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    Clinical Trial Results:
    BREVITY: A phase II study of brentuximab vedotin using a response adapted design in patients with Hodgkin lymphoma unsuitable for chemotherapy due to age, frailty or co-morbidity

    Summary
    EudraCT number
    2012-000214-11
    Trial protocol
    GB  
    Global end of trial date
    18 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Aug 2019
    First version publication date
    02 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_11-225
    Additional study identifiers
    ISRCTN number
    ISRCTN77650947
    US NCT number
    NCT02567851
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Sponsors SAF number: ERN_11-0718, Sponsors RG Number: RG_11-225
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham, Birmingham, United Kingdom, B15 2TT
    Public contact
    BREVITY trial coordinator, University of Birmingham, +44 1213717863, brevity@trials.bham.ac.uk
    Scientific contact
    BREVITY trial coordinator, University of Birmingham, +44 1213717863, brevity@trials.bham.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
    04 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine how many patients treated with 4 cycles of brentuximab vedotin, who are unsuitable for conventional chemotherapy, have a complete response to the treatment (as measured by PET scan Deauville score 1,2 or 3).
    Protection of trial subjects
    Patients were carefully monitored during and for 1-hour after the first infusion for infusion-related reactions. If an infusion-related reaction occurred, the infusion was interrupted and appropriate medical management instituted. All general supportive care measures, including red cell transfusion to alleviate disease related symptoms and treatment toxicities were allowed at the investigators discretion.
    Background therapy
    -
    Evidence for comparator
    Brentuximab vedotin (BV) is a new CD30 targeted antibody, composed of the anti-CD30 monoclonal antibody cAC10 and a potent antimictrotubule drug, monomethyl auristatin E (MMAE). It binds to CD30, which has very low expression in normal cells but is consistently expressed in Hodgkin Reed-Sternberg cells. Phase 1 and 2 data in the relapsed/refractory Hodgkin Lymphoma population suggest that BV has a high level of efficacy and a very manageable toxicity profile with no known cardiac or pulmonary toxicity when given as a single agent.
    Actual start date of recruitment
    14 Feb 2014
    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: 38
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    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)
    3
    From 65 to 84 years
    29
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were invited to attend from 13 UK Haematology-oncology centres, as selected for the LLR Trials Acceleration Programme (TAP) and additional UK Haemato-Oncology centres. Recruitment ran between 14-FEB-2014 and 20-OCT-2017.

    Pre-assignment
    Screening details
    Screening commenced following consent and prior to patient registration in order to confirm eligibility. All patients had a full medical and drug history, PET scan and physical examination, with particular attention paid to cardiovascular risk factors and assessments to exclude symptoms or signs of Progressive Multifocal Leukoencephalpathy.

    Pre-assignment period milestones
    Number of subjects started
    47 [1]
    Number of subjects completed
    38

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    ineligible: 5
    Reason: Number of subjects
    Died: 1
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Reason: Number of subjects
    PET accrediation issue, couldn't finish screening: 1
    Reason: Number of subjects
    Patient too unwell: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Patients were screened prior to enrolment into the study. This occurred prior to registration therefore the number in the pre-enrolment period is greater than the number registered into the trial.
    Period 1
    Period 1 title
    Registration
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Brentuximab vedotin
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    SGN-35
    Other name
    Adcetris
    Pharmaceutical forms
    Powder for concentrate
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin was administered at an initial dose of 1.8 mg/kg every 3 weeks as a 30-minute outpatient i.v. infusion. After the initial 4 cycles of BV, subsequent treatment was response-adapted. Dose reduction to 1.2mg/kg every 3 weeks was permitted in response to levels of toxicity.

    Number of subjects in period 1
    Brentuximab vedotin
    Started
    38
    Completed
    38
    Period 2
    Period 2 title
    Treated patients
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Brentuximab vedotin
    Arm description
    Treatment with 4 cycles of BV
    Arm type
    Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    SGN-35
    Other name
    Adcetris
    Pharmaceutical forms
    Powder for concentrate
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin was administered at an initial dose of 1.8 mg/kg every 3 weeks as a 30-minute outpatient i.v. infusion. After the initial 4 cycles of BV, subsequent treatment was response-adapted. Dose reduction to 1.2mg/kg every 3 weeks was permitted in response to levels of toxicity.

    Number of subjects in period 2
    Brentuximab vedotin
    Started
    38
    Completed
    31
    Not completed
    7
         Failed to start treatment
    1
         ineligible
    6
    Period 3
    Period 3 title
    Efficacy
    Is this the baseline period?
    Yes [2]
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Brentuximab vedotin
    Arm description
    Treatment with 4 cycles of BV
    Arm type
    Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    SGN-35
    Other name
    Adcetris
    Pharmaceutical forms
    Powder for concentrate
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin was administered at an initial dose of 1.8 mg/kg every 3 weeks as a 30-minute outpatient i.v. infusion. After the initial 4 cycles of BV, subsequent treatment was response-adapted. Dose reduction to 1.2mg/kg every 3 weeks was permitted in response to levels of toxicity.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: This is a single arm phase II trial in which 7 patients were replaced. Period one includes all patients registered to the trial, period three includes only those who were evaluable for efficacy. It is the baseline characteristics of those patients who were evaluated for efficacy which are of clinical importance.
    Number of subjects in period 3 [3]
    Brentuximab vedotin
    Started
    31
    Completed
    31
    Notes
    [3] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: This is a single arm phase II trial in which 7 patients were replaced. Period one includes all patients registered to the trial, period three includes only those who were evaluable for efficacy. It is the baseline characteristics of those patients who were evaluated for efficacy which are of clinical importance.

    Baseline characteristics

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

    Reporting group values
    Efficacy Total
    Number of subjects
    31 31
    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)
    2 2
        From 65-84 years
    25 25
        85 years and over
    4 4
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    77 (69 to 82) -
    Gender categorical
    Units: Subjects
        Female
    11 11
        Male
    20 20
    ECOG Performance Status
    Units: Subjects
        Zero
    1 1
        One
    16 16
        Two
    9 9
        Three
    5 5
    Disease stage
    Units: Subjects
        ll
    6 6
        lll
    9 9
        IV
    16 16
    B Symptoms
    Units: Subjects
        No
    8 8
        Yes
    23 23
    Extra Nodal Disease
    Units: Subjects
        No
    13 13
        Yes
    18 18
    Bulky Disease
    Units: Subjects
        No
    28 28
        Yes
    3 3
    Nodal Involvement
    Units: Subjects
        No
    4 4
        Yes
    26 26
        Not known
    1 1
    Histotype
    Units: Subjects
        Nodular Sclerosing
    16 16
        Mixed Cellularity
    8 8
        Not Known
    7 7
    Reason Standard Chemotherapy is Unsuitable
    Units: Subjects
        Left ventricular ejection fraction (LVEF)
    4 4
        Left ventricular ejection and ECOG
    7 7
        LVEF, Impaired respiratory and ECOG
    1 1
        Impaired respiratory and ECOG
    4 4
        ECOG
    9 9
        LVEF and Impaired respiratory
    1 1
        Impaired respiratory
    1 1
        Impiared cardiac, LVEF and ECOG
    1 1
        Imparied cardiac plus respiratory and ECOG
    1 1
        Impaired cardiac and ECOG
    2 2
    CIRS-G: Total number of categorised endorsed
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    3.00 (2.00 to 5.00) -
    CIRS-G: Total Score
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    6.00 (4.00 to 7.00) -
    CIRS-G: Severity Index
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    2.00 (2.00 to 2.00) -
    CIRS-G: Number categorised at level 3
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00) -
    CIRS-G: Number categorised at level 4
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 0.00) -

    End points

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    End points reporting groups
    Reporting group title
    Brentuximab vedotin
    Reporting group description
    -
    Reporting group title
    Brentuximab vedotin
    Reporting group description
    Treatment with 4 cycles of BV
    Reporting group title
    Brentuximab vedotin
    Reporting group description
    Treatment with 4 cycles of BV

    Primary: Complete (metabolic) response rate after 4 cycles of Brentuximab vedotin defined as Deauville Score of 1, 2 or 3 at PET 4.

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    End point title
    Complete (metabolic) response rate after 4 cycles of Brentuximab vedotin defined as Deauville Score of 1, 2 or 3 at PET 4. [1]
    End point description
    No statistical analysis were preformed. During the design of this trial a response rate of 40% was deemed unacceptable for further investigation and a response rate of 60% was deemed worthy of further investigation. These figures were used in the Simon's two-stage minimax design which determined that in order for the BV to be worthy of further investigation as a single agent treatment the trial needed to show a minimum of 15 complete metabolic responses.
    End point type
    Primary
    End point timeframe
    Assessed by PET-CT scan after 4 cycles of Brentuximab Vedotin. Scans were conducted within the day 15-19 window of cycle 4.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis were conducted in relation to this primary outcome as this is a single arm trial so the interpretation of the primary outcome was made in relation to desirable characteristics defined in the sample size calculation.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: Number of patients achieving CMR
    8
    No statistical analyses for this end point

    Secondary: Dose intensity

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    End point title
    Dose intensity
    End point description
    End point type
    Secondary
    End point timeframe
    Dose intensity reported as the median dose intensity over the treatment period for all patients across all cycles.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: Dose Intensity
        median (inter-quartile range (Q1-Q3))
    100 (70 to 100)
    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
    PFS estimates calculated using Kaplan-Meier method presented as median, 12 and 24 month survival.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: PFS
    median (confidence interval 95%)
        Median PFS time (months)
    7.3 (5.2 to 9.0)
        12 months PFS (%)
    13.7 (4.3 to 28.4)
        24 months PFS (%)
    6.9 (1.2 to 19.6)
    Attachments
    Untitled (Filename: PFS.pdf)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    The upper estimate of the 95% confidence interval for median overall survival has not yet been reached. Maximum range has been entered.
    End point type
    Secondary
    End point timeframe
    Overall survival is defined as the time from cycle 1 day 1 to the date of death from any cause.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: OS
    number (confidence interval 95%)
        Median OS time months
    19.5 (12.6 to 51.0)
        12 month OS (%)
    73.4 (53.7 to 85.7)
        24 months OS (%)
    42.0 (24.1 to 58.8)
    Attachments
    Untitled (Filename: OS.pdf)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) at PET 4

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    End point title
    Objective Response Rate (ORR) at PET 4
    End point description
    ORR is defined as achieving either complete or partial metabolic response and is calculated using Wilsons estimates due to its increased accuracy with small sample sizes.
    End point type
    Secondary
    End point timeframe
    ORR after 4 cycles of treatment with Brentuximab vedotin according to the Revised Response Criteria for malignant lymphoma.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: CMR or PMR %
        number (confidence interval 95%)
    83.9 (67.4 to 92.9)
    No statistical analyses for this end point

    Secondary: Tolerability

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    End point title
    Tolerability
    End point description
    Tolerability was defined in terms of the absence of toxicities related to Bretuximab Vedotin quantified by the CTCAE v4 criteria. All 35 treated patients experienced at least one related event during the trial. In total 246 related toxicities were reported, 55% were grade 1, 29% grade 2, 15% grade 3 and 0.5% was grade 4.
    End point type
    Secondary
    End point timeframe
    Patients were assessed for toxicities related to Brentuximab Vedotin throughout the treatment period.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: Patients without related toxicities
    0
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) at 16 cycles

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    End point title
    Objective Response Rate (ORR) at 16 cycles
    End point description
    ORR is defined as achieving either complete or partial metabolic response.
    End point type
    Secondary
    End point timeframe
    ORR after 16 cycles of treatment with Brentuximab vedotin according to the Revised Response Criteria for malignant lymphoma.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: CMR or PMR %
        number (confidence interval 95%)
    9.7 (3.3 to 24.9)
    No statistical analyses for this end point

    Secondary: Cumulative illness rating scale for geriatrics (CIRS-G)

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    End point title
    Cumulative illness rating scale for geriatrics (CIRS-G)
    End point description
    CIRS-G Index score of 1 = Current mild problems or past significant problems. CIRS-G Index score of 2 = Moderate disability of morbidity - requires first line therapy CIRS-G Index score of 3 = Severe - constant significant disability - 'uncontrollable' chronic pain.
    End point type
    Secondary
    End point timeframe
    Assessed as part of baseline measures prior to commencement of trial treatment.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: Number of patients
        Index score 1
    7
        Index score 2
    22
        Index score 3
    2
    No statistical analyses for this end point

    Secondary: Co-morbidities satisfying eligibility criteria

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    End point title
    Co-morbidities satisfying eligibility criteria
    End point description
    End point type
    Secondary
    End point timeframe
    Emergence of any new co-morbidity throughout the course of the trial which would satisfy the eligibility criteria
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: Number Patients
    0
    No statistical analyses for this end point

    Secondary: Deauville score after cycle 2 based on blinded PET2 scan

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    End point title
    Deauville score after cycle 2 based on blinded PET2 scan
    End point description
    End point type
    Secondary
    End point timeframe
    Blinded PET scans were taken following 2 cycles of BV.
    End point values
    Brentuximab vedotin
    Number of subjects analysed
    31
    Units: Number patients
        Deauville 1
    0
        Deauville 2
    3
        Deauville 3
    5
        Deauville 4
    15
        Deauville 5
    2
        Not done
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were reported from the date of commencement of protocol defined treatment until 30 days after the administration of treatment.
    Adverse event reporting additional description
    Adverse Events (AEs) were reported on an AE form and returned to the Trials Office. AE's were reviewed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4. SAE forms were faxed to the Trials Office; seriousness and causality were determined independently by a Clinical Coordinator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Treated patients
    Reporting group description
    All 35 patients who received Bretuximab Vedotin.

    Serious adverse events
    Treated patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 35 (60.00%)
         number of deaths (all causes)
    21
         number of deaths resulting from adverse events
    1
    Surgical and medical procedures
    Surgical and medical procedures other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorder other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Fever
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Facial muscle weakness
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhea
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythroderma
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalemia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypomagnesemia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations other
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Treated patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 35 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    4
    Hypotension
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Surgical and medical procedures
    Surgical and medical procedures - other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - other
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    5
    Immune system disorders
    Anaphylaxis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    2
    Chills
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    3
    Edema limbs
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Hypothermia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    18 / 35 (51.43%)
         occurrences all number
    35
    Fever
         subjects affected / exposed
    11 / 35 (31.43%)
         occurrences all number
    12
    Flu like symptoms
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    3
    Infusion related reaction
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Malaise
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    11 / 35 (31.43%)
         occurrences all number
    18
    General disorders and administration site conditions - other
         subjects affected / exposed
    9 / 35 (25.71%)
         occurrences all number
    16
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Anxiety
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Confusion
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Psychiatric disorders - other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Uterine pain
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    7
    Fracture
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Injury, poisoning and procedural complications - other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    5
    Alkaline phosphatase increased
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    2
    Creatinine increased
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    GGT increased
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    17
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    12
    Lymphocyte count increased
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Neutrophil count decreased
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    9
    Platelet count decreased
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    8
    Weight loss
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    7
    White blood cell decreased
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    8
    Investigations - other
         subjects affected / exposed
    8 / 35 (22.86%)
         occurrences all number
    117
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Palpitations
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    2
    Cardiac disorders - other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    8 / 35 (22.86%)
         occurrences all number
    29
    Leukocytosis
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    7
    Lymph node pain
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Febrile neutropenia
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    6
    Dyspnea
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    6
    Sore throat
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Bronchospasm
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Sleep apnea
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders - other
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    4
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Vasovagal reaction
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Dysesthesia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    2
    Facial muscle weakness
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    5
    Memory impairment
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Paresthesia
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Peripheral motor neuropathy
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    19 / 35 (54.29%)
         occurrences all number
    51
    Dizziness
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    5
    Lethargy
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    5
    Nervous system disorders - other
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Ear and labyrinth disorders
    External ear inflammation
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    6
    Constipation
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    7
    Diarrhea
         subjects affected / exposed
    11 / 35 (31.43%)
         occurrences all number
    27
    Dry mouth
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Gastric ulcer
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    4
    Hemorrhoids
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Mucositis oral
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Toothache
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    5
    Gastrointestinal disorders - other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    3
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    5
    Chronic kidney disease
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Urinary retention
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    4
    Dry skin
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Erythema multiforme
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Erythroderma
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    5
    Rash maculo-papular
         subjects affected / exposed
    11 / 35 (31.43%)
         occurrences all number
    18
    Skin induration
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Hirsutism
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Skin ulceration
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders - other
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Muscle weakness lower limb
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    8
    Myalgia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders - other
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    4
    Endocrine disorders
    Endocrine disorders - other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypercalcemia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    4
    Anorexia
         subjects affected / exposed
    13 / 35 (37.14%)
         occurrences all number
    15
    Dehydration
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Hyperglycemia
         subjects affected / exposed
    8 / 35 (22.86%)
         occurrences all number
    12
    Hyperkalemia
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Hyperuricemia
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    3
    Hypoalbuminemia
         subjects affected / exposed
    7 / 35 (20.00%)
         occurrences all number
    12
    Hypocalcemia
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    6
    Hypoglycemia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Hypokalemia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Hypomagnesemia
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    5
    Hyponatremia
         subjects affected / exposed
    5 / 35 (14.29%)
         occurrences all number
    11
    Hypophosphatemia
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    5
    Metabolism and nutrition disorders - other
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    3
    Infections and infestations
    Lung infection
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    3
    Upper respiratory infection
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    5
    Nail infection
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Sepsis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 35 (8.57%)
         occurrences all number
    5
    Wound infection
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Infections and infestations - other
         subjects affected / exposed
    6 / 35 (17.14%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2013
    Clarifications of the eligibility assessments; the addition of radionuclide GFR assessment to the ARSAC information and the correction of spelling and typographical errors.
    21 Mar 2014
    This amendment contained: • Change to dose rounding • Addition of serum amylase and lipase measurements • Addition of acute pancreatitis information • Increased duration of contraception usage required for patients and their partners
    28 Apr 2014
    This amendment covered the addition of 2 study sites and a change of PI at a current site.
    28 Aug 2014
    The RSI for the BREVITY trial was updated to reflect new information provided in the SPC. This was reported in the DSUR submitted on 01-August-14. The new information provided added pancreatitis, pulmonary toxicity, sepsis, septic shock and ALT/AST increase as new expected side effects and an extension to the period in which contraception should be used to 6 months after treatment. The Patient Information Sheet/Informed Consent Form was updated accordingly.
    04 Nov 2014
    Amendment was made to allow patients to continue on trial treatment if they had a partial response, and the addition of an extra PET scan for these patients. In addition several small changes were made to update the trial to the new lymphoma response criteria and to reduce the AE reporting.
    23 Jul 2015
    The BREVITY trial submitted this amendment in order to clarify the IMP processing for the trial following new information received and discussion with the MHRA pharmacist. No other changes were made to the trial.
    19 Jan 2016
    Amendment concerned the change of PI at an existing BREVITY site.
    30 Nov 2016
    Amendment resolved an inconsistency in end of trial definition on the NHS REC form and MHRA medicines (EudraCT application form). These have been amended bringing them in line with current practices.
    09 Apr 2018
    An update to the follow-up period; reducing the follow-up period from 5 to 2 years.

    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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