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    Clinical Trial Results:
    Phase III, multicentre, randomised study of fludarabine/cyclophosphamide combination with or without Rituximab in patients with untreated mantle cell lymphoma

    Summary
    EudraCT number
    2006-001965-41
    Trial protocol
    GB  
    Global end of trial date
    22 Apr 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    BRD/06/052
    Additional study identifiers
    ISRCTN number
    ISRCTN81133184
    US NCT number
    NCT00641095
    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
    MCL Trial Coordinator Haematology & Brain Trials Group , University College London CR UK & UCL Cancer Trials Centre , 44 2076799860, ctc.sponsor@ucl.ac.uk
    Scientific contact
    MCL Trial Coordinator Haematology & Brain Trials Group , University College London CR UK & UCL Cancer Trials Centre , 44 2076799860, 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
    25 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the overall survival of patients treated with cyclophoshamide and fludarabine in comparison to rituximab, cyclophosphamide and fludarabine.
    Protection of trial subjects
    The protocol suggested intravenous fludarabine for patients who could not tolerate the oral administration of the drug. Rituximab was administered in an environment where full resuscitation facilities were available and under close supervision of experienced clinicians. All patients were given paracetamol and anti-histamine 30-60 minutes prior to Rituximab infusion. The speed of the Rituximab infusion was increased gradually to alleviate infusion reactions. The initial dose rate was given at 50mg/hr for the first hour with increment steps of 50mg/hr every 30 minutes to a maximum of 400mg/hr. Vital signs were monitored every 15 minutes for the first hour and then hourly. Halving the speed of infusion was recommended in the case of specific adverse events. Septrin/Pentamidine was essential as an infection prophylaxis during treatment and for 6 months post therapy. Acyclovir was given during the course of therapy as a prophylaxis. For patients in need of it following fludarabine, all blood products were irradiated to reduce the risk of transfusion related GvHD. For specified haematological and renal toxicity, fludarabine and cyclophosphamide doses were to be reduced.
    Background therapy
    Septrin / Pentamidine Acyclovir Supportive care was as per institutional practice but Pneumocystis jirovecci (PJP) prophylaxis was mandated as was the use of irradiated blood products.
    Evidence for comparator
    Mantle Cell Lymphoma (MCL) is an uncommon and usually aggressive form of non-Hodgkin lymphoma with an annual incidence of approximately 1/100,000 population. In younger patients, the treatment of choice included a high-dose cytarabine-containing regimen usually followed by autologous stem cell transplantation. However, with a median age at presentation in the mid sixth decade, such therapy was not applicable to the majority of patients. There was no generally accepted standard of care for older patients and a variety of treatments had been widely used. As a single agent, Rituximab, a chimeric anti-CD20 monoclonal antibody produced response rates of approximately 35% in MCL and when added to the standard chemotherapeutic regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) within a phase II single arm study the combination demonstrated a very high overall response rate. A subsequent meta-analysis of 3 subsequent phase II randomised trials which included MCL patients, suggested an OS benefit for the addition of Rituximab. However, no individual phase-III study has yet demonstrated such a benefit, and thus the true impact of Rituximab remains uncertain. The purine nucleoside analogue class of drugs have demonstrable activity in the treatment of MCL, Fludarabine is the most widely used nucleoside analogue and when combined with cyclophosphamide in patients with MCL high response rates are achieved. As such a UK based randomised trial was initiated exploring the addition of Rituximab to oral FC.
    Actual start date of recruitment
    02 Sep 2002
    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: 348
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Poland: 17
    Worldwide total number of subjects
    370
    EEA total number of subjects
    365
    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)
    153
    From 65 to 84 years
    214
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    370 trial subjects were recruited over a period of 8 years and 3 months, 02/09/2002 – 02/12/2010, which included both the phase 2 and phase 3 subjects.

    Pre-assignment
    Screening details
    Eligible patients aged ≥18 years with previously untreated MCL were eligible. Central pathl confirmation of MCL diagnosis was performed retrospectively. Patients required adequate organ function and a life expectancy of ≥3 months. No malignancy in last 5 years, negative HBC, HCV or HIV and no condition which may affect compliance

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    FCR Arm
    Arm description
    Fludarabine, Cyclophosphamide & Rituximab
    Arm type
    Experimental

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    L01BB05
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg/m^2 on days 1-3 in a 28-day repeated cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on the response to treatment

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    L01BB05
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25mg/m^2 on days 1-3 in a 28-day repeated cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on the response to treatment For patients who could not tolerate oral administration of fludarabine, intravenous administration was allowed

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250mg/m^2 on days 1-3 in a 28-day repeated cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on the response to treatment

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    250mg/m^2 on days 1-3 in a 28-day repeated cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on the response to treatment For patients who could not tolerate oral administration of cyclophosphamide, intravenous administration was allowed

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    L01XC02
    Other name
    Mabthera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/m^2 to be given on day 1 of each 28-day cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on response to treatment Rituximab was not be given as an intravenous bolus injection

    Arm title
    FC Arm
    Arm description
    Fludarabine and Cyclophosphamide
    Arm type
    Active comparator

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    L01BB05
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg/m^2 on days 1-3 in a 28-day repeated cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on the response to treatment

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    L01BB05
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25mg/m^2 on days 1-3 in a 28-day repeated cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on the response to treatment For patients who could not tolerate oral administration of fludarabine, intravenous administration was allowed

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250mg/m^2 on days 1-3 in a 28-day repeated cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on the response to treatment

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    250mg/m^2 on days 1-3 in a 28-day repeated cycle for a minimum of 4 cycles to a maximum of 8 cycles depending on the response to treatment For patients who could not tolerate oral administration of cyclophosphamide, intravenous administration was allowed

    Number of subjects in period 1
    FCR Arm FC Arm
    Started
    186
    184
    Completed
    186
    184

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FCR Arm
    Reporting group description
    Fludarabine, Cyclophosphamide & Rituximab

    Reporting group title
    FC Arm
    Reporting group description
    Fludarabine and Cyclophosphamide

    Reporting group values
    FCR Arm FC Arm Total
    Number of subjects
    186 184 370
    Age categorical
    Age at Trial entry
    Units: Subjects
        Adults (18-64 years)
    78 75 153
        From 65-84 years
    106 108 214
        85 years and over
    2 1 3
    Age continuous
    Units: years
        median (full range (min-max))
    66 (36 to 88) 66 (37 to 85) -
    Gender categorical
    Units: Subjects
        Female
    49 38 87
        Male
    137 146 283
    ECOG performance status
    Score 0 - Asymptomatic and fully active Score 1 - Symptomatic; fully ambulatory, restricted in physically strenuous activity Score 2 - Symptomatic; ambulatory, capable of self-care; more than 50% of waking hours are spent out of bed Score 3 - Symptomatic - limited self-care; spends more than 50% of time in bed, but not bedridden Score 4 - Disabled - Completely disabled; no self-care; bedridden
    Units: Subjects
        Score 0
    93 87 180
        Score 1
    62 64 126
        Score 2
    17 15 32
        Score 3
    0 5 5
        Score 4
    0 1 1
        Missing
    14 12 26
    B symptoms
    Systemic symptoms of fever, night sweats, and weight loss
    Units: Subjects
        Absent
    97 106 203
        Present
    81 74 155
        Missing
    8 4 12
    Disease Stage
    Units: Subjects
        Stage 1
    4 2 6
        Stage II
    15 11 26
        Stage III
    25 32 57
        Stage IV
    134 134 268
        Missing
    8 5 13
    Serum LDH Level
    Units: Subjects
        Normal
    96 99 195
        Elevated
    77 80 157
        Missing
    13 5 18
    MIPI Risk Group
    Units: Subjects
        Low
    37 45 82
        Intermediate
    75 63 138
        High
    55 60 115
        Missing
    19 16 35

    End points

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    End points reporting groups
    Reporting group title
    FCR Arm
    Reporting group description
    Fludarabine, Cyclophosphamide & Rituximab

    Reporting group title
    FC Arm
    Reporting group description
    Fludarabine and Cyclophosphamide

    Subject analysis set title
    Patients who started trial treatment
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This population is used for response and toxicity endpoints

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    End point type
    Primary
    End point timeframe
    Analysis of OS was done after 240 events had occurred and all patients completed treatment
    End point values
    FCR Arm FC Arm
    Number of subjects analysed
    186
    184
    Units: Months
        number (not applicable)
    44.5
    37.0
    Attachments
    OS K-M Curve
    Statistical analysis title
    Overall survival HR
    Comparison groups
    FCR Arm v FC Arm
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    0.9

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    End point type
    Secondary
    End point timeframe
    Analysis of PFS was done after 291 events had occurred and all patients completed treatment
    End point values
    FCR Arm FC Arm
    Number of subjects analysed
    186
    184
    Units: Months
        number (not applicable)
    29.8
    14.9
    Attachments
    PFS K-M curve
    Statistical analysis title
    HR for PFS
    Comparison groups
    FCR Arm v FC Arm
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    0.67

    Secondary: Tumour response

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    End point title
    Tumour response
    End point description
    Objective response rate at last response assessment.
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    FCR Arm FC Arm
    Number of subjects analysed
    171 [1]
    170 [2]
    Units: Number of patients
    137
    125
    Notes
    [1] - All patients assessed for response
    [2] - All patients assessed for response
    Statistical analysis title
    Response
    Comparison groups
    FCR Arm v FC Arm
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.26
    Method
    Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (including serious) that occurred between informed consent and 30 days post last trial treatment administration
    Adverse event reporting additional description
    Trial subjects were assessed for adverse events prior the start of each treatment cycle. All adverse events (AEs) were recorded in the patient notes and the trial CRFs. Those meeting the definition of SAEs were also reported using the trial specific SAE Reporting template.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI - CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    FCR Arm
    Reporting group description
    Fludarabine, Cyclophosphamide & Rituximab

    Reporting group title
    FC Arm
    Reporting group description
    Fludarabine and Cyclophosphamide

    Serious adverse events
    FCR Arm FC Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 186 (33.87%)
    45 / 183 (24.59%)
         number of deaths (all causes)
    108
    132
         number of deaths resulting from adverse events
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplasia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction to excipient
         subjects affected / exposed
    4 / 186 (2.15%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 186 (1.08%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain - cardiac
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemoglobin
         subjects affected / exposed
    5 / 186 (2.69%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count
         subjects affected / exposed
    8 / 186 (4.30%)
    7 / 183 (3.83%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    7 / 186 (3.76%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    9 / 186 (4.84%)
    10 / 183 (5.46%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema limb
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ruptured spleen
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         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
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary NOS
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 186 (0.54%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CNS Ischaemia
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anorexia nervosa
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 186 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    2 / 186 (1.08%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (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
    Cellulitis
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other: Chest
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    6 / 186 (3.23%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 186 (1.08%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary/upper respiratory - lower respiratory tract
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 186 (2.69%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General - Blood
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection (documented clinically) with grade 3 or 4 ANC
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC - pulmonary/upper respiratory - lung (pneumonia)
         subjects affected / exposed
    3 / 186 (1.61%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    FCR Arm FC Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    141 / 186 (75.81%)
    127 / 183 (69.40%)
    Respiratory, thoracic and mediastinal disorders
    Pulmonary NOS
         subjects affected / exposed
    7 / 186 (3.76%)
    10 / 183 (5.46%)
         occurrences all number
    7
    10
    Blood and lymphatic system disorders
    Haemoglobin
         subjects affected / exposed
    24 / 186 (12.90%)
    25 / 183 (13.66%)
         occurrences all number
    24
    25
    Leukocytes
         subjects affected / exposed
    99 / 186 (53.23%)
    79 / 183 (43.17%)
         occurrences all number
    99
    79
    Neutrophil count
         subjects affected / exposed
    102 / 186 (54.84%)
    87 / 183 (47.54%)
         occurrences all number
    102
    87
    Platelet count
         subjects affected / exposed
    53 / 186 (28.49%)
    31 / 183 (16.94%)
         occurrences all number
    53
    31
    Immune system disorders
    Allergy NOS
         subjects affected / exposed
    10 / 186 (5.38%)
    1 / 183 (0.55%)
         occurrences all number
    10
    1
    Blood and platelet reaction
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 183 (0.55%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 186 (6.45%)
    16 / 183 (8.74%)
         occurrences all number
    12
    16
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 186 (3.76%)
    10 / 183 (5.46%)
         occurrences all number
    7
    10
    Infections and infestations
    Infection
         subjects affected / exposed
    23 / 186 (12.37%)
    21 / 183 (11.48%)
         occurrences all number
    23
    21

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2008
    Protocol was updated to change the contact details for drug supply order
    02 Dec 2008
    The protocol, Patient Information Sheet and Informed Consent form were updated to reflect the change in the samples to be collected from trial subjects. The Trial outline in the protocol was re-designed to make it easier to understand. The pharmacovigilance section of the protocol was also updated.
    28 Apr 2009
    On reviewing the timings of investigations at study entry, the time period for CT scan and bone marrow biopsy were extended to 6 weeks before randomisation. The protocol was updated to reflect this and the Mabthera order form was removed as an appendix.
    21 Jun 2010
    An audit of the patient information sheet showed that contraception guidelines given to patients in the PIS was not accurate, the patient information sheet did not specify for how long after completing treatment patients should continue using contraception, thus leading to an Urgent Safety Measure being taken. The PIS was amended to advice patients to use adequate contraception for 12 months after stopping trial treatment (as suggested in the IB v 14 May 2009 for Rituximab, which is one of the trial drugs for the study). A paragraph justifying the need of using contraception and listing examples of reliable forms of contraception was also added to the PIS. An Addendum to the previous PIS emphasising the need to use contraception for 12 months post trial treatment and Consent form confirming patient is aware of this new information was also sent to sites with clear instructions that all patients of child bearing potential or with female partners of child bearing potential, patients on treatment or who have completed treatment within 12 months needed to be re-consented.
    13 Sep 2010
    In the protocol; a requirement for contraceptive precautions up to 12 months post last trial treatment was included as an exclusion criteria, the statistical consideration was reviewed and the sample size was reduced with new calculations given, participating sites were no longer required to perform evaluation of SAE expectedness as this was transferred to UCL CTC, SAE expectedness assessment against the current IB/SmPCs was included as a requirement thus removing the existing AEs list for each separate IMP from the appendix. The PIS was updated to include new safety information regarding Rituximab and an addendum was created to be used to re-consent trial patients randomised to the Rituximab arm to the new safety information from Roche.
    22 Mar 2011
    Reg 46 Labelling exemption was granted for intravenous fludarabine and cyclophosphamide based on the facts that they were marketed products used broadly within their authorisations, they were to be dispensed to subjects in accordance with a prescription given by an authorised health care professional and they were labelled in accordance with the requirements of Schedule 5 to the Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994 that apply in relation to dispensed relevant medicinal products. Abridged labels were to be used for the oral administrations of these drugs. Rituximab, given intravenously, was supplied from Roche as commercial stock. They were to be labelled on receipt at pharmacy and designated as use for the trial. Rituximab labels were amended to comply with Annex 13 requirements.
    19 Jun 2014
    The protocol was amended to update the change in the End of Trial definition, so as to include the time points for the primary endpoint, Overall Survival.

    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.
    Non-serious AEs: occurrences all number can't be provided as only highest grade experienced by patients are collected on CRFs; subjects affected is entered instead (only grade 3-4 reported) Treatment related death/relatedness to SAEs not available

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26611473
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