
    1
        20mg No DLT
    5
    Notes
    [2] - 15 Participants evaluable for endpoint in escalation phase. Registered Panobinostat dose given
    No statistical analyses for this end point

    Primary: Overall Response >=PR

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    End point title
    Overall Response >=PR [3]
    End point description
    Proportion of participants achieving at least a partial response within 16 cycles of VTD-pano are analysed using the local response assessment. Response to treatment was assessed after a participant has received each cycle of treatment, following the Modified IWG Uniform Response Criteria. A participant who achieved at least a partial response within 16 cycles of treatment but subsequently progressed (within 16 cycles) or stopped treatment (within 16 cycles), is classed as achieving at least a partial response within 16 cycles of treatment.
    End point type
    Primary
    End point timeframe
    Within 16 cycles of treatment
    Notes
    [3] - 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: Single arm trial; data used to estimate response rate with no formal analysis conducted as no comparator arm
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Subjects
        Not acheived
    4
        PR or greater acheived
    42
    No statistical analyses for this end point

    Primary: Overall response rate

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    End point title
    Overall response rate [4]
    End point description
    Percentage of participants achieving at least a partial response within 16 cycles of VTD-pano are analysed using the local response assessment. Response to treatment was assessed after a participant has received each cycle of treatment, following the Modified IWG Uniform Response Criteria. A participant who achieved at least a partial response within 16 cycles of treatment but subsequently progressed (within 16 cycles) or stopped treatment (within 16 cycles), is classed as achieving at least a partial response within 16 cycles of treatment.
    End point type
    Primary
    End point timeframe
    Within 16 cycles
    Notes
    [4] - 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: Single arm trial; parameter estimate with no formal analysis conducted as no comparator arm
    End point values
    RD ITT
    Number of subjects analysed
    Units: percent
        number (confidence interval 80%)
    91 (83.4 to 96.2)
    No statistical analyses for this end point

    Secondary: Maximum Response

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    End point title
    Maximum Response
    End point description
    Maximum response is defined as the proportion of participants achieving each of the response categories; Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Minimal Response (MR) or Stable Disease (SD) as their maximum response within sixteen cycles of treatment. Response assessments for a given cycle were taken at the beginning of the subsequent cycle of treatment or separately at the end of treatment if no further cycles of treatment were received.
    End point type
    Secondary
    End point timeframe
    Within 16 Cycles of treatment
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Subjects
        CR
    3
        VGPR
    18
        PR
    21
        MR
    2
        SD
    2
    No statistical analyses for this end point

    Secondary: Median Time to Maximum response

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    End point title
    Median Time to Maximum response
    End point description
    Time to maximum response is defined as the time from registration until the participant achieves any of the categories CR, VGPR, PR, MR or SD as their maximum response. Time to maximum response is calculated using the Kaplan Meier method. Median time to maximum response is presented, with corresponding 95% confidence intervals.
    End point type
    Secondary
    End point timeframe
    Within 16 cycles of treatment
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Months
        number (confidence interval 95%)
    2.46 (1.91 to 3.52)
    No statistical analyses for this end point

    Secondary: Median Progression free survival

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    End point title
    Median Progression free survival
    End point description
    Progression-free survival is defined as the time from registration to first documented evidence of disease progression or death. Participants who, at the time of analysis, have not progressed or died are censored at the last date they were known to be alive and progression free. Patients who go on to receive a stem cell transplant are censored at the date of stem cell harvest if a harvest was carried out or infusion if not. Calculated using the Kaplan Meier method
    End point type
    Secondary
    End point timeframe
    Median follow up of 15months.
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Months
        number (confidence interval 95%)
    15.6 (13.4 to 20.47)
    No statistical analyses for this end point

    Secondary: Proportion progression free at 12 months

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    End point title
    Proportion progression free at 12 months
    End point description
    Progression-free survival is defined as the time from registration to first documented evidence of disease progression or death. Participants who, at the time of analysis, have not progressed or died are censored at the last date they were known to be alive and progression free. Patients who go on to receive a stem cell transplant are censored at the date of stem cell harvest if a harvest was carried out or infusion if not. Calculated using the Kaplan Meier method
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Percentage
        number (confidence interval 95%)
    75.4 (56.7 to 86.8)
    No statistical analyses for this end point

    Secondary: Mean Panobinostat dose

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    End point title
    Mean Panobinostat dose
    End point description
    Calculated as mean dose over all cycles recieved
    End point type
    Secondary
    End point timeframe
    16 cycles of treatment
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: mg
        arithmetic mean (standard error)
    17.2 ± 0.1
    No statistical analyses for this end point

    Secondary: Panobinostat dose reduction

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    End point title
    Panobinostat dose reduction
    End point description
    Participant required at least 1 dose reduction of panobinostat during therapy. Binary Yes/No
    End point type
    Secondary
    End point timeframe
    16 Cycles of treatment
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Subjects
        Yes
    19
        No
    27
    No statistical analyses for this end point

    Secondary: Thalidomide dose reduction

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    End point title
    Thalidomide dose reduction
    End point description
    Participants requiring at least one dose reduction of thalidomide. Binary Yes/No
    End point type
    Secondary
    End point timeframe
    16 cycles
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Subjects
        Yes
    20
        No
    26
    No statistical analyses for this end point

    Secondary: Bortezomib dose reduction

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    End point title
    Bortezomib dose reduction
    End point description
    Participants who received at least 1 dose reduction during therapy. Binary Yes/No
    End point type
    Secondary
    End point timeframe
    16 cycles
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Subjects
        Yes
    5
        No
    41
    No statistical analyses for this end point

    Secondary: Dexamethasone dose reduction

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    End point title
    Dexamethasone dose reduction
    End point description
    Number of participants requiring at least one dose reduction of dexamethasone within 1 cycle of treatment.
    End point type
    Secondary
    End point timeframe
    Within 16 cycles
    End point values
    RD ITT
    Number of subjects analysed
    46
    Units: Subjects
        Yes
    6
        No
    40
    No statistical analyses for this end point

    Secondary: Participants proceeding to Maintenance

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    End point title
    Participants proceeding to Maintenance
    End point description
    Upon Completion of 16 cycles of initial therapy participants were eligible for maintenance therapy
    End point type
    Secondary
    End point timeframe
    16 cycles
    End point values
    Safety Population
    Number of subjects analysed
    57
    Units: Subjects
        Maintenance
    15
        No maintenance
    42
    No statistical analyses for this end point

    Secondary: Mean Panobinostat dose maintenance

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    End point title
    Mean Panobinostat dose maintenance
    End point description
    The mean dose of panobinostat received during maintenance therapy. Four participants of the 15 patients proceeding to maintenance had not completed maintenance at the time of analysis.
    End point type
    Secondary
    End point timeframe
    1-year Maintenance therapy
    End point values
    Safety Population
    Number of subjects analysed
    15
    Units: mg
        arithmetic mean (standard error)
    16.5 ± 0.18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs occurring for all participants from the time of consent until 30 days post cessation of trial therapy
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    The safety population includes all participants who have received at least one dose of any trial treatment. Only patients for whom written informed consent was not received are excluded.

    Serious adverse events
    Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 57 (47.37%)
         number of deaths (all causes)
    6
         number of deaths resulting from adverse events
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    8 / 57 (14.04%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Creatinine increased
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial muscle weakness
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischemic attacks
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Hemolysis
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Hemolytic uremic syndrome
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhea
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Esophageal perforation
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 57 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Hypotension
         subjects affected / exposed
    6 / 57 (10.53%)
         occurrences all number
    8
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    23 / 57 (40.35%)
         occurrences all number
    43
    Fever
         subjects affected / exposed
    11 / 57 (19.30%)
         occurrences all number
    15
    Fatigue
         subjects affected / exposed
    51 / 57 (89.47%)
         occurrences all number
    94
    Localized edema
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    6
    Malaise
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 57 (26.32%)
         occurrences all number
    16
    Dyspnea
         subjects affected / exposed
    20 / 57 (35.09%)
         occurrences all number
    31
    Epistaxis
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Hiccups
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    4
    Productive cough
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Sore throat
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    4
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    6 / 57 (10.53%)
         occurrences all number
    7
    Depression
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    9
    Insomnia
         subjects affected / exposed
    8 / 57 (14.04%)
         occurrences all number
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 57 (14.04%)
         occurrences all number
    25
    Alkaline phosphatase increased
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    7
    Creatinine increased
         subjects affected / exposed
    16 / 57 (28.07%)
         occurrences all number
    31
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    5
    Investigations - Other, specify
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Neutrophil count decreased
         subjects affected / exposed
    22 / 57 (38.60%)
         occurrences all number
    66
    Platelet count decreased
         subjects affected / exposed
    20 / 57 (35.09%)
         occurrences all number
    65
    Weight loss
         subjects affected / exposed
    8 / 57 (14.04%)
         occurrences all number
    9
    White blood cell decreased
         subjects affected / exposed
    7 / 57 (12.28%)
         occurrences all number
    15
    Cardiac disorders
    Cardiac disorders - Other, specify
         subjects affected / exposed
    6 / 57 (10.53%)
         occurrences all number
    13
    Palpitations
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    4
    Sinus bradycardia
         subjects affected / exposed
    9 / 57 (15.79%)
         occurrences all number
    12
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 57 (31.58%)
         occurrences all number
    32
    Dysgeusia
         subjects affected / exposed
    11 / 57 (19.30%)
         occurrences all number
    14
    Headache
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    4
    Peripheral sensory neuropathy
         subjects affected / exposed
    44 / 57 (77.19%)
         occurrences all number
    83
    Somnolence
         subjects affected / exposed
    19 / 57 (33.33%)
         occurrences all number
    26
    Tremor
         subjects affected / exposed
    22 / 57 (38.60%)
         occurrences all number
    32
    Syncope
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    21 / 57 (36.84%)
         occurrences all number
    53
    Eye disorders
    Blurred vision
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    4
    Dry eye
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 57 (15.79%)
         occurrences all number
    9
    Constipation
         subjects affected / exposed
    36 / 57 (63.16%)
         occurrences all number
    59
    Diarrhea
         subjects affected / exposed
    38 / 57 (66.67%)
         occurrences all number
    110
    Dry mouth
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Dyspepsia
         subjects affected / exposed
    6 / 57 (10.53%)
         occurrences all number
    7
    Gastrointestinal disorders - Other, specify
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    6
    Mucositis oral
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    27 / 57 (47.37%)
         occurrences all number
    34
    Vomiting
         subjects affected / exposed
    10 / 57 (17.54%)
         occurrences all number
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 57 (10.53%)
         occurrences all number
    7
    Hyperhidrosis
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Rash maculo-papular
         subjects affected / exposed
    14 / 57 (24.56%)
         occurrences all number
    19
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    7
    Back pain
         subjects affected / exposed
    25 / 57 (43.86%)
         occurrences all number
    36
    Bone pain
         subjects affected / exposed
    35 / 57 (61.40%)
         occurrences all number
    60
    Generalized muscle weakness
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    4
    Myalgia
         subjects affected / exposed
    15 / 57 (26.32%)
         occurrences all number
    19
    Infections and infestations
    Infections and infestations - Other, specify
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    4
    Lung infection
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Skin infection
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Upper respiratory infection
         subjects affected / exposed
    25 / 57 (43.86%)
         occurrences all number
    41
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    16 / 57 (28.07%)
         occurrences all number
    16
    Hyperglycemia
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    12
    Hypermagnesemia
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Hypernatremia
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Hypoalbuminemia
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    4
    Hypocalcemia
         subjects affected / exposed
    12 / 57 (21.05%)
         occurrences all number
    18
    Hypomagnesemia
         subjects affected / exposed
    7 / 57 (12.28%)
         occurrences all number
    12
    Hyponatremia
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    6
    Hypophosphatemia
         subjects affected / exposed
    19 / 57 (33.33%)
         occurrences all number
    63

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Dec 2012
    Substantial amendment relating to the CTA. Novartis has been included as the company responsible for the final certification of the IMP in the community. The responsibility is now with St Mary's Pharmaceutical Unit (SMPU). A copy of SMPUs manufacturers authorisation is enclosed.
    07 Aug 2013
    Clarified contraception for use in the trial. Excluded patients with diffuse infiltrative pulmonary disease Excluded growth factors and platelet support to meet eligibility criteria Clarified the informed consent process Added panobinostat, dexamethasone and thalidomide administration information for clarification Added dose delay periods for clarity Added that parameters outlined in the eligibility criteria need to be met to proceed with treatment.
    03 Feb 2014
    Clarification of parameters to start treatment at each cycle. Clarification that toxicities must have resolved to start treatment. Dose modifications for neutropenia amended. Wording for anaemia and grade 3 & 4 non haematological toxicities clarified.
    12 Aug 2014
    Clarification of laboratory values to continue treatment and dose reductions. Reporting of SARs and SUSARs until the end of the trial not 30 days after the end of treatment Pregnancy testing requirements clarified. Reporting to the sponsor clarified. Breastfeeding excluded.
    18 Dec 2014
    Sample size and analysis population amended in the expansion phase as this was incorrect. Frequency of analyses amended in line with the design.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27843120
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