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    Clinical Trial Results:
    Subcutaneous Bortezomib, Cyclophosphamide and Rituximab (BCR) versus Fludarabine, Cyclophosphamide and Rituximab (FCR) for initial therapy of Waldenstrőm macroglobulinaemia: a randomised phase II study.

    Summary
    EudraCT number
    2011-005156-34
    Trial protocol
    GB  
    Global end of trial date
    02 Aug 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Aug 2021
    First version publication date
    20 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/11/0353
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01592981
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Haematology Trials Group, Cancer Research UK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Scientific contact
    Haematology Trials Group, Cancer Research UK and UCL Cancer Trials Centre, ctc.sponsor@ucl.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
    10 Aug 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a Phase II trial of bortezomib / cyclophosphamide / rituximab (BCR) in initial therapy of Waldenstrom's Macroglobulinaemia (WM). The overall aim was to make a preliminary examination of the safety and efficacy of the proposed BCR combination in patients with symptomatic, previously untreated WM and determine whether BCR warrants further investigation in a randomised phase III setting. During the first non-randomised stage of the trial, the number and severity of adverse events experienced by patients treated with BCR were analysed. Only when the BCR combination was considered tolerable (as defined in the study protocol), the trial continued to a randomised second stage where efficacy of BCR was assessed in terms of response to treatment and a second arm of fludarabine, cyclophosphamide and rituximab (FCR) was added to the design. The two arms were randomised in a 2:1 ratio.
    Protection of trial subjects
    The risks to the safety of the trial subjects were those generally associated with chemotherapy. With limited published data on the BCR combination of drugs in WM, a safety run-in phase was designed to assess the safety and tolerability of the regimen. This included 6 patients with regular monitoring of the laboratory and safety data. A formal review followed after the 6th patient reached day 1 of the second treatment cycle. The IDMC confirmed the study could continue with the laboratory and safety data continuing to be monitored regularly by trials unit staff and the TMG, with an annual review by the IDMC. The protocol contained specific instructions regarding clinical assessments for potential side effects, including neuropathy, and resultant dose modifications, or cessation of treatment. The protocol also had instructions on medications that should be used with caution and those that could be prescribed for specific conditions at the discretion of the treating physician. Patients were counselled about the potential side effects prior to starting treatment. Pregnant or lactating women were excluded from the study. Women of childbearing potential and male patients were informed they must use an effective form of contraception during the course of the study.
    Background therapy
    Supportive care for this study was as per local guidelines with the following recommendations: • Aciclovir prophylaxis should be given whilst patients are receiving treatment because of the increased incidence of herpes zoster infection reported in patients treated on a similar regimen • Anti-emetic prophylaxis is recommended for at least 5 days with a 5 HT3 antagonist • Allopurinol is advised for the first cycle of therapy
    Evidence for comparator
    There is no agreed standard on first-line therapy of WM but a consensus panel of international experts has provided treatment recommendations based on the most recently published clinical trial results. Combination therapy of rituximab with purine analogues with or without alkylators or with cyclophosphamide based therapies have been recommended in the front-line setting with comparable response rates for both Fludarabine, Cyclophosphamide, Rituximab (FCR) and Dexamethasone, Rituximab, Cyclophosphamide (DRC). Within the UK, experience is greatest with FCR which is favoured by the participating centres as the non-comparative control arm following the results of a national survey.
    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: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    0
    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)
    23
    From 65 to 84 years
    36
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The 60 trial subjects were recruited between 20/02/2013 and 04/09/2015 from 24 trial hospitals.

    Pre-assignment
    Screening details
    Treatment-naïve patients with symptomatic WM were enrolled. Patients aged ≥18 years with a confirmed diagnosis of WM according to World Health Organisation (WHO) criteria and ECOG Performance Status 0-2 were included.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BCR (experimental) arm
    Arm description
    BCR (experimental) arm: Bortezomib: 1.6 mg/m2 s.c. days 1, 8, 15 Cyclophosphamide: 250 mg/m2 oral days 1, 8, 15 Rituximab: 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with a further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed.
    Arm type
    Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    1.6 mg/m2. - Based on body surface area (BSA) calculated using actual body weight according to local policy - Calculated prior to each cycle and remained the same throughout each cycle and if a patient experienced a notable change in weight (e.g. loss or gain of 8lbs or 3.6kg or 5% change in weight) within a cycle Administration: Suggested anatomical areas were the thighs or abdomen and injection sites were rotated within a treatment cycle. Intravenous bortezomib administration was allowed if a patient did not tolerate subcutaneous administration (e.g. >grade 2 local reaction). The change of administration route would have been approved by the Chief Investigator. Patients who switched to the IV route maintained this route for the remaining treatment. Where bortezomib needed to be administered intravenously, the most recent SPC was checked for details on diluent, volume, duration of infusion, stability and storage of bortezomib. Schedule: Days 1, 8 and 15 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Powder for solution for injection
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    250mg/m2 - based on BSA calculated using actual body weight according to local policy Administration: Oral If the oral preparation of cyclophosphamide is not tolerated this can be given intravenously at the same dose (250 mg/m2). Schedule: BCR (experimental) arm: days 1, 8 and 15 of each cycle

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/m2 Administration: i.v infusion If the IgM paraprotein is ≥ 50g/L at the time of the first treatment, prophylactic use of plasmapheresis is recommended before the administration of rituximab because of the potential for rituximab-mediated IgM flare and aggravation of hyperviscosity. If the IgM paraprotein is ≥ 50g/L but plasmapheresis is not available, Rituximab administration should be delayed to cycle 3 and 6. Administration of rituximab including pre-medications (paracetamol, anti-histamines, steroids) and infusion rates during the first and subsequent infusions are according to the site local guidelines and policies. Rituximab must not be administered as an intravenous bolus injection. Schedule: days 1, 8, 15 and 22 of cycles 2 and 5 only

    Arm title
    FCR (control) arm
    Arm description
    Fludarabine: 40 mg/m2 oral days 1-3 Cyclophosphamide: 250 mg/m2 oral days 1-3 Rituximab 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with a further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed.
    Arm type
    Active comparator

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg/m2 Based on BSA calculated using actual body weight according to local policy. Administration: Oral If the oral preparation of fludarabine is not tolerated this can be given intravenously at 25 mg/m2. Schedule: days 1, 2 and 3 of each cycle

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    250mg/m2 - based on BSA calculated using actual body weight according to local policy Administration: Oral If the oral preparation of cyclophosphamide is not tolerated this can be given intravenously at the same dose (250 mg/m2). Schedule: BCR (experimental) arm: days 1, 8 and 15 of each cycle

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/m2 Administration: i.v infusion If the IgM paraprotein is ≥ 50g/L at the time of the first treatment, prophylactic use of plasmapheresis is recommended before the administration of rituximab because of the potential for rituximab-mediated IgM flare and aggravation of hyperviscosity. If the IgM paraprotein is ≥ 50g/L but plasmapheresis is not available, Rituximab administration should be delayed to cycle 3 and 6. Administration of rituximab including pre-medications (paracetamol, anti-histamines, steroids) and infusion rates during the first and subsequent infusions are according to the site local guidelines and policies. Rituximab must not be administered as an intravenous bolus injection. Schedule: days 1, 8, 15 and 22 of cycles 2 and 5 only

    Number of subjects in period 1
    BCR (experimental) arm FCR (control) arm
    Started
    43
    17
    Completed
    39
    13
    Not completed
    4
    4
         Physician decision
    -
    1
         Patient withdrew prior to treatment
    1
    -
         Ineligible for study, withdrawn mid cycle 1
    1
    -
         Adverse event, non-fatal
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    Patient Inclusion Criteria -Age ≥ 18 years -Confirmed diagnosis of WM (according to consensus panel / WHO criteria) with measurable IgM paraprotein -Previously untreated disease at any stage requiring therapy -Performance status grade 0 - 2 -Life expectancy of greater than 6 months -Informed consent -Agreed compliance with recommended contraceptive precautions where appropriate Exclusion Criteria -Lymphoplasmacytic lymphoma with no detectable serum IgM paraprotein -Severe pre-existing neuropathy (> grade 2) -Autoimmune cytopenias -Evidence of active Hepatitis B or C infection -Serological positivity for HIV -Pregnant or lactating women -Life expectancy severely limited by other illness -Diagnosed or treated for a malignancy other than WM within 5 years -Renal failure -Severe impairment of liver function -Concurrent treatment with another investigational agent -Severe or life-threatening cardiac, pulmonary, neurological, psychiatric or metabolic disease

    Reporting group values
    Overall trial (overall period) Total
    Number of subjects
    60 60
    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)
    23 23
        From 65-84 years
    36 36
        85 years and over
    1 1
    Gender categorical
    Units: Subjects
        Female
    16 16
        Male
    44 44
    IPSSWM
    International Prognostic Scoring System for WM
    Units: Subjects
        Low risk
    16 16
        Intermediate risk
    17 17
        High risk
    27 27
    Hyperviscosity
    Units: Subjects
        Present
    38 38
        Not present
    22 22
    Lymphadenopathy
    Units: Subjects
        Present
    18 18
        Not present
    42 42
    B symptoms
    Units: Subjects
        Present
    18 18
        Not present
    42 42
    Splenomegaly
    Units: Subjects
        Present
    9 9
        Not present
    51 51
    Peripheral neuropathy
    Units: Subjects
        Present
    8 8
        Not present
    52 52
    MYD88 L265P mutation
    Units: Subjects
        Demonstrable
    53 53
        Non demonstrable
    4 4
        Not evaluable
    3 3
    CXCR4 mutation
    Units: Subjects
        Demonstrable
    6 6
        Not demonstrable
    21 21
        Not evaluable
    33 33
    Haemoglobin
    Units: g/dl
        median (full range (min-max))
    9.8 (6.5 to 14) -
    Serum IgM paraprotein
    Units: g/L
        median (full range (min-max))
    34.0 (3.2 to 80.2) -

    End points

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    End points reporting groups
    Reporting group title
    BCR (experimental) arm
    Reporting group description
    BCR (experimental) arm: Bortezomib: 1.6 mg/m2 s.c. days 1, 8, 15 Cyclophosphamide: 250 mg/m2 oral days 1, 8, 15 Rituximab: 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with a further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed.

    Reporting group title
    FCR (control) arm
    Reporting group description
    Fludarabine: 40 mg/m2 oral days 1-3 Cyclophosphamide: 250 mg/m2 oral days 1-3 Rituximab 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with a further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed.

    Primary: Overall response rate

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    End point title
    Overall response rate [1]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to end of treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint is the number/proportion of patients in each of the response categories. No specific statistical analyses are required to establish the percentage of patients. This can be calculated using the number of patients who were in the trial and the number of patients in each response category.
    End point values
    BCR (experimental) arm FCR (control) arm
    Number of subjects analysed
    41
    17
    Units: Patients
        Complete response
    1
    0
        Very good partial response
    8
    3
        Partial response
    24
    10
        Stable disease
    1
    2
        Minor response
    7
    1
        Not evaluated
    0
    1
    No statistical analyses for this end point

    Secondary: Speed of response

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    End point title
    Speed of response
    End point description
    End point type
    Secondary
    End point timeframe
    Start of treatment to 25% reduction (minor response) in serum IgM
    End point values
    BCR (experimental) arm FCR (control) arm
    Number of subjects analysed
    41
    17
    Units: Months
        median (confidence interval 95%)
    2.1 (1.6 to 2.5)
    1.5 (0.7 to 2.7)
    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
    Baseline to two and three year follow up
    End point values
    BCR (experimental) arm FCR (control) arm
    Number of subjects analysed
    41
    17
    Units: Patients
        Patients progression free at 2 years
    38
    14
        Patients progression free at 3 years
    33
    10
    No statistical analyses for this end point

    Secondary: Time to next treatment

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    End point title
    Time to next treatment
    End point description
    Number of patients receiving further treatment within 61.2 months
    End point type
    Secondary
    End point timeframe
    Baseline to a median follow up of 61.2 months
    End point values
    BCR (experimental) arm FCR (control) arm
    Number of subjects analysed
    41
    17
    Units: Patients
    8
    1
    No statistical analyses for this end point

    Secondary: Toxicity

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    End point title
    Toxicity
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to End of Trial
    End point values
    BCR (experimental) arm FCR (control) arm
    Number of subjects analysed
    41
    17
    Units: Patients
        No. stopping treatment early due to toxicity
    2
    4
        No. developing treatment related myelodysplasia
    0
    3
        No. requiring dose reductions
    16
    9
        No. requiring treatment delays
    27
    11
        No. with grade 3 or higher adverse events
    27
    13
    No statistical analyses for this end point

    Secondary: Overall surivival

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    End point title
    Overall surivival
    End point description
    Number of patients who died
    End point type
    Secondary
    End point timeframe
    Baseline to End of Trial
    End point values
    BCR (experimental) arm FCR (control) arm
    Number of subjects analysed
    41
    17
    Units: Patients
    2
    7
    No statistical analyses for this end point

    Secondary: Quality of life

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    End point title
    Quality of life
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to End of Trial
    End point values
    BCR (experimental) arm FCR (control) arm
    Number of subjects analysed
    41
    17
    Units: Patients
        Baseline Mobility - No problems
    24
    13
        End of Trial Mobiility - No Problems
    24
    12
        Baseline Mobility - Some problems
    12
    3
        End of Trial Mobility - Some Problems
    11
    1
        Baseline Mobility - Extreme problems
    0
    0
        End of Trial Mobility - Extreme problems
    0
    0
        Baseline Mobility - Missing
    5
    1
        End of Trial Mobility - Missing
    6
    4
        Baseline Self-care - No problems
    34
    15
        End of Trial Self-care - No problems
    31
    13
        Baseline Self-care - Some problems
    2
    1
        End of Trial Self-care - Some problems
    4
    0
        Baseline Self-care - Extreme problems
    0
    0
        End of Trial Self-care - Extreme problems
    0
    0
        Baseline Self-care - Missing
    5
    1
        End of Trial Self-care - Missing
    6
    4
        Baseline Usual Activities - No problems
    17
    14
        End of Trial Usual Activities - No problems
    22
    10
        Baseline Usual Activities - Some problems
    17
    2
        End of Trial Usual Activities - Some problems
    12
    3
        Baseline Usual Activities - Extreme problems
    2
    0
        End of Trial Usual Activities - Extreme problems
    1
    0
        Baseline Usual Activities - Missing
    5
    1
        End of Trial Usual Activities - Missing
    6
    4
        Baseline Pain/discomfort - No problems
    17
    12
        End of Trial Pain/discomfort - No problems
    20
    9
        Baseline Pain/discomfort - Some problems
    19
    4
        End of Trial Pain/discomfort - Some problems
    12
    4
        Baseline Pain/discomfort - Extreme problems
    0
    0
        End of Trial Pain/discomfort - Extreme problems
    3
    0
        Baseline Pain/discomfort - Missing
    5
    1
        End of Trial Pain/discomfort - Missing
    6
    4
        Baseline Anxiety/depression - No problems
    22
    12
        End of Trial Anxiety/depression - No problems
    27
    11
        Baseline Anxiety/depression - Some problems
    14
    4
        End of Trial Anxiety/depression - Some problems
    8
    2
        Baseline Anxiety/depression - Extreme problems
    0
    0
        End of Trial Anxiety/depression - Extreme Problems
    0
    0
        Baseline Anxiety/depression -Missing
    5
    4
        End of Trial Anxiety/depression - Missing
    6
    6
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    Duration of response
    End point description
    End point type
    Secondary
    End point timeframe
    Response to two or three year follow up
    End point values
    BCR (experimental) arm FCR (control) arm
    Number of subjects analysed
    41
    17
    Units: Patients
        Number of patients with a two-year response
    36
    15
        Number of patients with a three year response
    32
    11
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events, and all serious adverse events (SAEs), that occurred between informed consent and 30 days post last trial treatment administration (or after this date if thought to be related to trial treatment) had to be reported.
    Adverse event reporting additional description
    Adverse events were recorded in the patient notes and trial Case Report Forms. Those meeting the definition of a Serious Adverse Event were also reported to UCL CTC using the trial specific SAE Report Form.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI-CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    BCR (experimental) arm
    Reporting group description
    BCR (experimental) arm: Bortezomib: 1.6 mg/m2 s.c. days 1, 8, 15 Cyclophosphamide: 250 mg/m2 oral days 1, 8, 15 Rituximab: 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed.

    Reporting group title
    FCR (control) arm
    Reporting group description
    Fludarabine: 40 mg/m2 oral days 1-3 Cyclophosphamide: 250 mg/m2 oral days 1-3 Rituximab 375 mg/m2 i.v. days 1, 8, 15, 22 cycles 2 & 5 only Cycle repeated every 28 days After 3 cycles of treatment, patients were reassessed and those with evidence of progression stopped trial treatment. All other patients continued with further 3 cycles (to a total of 6) unless a clear clinical contraindication to further treatment existed.

    Serious adverse events
    BCR (experimental) arm FCR (control) arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 42 (19.05%)
    9 / 17 (52.94%)
         number of deaths (all causes)
    2
    7
         number of deaths resulting from adverse events
    0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other: Malignant polyp
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus Bradycardia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 17 (29.41%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu like symptoms
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lung infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper respiratory infection
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BCR (experimental) arm FCR (control) arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 42 (100.00%)
    17 / 17 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    8 / 42 (19.05%)
    1 / 17 (5.88%)
         occurrences all number
    8
    1
    Investigations
    Febrile neutropenia
         subjects affected / exposed
    2 / 42 (4.76%)
    5 / 17 (29.41%)
         occurrences all number
    2
    5
    Neutrophil count decreased
         subjects affected / exposed
    24 / 42 (57.14%)
    15 / 17 (88.24%)
         occurrences all number
    24
    15
    Platelet count decreased
         subjects affected / exposed
    23 / 42 (54.76%)
    11 / 17 (64.71%)
         occurrences all number
    23
    11
    Respiratory, thoracic and mediastinal disorders
    Anorexia
         subjects affected / exposed
    5 / 42 (11.90%)
    2 / 17 (11.76%)
         occurrences all number
    5
    2
    Cough
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 17 (17.65%)
         occurrences all number
    3
    3
    Dyspnea
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 17 (5.88%)
         occurrences all number
    4
    1
    Epistaxis
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 17 (11.76%)
         occurrences all number
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 42 (73.81%)
    11 / 17 (64.71%)
         occurrences all number
    31
    11
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 42 (28.57%)
    2 / 17 (11.76%)
         occurrences all number
    12
    2
    Dysgeusia
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Headache
         subjects affected / exposed
    8 / 42 (19.05%)
    1 / 17 (5.88%)
         occurrences all number
    8
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    9 / 42 (21.43%)
    0 / 17 (0.00%)
         occurrences all number
    9
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    20 / 42 (47.62%)
    1 / 17 (5.88%)
         occurrences all number
    20
    1
    Eye disorders
    Blurred vision
         subjects affected / exposed
    5 / 42 (11.90%)
    0 / 17 (0.00%)
         occurrences all number
    5
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    8 / 42 (19.05%)
    1 / 17 (5.88%)
         occurrences all number
    8
    1
    Fatigue
         subjects affected / exposed
    26 / 42 (61.90%)
    10 / 17 (58.82%)
         occurrences all number
    26
    10
    Fever
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 17 (11.76%)
         occurrences all number
    4
    2
    Flu like symptoms
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 17 (5.88%)
         occurrences all number
    4
    1
    Injection site reaction
         subjects affected / exposed
    8 / 42 (19.05%)
    0 / 17 (0.00%)
         occurrences all number
    8
    0
    Pain
         subjects affected / exposed
    8 / 42 (19.05%)
    1 / 17 (5.88%)
         occurrences all number
    8
    1
    Rituximab infusion related reaction
         subjects affected / exposed
    15 / 42 (35.71%)
    4 / 17 (23.53%)
         occurrences all number
    15
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 17 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 42 (21.43%)
    4 / 17 (23.53%)
         occurrences all number
    9
    4
    Constipation
         subjects affected / exposed
    21 / 42 (50.00%)
    7 / 17 (41.18%)
         occurrences all number
    21
    7
    Diarrhoea
         subjects affected / exposed
    21 / 42 (50.00%)
    4 / 17 (23.53%)
         occurrences all number
    21
    4
    Dyspepsia
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 17 (0.00%)
         occurrences all number
    4
    0
    Mucositis oral
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    28 / 42 (66.67%)
    14 / 17 (82.35%)
         occurrences all number
    28
    14
    Vomiting
         subjects affected / exposed
    6 / 42 (14.29%)
    2 / 17 (11.76%)
         occurrences all number
    6
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 17 (0.00%)
         occurrences all number
    3
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 17 (17.65%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Back pain
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Myalgia
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 17 (5.88%)
         occurrences all number
    4
    1
    Pain in extremity
         subjects affected / exposed
    8 / 42 (19.05%)
    0 / 17 (0.00%)
         occurrences all number
    8
    0
    Other: Joint pain
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Other: Muscle cramp
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 17 (5.88%)
         occurrences all number
    4
    1
    Infections and infestations
    Upper respiratory infection
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 17 (11.76%)
         occurrences all number
    4
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2013
    Documents updated: Protocol v2.0 30/11/2012 PIS-stage1 v2.0 30/11/2012 PIS-stage2 v2.0 30/11/2012 Pregnancy Monitoring IS (patient) v1 30/11/2012 Pregnancy Monitoring IS (partner) v1 30/11/2012 Pregnancy Monitoring IC (patient) v1 30/11/2012 Pregnancy Monitoring IC (partner) v1 30/11/2012 Main Changes: Protocol - Details for patients who may need to switch to IV bortezomib added, removal of NHS number from sample label, clarification to analysis of 'speed and duration of response', list of expected AEs for sc bortezomib removed and replaced with reference to the current SPC as it covers both sc and iv administration, reference to bortezomib IB removed and replaced with current SPC PIS: - Section on bortezomib side effects expanded as requested by company supplying bortezomib - Removal of statement regarding 'commercial use' of biological samples as this may be misleading
    13 Sep 2013
    Documents updated: Protocol v3.0 08/08/2013 PIS-stage1 v3.0 08/08/2013 PIS-stage2 v3.0 08/08/2013 CTA Main Changes: Protocol - Paragraph clarifying whether interpreter may be required to be provided by the site to obtain informed consent - Clarification that patients must be consented before any trial specific screening investigations are carried out - Clarification that FBC can be performed 1 day before D1 and 8 of each cycle, and that patients in the FCR arm need checked only on D1 (or -1) - Neutropenia changed from unusual to common side effect to reflect changes in the SPC - Addition of optional plasma viscosity test for cycle 1-3 - Removing requirement for Sites to have written procedures for informing Sponsor of Serious Breaches - Clarification to 'failure to start cycle 2 on time' when due to grade 3 or 4 heamatological toxicities - Reducing number of blood samples to be sent to Leeds during treatment and follow up - Serum samples for SFLC/ HeveyLite analysis to be sent to HMDS Leeds instead of Binding Site, Birmingham - NHS number to be listed on biological sample label (if applicable) - Clarification that either M protein or serum IgM can be used to assess changes in serum IgM level PIS: - Statement that Quality of Life questionnaire will be completed at 3 visits added - Addition of PML as a rare side effect of bortezomib - Details added to the paragraph on confidentiality that NHS numbers will be used - Reference to the Binding Site in Birmingham removed
    11 Apr 2014
    Documents changed: Protocol v4.0 18/02/2014 PIS-stage2 v4.0 18/02/2014 Main Changes: Protocol - 1. Clarification that the Hep B serology tests include HBsAg, HBsAb and HBcAB; HBV DNA test required if HBcAb result is positive (Prerandomisation evaluation section 5.1 of protocol). 2. Details regarding rituximab administration (premedication, infusion rates during 1st and subsequent infusion) removed and sites referred to their local policy (Treatment details section 7.3 Rituximab). 3. Addition that dose banding and dose capping for IMPs is allowed according to the site’s standard practice’ (Treatment details section 7.3 of protocol). 4. Addition of details regarding ‘dose attenuation’ at treatment start for patients with cytopenia or PS=2 randomised to FCR (Dose modifications section 7.4 of protocol). 5. Clarification on FBC timing during treatment (within 3 days of D1 and D8 of each cycle, repeated on the day if abnormal) (sections 7.4.1 Haematological toxicity and 8.2 Assessments during treatment). 6. Clarification that nonhaematological treatmentrelated grade 3 or higher adverse events are used to assess the toxicity rate (Interim analyses section 15.6 of protocol). 7. Correction of error in the ‘number of patients’ corresponding to toxicity rate of 20% in the second randomised stage of the study (Interim analyses section 15.6 of protocol). 8. Addition of ‘febrile neutropenia’ and ‘fever’ to the list of expected AEs for the FCR regimen, and of ‘rituximab related infusion reactions’ to the BCR arm (Expected Adverse Events Appendix 5 of protocol). PIS: 1. Addition of 'hyperaemia' as uncommon side effect and of thrombocytosis, amyloidosis, erythrosis, cough syndrome, coma and multiorgan failure as rare side effects of bortezomib. 2. Addition of hypogammaglobulinaemia and increased risk of infection as a side effect of rituximab
    24 Oct 2014
    Documents updated: PIS RSI update Main changes: PIS - Further information on rituximab side effects added RSI - Cyclophosphamide SPC tablets changed from Pharmacia to the SPC from Baxter as the section on 'undesirable effects' in the latter contained a more comprehensive and detailed list of the known side effects using the System Organ Class and frequency - Bortezomib and rituximab SPCs changed to the most recent (at the time) of bortezomib (10/01/2014) and rituximab (23/05/2014).

    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.
    Serious and non-serious adverse events are listed under non-serious adverse events Non-serious AEs:'Occurrences all number' cannot be provided-only the highest grade experienced by patients was collected. Subjects affected number is entered instead.
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