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    Clinical Trial Results:
    Safety of Vorinostat in combination with Bortezomib, Doxorubicin and Dexamethasone (VBDD) in patients with refractory or relapsed multiple myeloma

    Summary
    EudraCT number
    		 2011-000388-28
    Trial protocol
    		 DE  
    Global end of trial date
    01 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2020
    First version publication date
    05 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    00658;MK-0683-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01394354
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical Center – University of Freiburg
    Sponsor organisation address
    Breisacher Str. 153, Freiburg, Germany, 79110
    Public contact
    Prof. Dr. med. Monika Engelhardt, Abt. Innere Medizin I, Dept. Hematology and Oncology, 0049 76127032460, monika.engelhardt@uniklinik-freiburg.de
    Scientific contact
    Prof. Dr. med. Monika Engelhardt, Abt. Innere Medizin I, Dept. Hematology and Oncology, 0049 76127032460, monika.engelhardt@uniklinik-freiburg.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective of the study is the determination of the maximum tolerated dose (MTD) of Vorinostat (V), given in combination with fixed doses of Doxorubicin (D), Bortezomib (B) and Dexamethasone (D).
    Protection of trial subjects
    Possibility to withdraw consent by patient. Assessment of safety and tolerability of VBDD, evaluated in terms of AEs, SAEs, laboratory parameters.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 33
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    19
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Mono-center study at the University Medical Center Freiburg in Germany. Recruitment period: 20 Sept 2011 - 1 Dec 2014.

    Pre-assignment
    Screening details
    		 Included and analysed were 33 patients, included from study start on 20th September 2011 (inclusion of the first patient) until closure on 1st December 2015 (last patient out, i.e. one year follow-up period after inclusion of the last patient).

    Pre-assignment period milestones
    Number of subjects started
    		 33
    Number of subjects completed
    		 33

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

    Arms
    Arm title
    		 Combination therapy
    Arm description
    		 Vorinostat 100 mg/d vs. 200 mg/d vs. 300 mg/d given on days 1-4, 8-11, 15-18 in combination with doxorubicin (9 mg/m2 body surface area on d1 and d8) and bortezomib (1.3 mg/m2 on d1, d8, and d15) as well as dexamethasone (VBDD) in patients with refractory or relapsed multiple myeloma.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vorinostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    A first cohort of 3 patients was treated at the starting dose level of Vorinostat 100 mg/d, on days 1-4, 8-11, and 15-18 in combination with Bortezomib, Doxorubicin and Dexamethasone (BDD). The dose level of Vorinostat was escalated in each new cohort: if no dose limiting toxicity had been observed in the previos dose level in 3 patients, the second cohort of 3 new patients were treated with Vorinostat 200 mg/d in combination with BDD and the third cohort was given Vorinostat with 300 mg/d in combination with BDD.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Bortezomib was administered with a dose of 1.3 mg/m2 on d1, d8 and d15 intravenously (i.v.), or (after amendment) subcutaneously (s.c.). After the amendment in April 2013, Bortezomib administration was switched to s.c. whenever possible for the patient in the phase II, because results of another study had shown in the meantime that s.c. is as effective as i.v. application but had fewer sid effects.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin was administered i.v. with a total dose of 18 mg/m2 per cycle (9 mg/m2, d1 and d8).

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered per os (p.o.) with 40 mg (first cycle) and 20 mg (all other subsequent cycles) on d1, d8, d15 and d22.

    Number of subjects in period 1
    		Combination therapy
    Started
    33
    Completed
    33

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 33 33
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 19 19
        From 65-84 years
    		 14 14
        85 years and over
    		 0 0
        Years of age
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 62 (47 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 19 19
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set included 33 patients.

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    33
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    19
        From 65-84 years
    14
        85 years and over
    0
        Years of age
    0
    Age continuous
    Units: years
        median (full range (min-max))
    62 (47 to 77)
    Gender categorical
    Units: Subjects
        Female
    14
        Male
    19

    End points

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    End points reporting groups
    Reporting group title
    Combination therapy
    Reporting group description
    		 Vorinostat 100 mg/d vs. 200 mg/d vs. 300 mg/d given on days 1-4, 8-11, 15-18 in combination with doxorubicin (9 mg/m2 body surface area on d1 and d8) and bortezomib (1.3 mg/m2 on d1, d8, and d15) as well as dexamethasone (VBDD) in patients with refractory or relapsed multiple myeloma.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set included 33 patients.

    Primary: Maximum tolerated dose of Vorinostat

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    End point title
    		 Maximum tolerated dose of Vorinostat [1]
    End point description
    Maximum tolerated dose of Vorinostat, given in combination with fixed doses of Doxorubicin, Bortezomib and Dexamethasone was defined as the highest dose of vorinostat at which six patients have been treated and less than two patients experienced dose limiting toxicity within the first cycle of treatment. No DLT occurred in 9 patients who were consecutively included in the phase I part of the study (levels 0, + 1 and +2) (see section 7.3), therefore the MTD for vorinostat could not be determined within this trial with planned vorinostat <loses up to 300 mg/d p.o.. Thus, the recommended dose of vorinostat for Phase II (RDP2) was 300 mg/d p.o.. With this dose the remaining 24 patients were treated throughout the phase II part of the study.
    End point type
    Primary
    End point timeframe
    Maximum tolerated dose of Vorinostat is based on safety data from the first cycle.
    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: Descriptive analyses, as the primary objective of the study was the determination of the maximum tolerated dose of vorinostat.
    End point values
    		 Full analysis set
    Number of subjects analysed
    9
    Units: mg/d
    300
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Secondary
    End point timeframe
    Time from start of treatment until death or the first observation of disease progression, whichever occured first.
    End point values
    		 Full analysis set
    Number of subjects analysed
    33
    Units: Months
        median (confidence interval 95%)
    9.6263 (6.0780 to 13.3717)
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Time from start of treatment until death from any cause.
    End point values
    		 Full analysis set
    Number of subjects analysed
    33
    Units: Months
        median (confidence interval 95%)
    33.8 (14.8 to 9999)
    No statistical analyses for this end point

    Secondary: Safety: dose-limiting toxicity

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    End point title
    		 Safety: dose-limiting toxicity
    End point description
    End point type
    Secondary
    End point timeframe
    At the end of the study
    End point values
    		 Full analysis set
    Number of subjects analysed
    33
    Units: Number of patients
    9
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    Complete response occured only in one patient so that duration of response could only be determined for this single patient.
    End point type
    Secondary
    End point timeframe
    During study
    End point values
    		 Full analysis set
    Number of subjects analysed
    1
    Units: Months
        median (confidence interval 95%)
    6.8 (0.1 to 9999)
    No statistical analyses for this end point

    Secondary: Geriatric depression scale score

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    End point title
    		 Geriatric depression scale score
    End point description
    End point type
    Secondary
    End point timeframe
    Change from screening to end of therapy
    End point values
    		 Full analysis set
    Number of subjects analysed
    17
    Units: Score difference
        arithmetic mean (confidence interval 95%)
    0.3 (-0.9 to 2.0)
    No statistical analyses for this end point

    Secondary: Geriatric assessment: Timed "up and go" test

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    End point title
    		 Geriatric assessment: Timed "up and go" test
    End point description
    End point type
    Secondary
    End point timeframe
    Change from screening to end of therapy
    End point values
    		 Full analysis set
    Number of subjects analysed
    16
    Units: sec
        arithmetic mean (confidence interval 95%)
    0.3 (-0.6 to 1.2)
    No statistical analyses for this end point

    Secondary: Geriatric assessment: instrumental activities of daily living (IADL) score

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    End point title
    		 Geriatric assessment: instrumental activities of daily living (IADL) score
    End point description
    End point type
    Secondary
    End point timeframe
    Change from screening to end of therapy
    End point values
    		 Full analysis set
    Number of subjects analysed
    19
    Units: Score difference
        arithmetic mean (confidence interval 95%)
    0.5 (-0.4 to 1.3)
    No statistical analyses for this end point

    Secondary: Geriatric assessment: Mini-Mental Status score

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    End point title
    		 Geriatric assessment: Mini-Mental Status score
    End point description
    End point type
    Secondary
    End point timeframe
    Change from screening to end of therapy
    End point values
    		 Full analysis set
    Number of subjects analysed
    17
    Units: Score difference
        arithmetic mean (confidence interval 95%)
    0.2 (-1.1 to 1.4)
    No statistical analyses for this end point

    Secondary: Geriatric assessment: hematopoietic cell transplantation-comorbidity index (HCT-CI) score

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    End point title
    		 Geriatric assessment: hematopoietic cell transplantation-comorbidity index (HCT-CI) score
    End point description
    End point type
    Secondary
    End point timeframe
    Change from screening to end of therapy
    End point values
    		 Full analysis set
    Number of subjects analysed
    17
    Units: Score difference
        arithmetic mean (standard deviation)
    0.4 ± 0.8
    No statistical analyses for this end point

    Secondary: Geriatric assessment: Freiburg comorbidity index (FCI) score

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    End point title
    		 Geriatric assessment: Freiburg comorbidity index (FCI) score
    End point description
    End point type
    Secondary
    End point timeframe
    Change from screening to end of therapy
    End point values
    		 Full analysis set
    Number of subjects analysed
    20
    Units: FCI score difference
        arithmetic mean (confidence interval 95%)
    0.1 (-0.3 to 0.4)
    No statistical analyses for this end point

    Secondary: Geriatric assessment: Kaplan-Feinsteinindex (KF) score

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    End point title
    		 Geriatric assessment: Kaplan-Feinsteinindex (KF) score
    End point description
    End point type
    Secondary
    End point timeframe
    Change from screening to end of therapy
    End point values
    		 Full analysis set
    Number of subjects analysed
    17
    Units: Score difference
        arithmetic mean (confidence interval 95%)
    0.1 (-0.2 to 0.3)
    No statistical analyses for this end point

    Secondary: Response rates

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    End point title
    		 Response rates
    End point description
    End point type
    Secondary
    End point timeframe
    Best response observed until end of treatment
    End point values
    		 Full analysis set
    Number of subjects analysed
    33
    Units: Number of patients
        Stringent complete remission
    0
        Complete remission
    1
        Very good partial response
    7
        Partial remission
    14
        Stable disease
    9
        Progressive disease
    2
    No statistical analyses for this end point

    Secondary: Response rates

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    End point title
    		 Response rates
    End point description
    End point type
    Secondary
    End point timeframe
    Study end
    End point values
    		 Full analysis set
    Number of subjects analysed
    33
    Units: Number of patients
        Stringent complete remission
    0
        Complete remission
    3
        Very good partial response
    1
        Partial remission
    3
        Stable disease
    1
        Progressive disease
    23
        n.e.
    1
        Missing
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Complete study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    VBDD
    Reporting group description
    		 Vorinostat, Bortezomib, Doxorubicin and Dexamethason

    Serious adverse events
    		 VBDD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 33 (27.27%)
         number of deaths (all causes)
    15
         number of deaths resulting from adverse events
    2
    Injury, poisoning and procedural complications
    Spinal cord injury thoracic
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Septic shock
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 VBDD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 33 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Haematoma
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    3
    Surgical and medical procedures
    Catheterisation venous
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Glaucoma surgery
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    General disorders and administration site conditions
    Administration site extravasation
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Application site erythema
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Asthenia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Chest discomfort
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Chills
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Face oedema
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    9 / 33 (27.27%)
         occurrences all number
    9
    Feeling hot
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Influenza like illness
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    3
    Pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Puncture site pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    3
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Epistaxis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Sleep disorder
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    C-reactive protein increased
         subjects affected / exposed
    5 / 33 (15.15%)
         occurrences all number
    6
    Creatinine renal clearance decreased
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    3
    Sputum abnormal
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Spinal compression fracture
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    3
    Paraesthesia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Polyneuropathy
         subjects affected / exposed
    4 / 33 (12.12%)
         occurrences all number
    4
    Radial nerve palsy
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Speech disorder
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 33 (30.30%)
         occurrences all number
    14
    Cytopenia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    2
    Febrile neutropenia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Leukopenia
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Neutropenia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    2
    Thrombocytopenia
         subjects affected / exposed
    8 / 33 (24.24%)
         occurrences all number
    10
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Eye haemorrhage
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Eyelid haematoma
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Ocular discomfort
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    9 / 33 (27.27%)
         occurrences all number
    11
    Diarrhoea
         subjects affected / exposed
    4 / 33 (12.12%)
         occurrences all number
    4
    Dysphagia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    6 / 33 (18.18%)
         occurrences all number
    6
    Vomiting
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    4 / 33 (12.12%)
         occurrences all number
    4
    Rosacea
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Scar pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Skin lesion
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Hypothyroidism
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Muscle spasms
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Osteolysis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Pathological fracture
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Bronchitis
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Candida infection
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Herpes zoster
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Herpes zoster oticus
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    5 / 33 (15.15%)
         occurrences all number
    5
    Influenza
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Klebsiella sepsis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    4
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Skin infection
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    2
    Hyperkalaemia
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1
    Increased appetite
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Apr 2013
    Bortezomib application was switched from i.v. to s.c., as s.c. has been shown (according to Moreau et al. 2011) to be equally effective but with fewer side effects. Ultrasound examination was included to diagnose soft tissue plasmacytoma. Adequate bone marrow function was redefined.

    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/29674494
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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