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    Clinical Trial Results:
    A Phase II Single Arm Study of the use of CODOX-M/IVAC with Rituximab (R-CODOX-M/IVAC) in the treatment of patients with Diffuse Large B-Cell Lymphoma (DLBCL) or Burkitt's Lymphoma (BL) of International Prognostic Index (IPI) High or High-Intermediate Risk

    Summary
    EudraCT number
    2005-003479-19
    Trial protocol
    GB  
    Global end of trial date
    26 May 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jan 2020
    First version publication date
    03 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/05/134
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00974792
    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
    Public Contact, Cancer Research UK & UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Scientific contact
    Scientific Contact, Cancer Research UK & 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
    03 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does the combination of Rituximab and CODOX-M/IVAC improve the progression free survival in patients with newly diagnosed diffuse large B cell lymphoma or Burkitt's lymphoma of international prognostic index high or high-intermediate risk? Caveats AEs: Only events experienced by 5% or more patients are given. Relationships are to R-CODOX-M/R-IVAC treatment (i.e. any IMP) Non-serious AEs: • Non-serious adverse events includes both serious and non-serious events. Only grade 3+ events given. • Some terms were not recorded as per CTCAE so e.g. “Neurological - NOS” so could not be categorised any further. • The total number of events is the number of patients experiencing an event as only worst grades were reported
    Protection of trial subjects
    CODOX-M/IVAC had previously been given to patients with Burkitt lymphoma and it was suggested that DLBCL patients would do better with the more intense regimen. Rituximab was added as it was unlikely to alter the toxicity but could improve responses. Etoposide was used outside its licensed indication (testicular tumour, small cell lung cancer and monoblastic leukaemia). Drug accountability logs were kept by sites, and sent to UCL CTC on request. Though DLBCL is not listed as an indication for etoposide in the SmPC, more than a dozen published clinical trials have used this drug in the treatment of DLBCL patients. Only investigators/nurses experienced in using these IMPs according to the protocol were delegated treatment responsibilities. IDMC committee met at least annually to review safety data. Patients were closely monitored for toxicity and the protocol detailed non-haematological toxicity dose modifications.
    Background therapy
    Leucovorin (15mg/m^2, IV) was administered as part of the R-CODOX-M regimen. It was administered at hour 36 and then every three hours until hour 48. From then it was administered every 6 hours until methotrexate level was below 5x10^-8M. Patients also received Mesna as part of the R-IVAC regimen on days 1-5. Intravenous Mesna 300mg/m^2 was administered mixed with ifosfamide (1.5g/m^2) over a one hour period. Co-trimoxazole 480mg (PO) was administered twice daily on Mondays, Wednesdays and Fridays during treatment and for six months post therapy. Mouth care, antacids and anti-emetics were given according to local protocols. The suggested regimen was: Corsdyl 5ml qd mouthwash; Acyclovir 200mg qd or 400mg bd; lansoprazole 30mg od (po); metoclompramide 10mg tds for 3 days. Radiotherapy was permitted in specific situations and the protocol detailed guidance on CNS prophlyaxis and treatment, and post-treatment neutropenia.
    Evidence for comparator
    This trial was a single arm study and therefore no comparator was used.
    Actual start date of recruitment
    05 Dec 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 150
    Worldwide total number of subjects
    150
    EEA total number of subjects
    150
    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)
    146
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The first site opened on the 5th December 2007 and the first patient was recruited on the 21st May 2008. Recruitment completed on the 2nd April 2013 with a total of 150 patients recruited to the trial. A total of 52 sites participated in the trial, 36 sites recruited patients and 16 sites did not recruit any patients.

    Pre-assignment
    Screening details
    No screening information to provide for this trial. Patients were screened for eligibility for inclusion into the trial as per trial protocol.

    Period 1
    Period 1 title
    Main trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable.

    Arms
    Arm title
    CODOX-M/IVAC with Rituximab
    Arm description
    A phase II single arm study of the use of CODOX-M/IVAC with rituximab (R-CODOX-M/IVAC) in the treatment of patients with diffuse large B-cell lymphoma DLBCL) or Burkitt's lymphoma (BL) of international Prognostic Index (PI) high or high intermediate risk. Efficacy, compliance and Baseline tables are given for eligible patients only (N=27 BL and N=111). Toxicity is given for all patients who started treatment (N=145)
    Arm type
    Single

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    L01XC02
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Four 375mg/m2 IV doses of rituximab given with 2 cycles of CODOX-M on Day 1 and Day 11, and two IV 375mg/m2 doses of rituxmimab given with 2 cycles of IVAC on Day 1. Two further IV doses of rituximab given on Day 21 and Day 42 after day one of the final course of IVAC.

    Investigational medicinal product name
    Cyclophoshamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide given IV on Day 1 800mg/m2 and Day 2-5 200mg/m2 daily of CODOX-M treatment.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01C A02
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given IV on Day 1 1.5mg/m2 (max 2mg) and Day 8 1.5mg/m2 (max 2mg) of CODOX-M.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40mg/m2 given IV on Day 1 of CODOX-M.

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    L01BC01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intrathecal use, Intravenous use
    Dosage and administration details
    Given on Day 2 70mg intrathecal, Day 4 70mg intrathecal, Day 6 (for patients with proven or suspected CNS disease) 70mg intrathecal of CODOX-M. For IVAC - given on Day 1 & 2 2g/m2 IV over 3 hours, 12 hourly total of 4 doses; Day 7 (for patients with proved or suspected CNS disease) 70mg intrathecal; Day 9 (for patients with proven or suspected CNS disease) 70mg intrathecal.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    L01BA01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For R-CODOX-M: Given on Day 10 300mg/m2 IV for 1 hour and 2700mg/m2 IV given over 23 hours. It was given on Day 15 12mg intrathecal and Day 17 (for patients with proven or suspected CNS disease) 12mg intrathecal. For IVAC: Given on day 5 12mg intrathecal.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    L01CB01
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For IVAC: Days 1-5 etoposide 60mg/m2 IV (in 500ml of N. saline or 5% dextrose) daily over 1 hour.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    L01AA06
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    For IVAC: Day 1-5 Ifosfamide IV 1.5g/m2 daily over an hour.

    Investigational medicinal product name
    Pegylated G-CSF
    Investigational medicinal product code
    L03AA13
    Other name
    Neulasta
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    For R-CODOX-M: Day 13 Neulasta 6mg subcutaneous For IVAC: Day 7 Neulasta 6mg subcutaneous

    Number of subjects in period 1
    CODOX-M/IVAC with Rituximab
    Started
    150
    Completed
    107
    Not completed
    43
         Progressive disease
    1
         Protocol deviation
    2
         Other medical conditions
    1
         Not eligible
    12
         Lack of understanding
    1
         death (NHL)
    2
         Adverse event, serious fatal
    4
         Rapid progression (did not start)
    1
         Adverse event, non-fatal
    16
         Patient refusal
    2
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CODOX-M/IVAC with Rituximab
    Reporting group description
    A phase II single arm study of the use of CODOX-M/IVAC with rituximab (R-CODOX-M/IVAC) in the treatment of patients with diffuse large B-cell lymphoma DLBCL) or Burkitt's lymphoma (BL) of international Prognostic Index (PI) high or high intermediate risk. Efficacy, compliance and Baseline tables are given for eligible patients only (N=27 BL and N=111). Toxicity is given for all patients who started treatment (N=145)

    Reporting group values
    CODOX-M/IVAC with Rituximab Total
    Number of subjects
    150 150
    Age categorical
    Units: Subjects
        BL Under 40 yrs
    15 15
        BL 40-60 yrs
    10 10
        BL 60 yrs and over
    2 2
        DLBCL 60 yrs and under
    98 98
        DLBCL Over 60 yrs
    13 13
        Ineligible
    12 12
    Age continuous
    BL Age Median = 35 years BL Range = 20-64 years DLBCL Age Median = 50 years DLBCL Range = 18-65 years
    Units: years
        median (full range (min-max))
    48 (18 to 65) -
    Gender categorical
    Units: Subjects
        BL Female
    3 3
        BL Male
    24 24
        DLBCL Female
    45 45
        DLBCL Male
    66 66
        Ineligible
    12 12
    Diagnosis
    Units: Subjects
        DLBCL
    111 111
        BL
    27 27
        Ineligible
    12 12
    WHO performance status
    Units: Subjects
        BL Nil (0)
    6 6
        BL One (1)
    8 8
        BL Two (2)
    8 8
        BL Three (3)
    5 5
        DLBCL Nil (0)
    23 23
        DLBCL One (1)
    28 28
        DLBCL Two (2)
    38 38
        DLBCL Three (3)
    22 22
        Ineligible
    12 12
    >1 extra nodal sites
    Units: Subjects
        BL >1 extra nodal site - Yes
    24 24
        BL >1 extra nodal site - No
    3 3
        DLBCL >1 extra nodal site - Yes
    88 88
        DLBCL >1 extra nodal site - No
    23 23
        Ineligible
    12 12
    CNS involvement
    Units: Subjects
        BL - Yes
    4 4
        BL - No
    23 23
        DLBCL - Yes
    10 10
        DLBCL - No
    101 101
        Ineligible
    12 12
    B Symptoms
    Units: Subjects
        BL Absent
    12 12
        BL Present
    15 15
        DLBCL Absent
    34 34
        DLBCL Present
    77 77
        Ineligible
    12 12
    Tumour Stage
    Units: Subjects
        BL Stage III
    3 3
        BL Stage IV
    24 24
        DLBCL Stage III
    7 7
        DLBCL Stage IV
    104 104
        Ineligible
    12 12
    Lactate Dehydrogenase
    Units: Subjects
        BL Elevated LDH
    27 27
        DLBCL LDH above upper limit of normal - No
    5 5
        DLBCL LDH above upper limit of normal - Yes
    106 106
        Ineligible
    12 12
    IPI Score
    Units: Subjects
        BL Three (3)
    14 14
        BL Four (4)
    13 13
        DLBCL Three (3)
    67 67
        DLBCL Four (4)
    43 43
        DLBCL Five (5)
    1 1
        Ineligible
    12 12
    Bone marrow involvement
    Units: Subjects
        BL No
    10 10
        BL Yes
    14 14
        BL Unknown
    3 3
        DLBCL bone marrow at baseline not involved
    111 111
        Ineligible
    12 12
    HIV Status
    Units: Subjects
        BL Negative
    22 22
        BL Positive
    5 5
        DLBCL Negative
    108 108
        DLBCL Positive
    1 1
        DLBCL Unknown
    2 2
        Ineligible
    12 12

    End points

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    End points reporting groups
    Reporting group title
    CODOX-M/IVAC with Rituximab
    Reporting group description
    A phase II single arm study of the use of CODOX-M/IVAC with rituximab (R-CODOX-M/IVAC) in the treatment of patients with diffuse large B-cell lymphoma DLBCL) or Burkitt's lymphoma (BL) of international Prognostic Index (PI) high or high intermediate risk. Efficacy, compliance and Baseline tables are given for eligible patients only (N=27 BL and N=111). Toxicity is given for all patients who started treatment (N=145)

    Primary: Progression-free survival (BL)

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    End point title
    Progression-free survival (BL) [1]
    End point description
    End point type
    Primary
    End point timeframe
    2 years from time of registration
    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 test for this endpoint, the historical rate was compared to the 2 year PFS found and its confidence interval.
    End point values
    CODOX-M/IVAC with Rituximab
    Number of subjects analysed
    27 [2]
    Units: % patients alive without PD
        number (confidence interval 90%)
    77.2 (60.1 to 87.6)
    Attachments
    PFS KM curve BL all
    Notes
    [2] - BL cohort only
    No statistical analyses for this end point

    Primary: Progression Free Survival (DLBCL)

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    End point title
    Progression Free Survival (DLBCL) [3]
    End point description
    End point type
    Primary
    End point timeframe
    2 years from ranomisation
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical test for this endpoint, the historical rate was compared to the 2 year PFS found and its confidence interval.
    End point values
    CODOX-M/IVAC with Rituximab
    Number of subjects analysed
    111 [4]
    Units: % of patients alive without PD
        number (confidence interval 90%)
    67.9 (59.9 to 74.6)
    Attachments
    PFS KM curve DLBCL all
    Notes
    [4] - DLBCL cohort only
    No statistical analyses for this end point

    Secondary: Overall Survival (BL)

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    End point title
    Overall Survival (BL)
    End point description
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CODOX-M/IVAC with Rituximab
    Number of subjects analysed
    27 [5]
    Units: % alive at 2 years
        number (confidence interval 90%)
    80.7 (63.8 to 90.3)
    Attachments
    OS KM curve BL all
    Notes
    [5] - BL cohort only
    No statistical analyses for this end point

    Secondary: Overall Survival (DLBCL)

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    End point title
    Overall Survival (DLBCL)
    End point description
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CODOX-M/IVAC with Rituximab
    Number of subjects analysed
    111 [6]
    Units: % alive at 2 years
        number (confidence interval 90%)
    76.0 (68.5 to 82.0)
    Notes
    [6] - DLBCL cohort only
    No statistical analyses for this end point

    Secondary: Response (BL)

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    End point title
    Response (BL)
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    CODOX-M/IVAC with Rituximab
    Number of subjects analysed
    27 [7]
    Units: patients
        CR
    17
        CRu
    4
        PR
    2
        SD
    0
        PD
    0
        Not evaluable
    4
    Notes
    [7] - BL cohort only
    No statistical analyses for this end point

    Secondary: Response (DLBCL)

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    End point title
    Response (DLBCL)
    End point description
    End point type
    Secondary
    End point timeframe
    end of treatment
    End point values
    CODOX-M/IVAC with Rituximab
    Number of subjects analysed
    110 [8]
    Units: patients
        CR
    41
        CRu
    11
        PR
    30
        SD
    3
        PD
    4
        Not evaluable
    21
    Notes
    [8] - DLBCL who started treatment only
    No statistical analyses for this end point

    Secondary: Treatment compliance (BL)

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    End point title
    Treatment compliance (BL)
    End point description
    Numbers of patients who were given cycles 1-4
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    CODOX-M/IVAC with Rituximab
    Number of subjects analysed
    27 [9]
    Units: Patients
        Cycle 1
    1
        Cycle 2
    2
        Cycle 3
    2
        Cycle 4
    22
    Notes
    [9] - BL cohort only
    No statistical analyses for this end point

    Secondary: Treatment Compliance (DLBCL)

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    End point title
    Treatment Compliance (DLBCL)
    End point description
    Number of patients who were given each cycle
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    CODOX-M/IVAC with Rituximab
    Number of subjects analysed
    110 [10]
    Units: Patients
        Cycle 1
    16
        Cycle 2
    3
        Cycle 3
    6
        Cycle 4
    85
    Notes
    [10] - DLBCL patients who started treatment only
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) that occur between informed consent and 30 days post treatment.
    Adverse event reporting additional description
    Patients were assessed for adverse events prior to each treatment cycle. Pre-existing conditions did not qualify as adverse events unless they worsened. Relationships are to R-CODOX-M R-IVAC treatment (i.e. counted as related if possibly, probably or definitely related to any IMP in the regimen). 145 out of 145 patients experienced at least one AE.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    AEs are reported including both cohorts (DLBCL and BL). Both groups were given the trial treatment as per protocol; alternating CODOX-M/IVAC x 2 cycles + G-CSF, + rituximab x 8 doses, + cytarabine (4/7 doses), + methotrexate (4/5 doses).

    Serious adverse events
    Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    70 / 145 (48.28%)
         number of deaths (all causes)
    39
         number of deaths resulting from adverse events
    6
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac infarction
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Plural effusion
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Adult Respiratory Distress Syndrome (ARDS)
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Bone marrow suppression
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    20 / 145 (13.79%)
         occurrences causally related to treatment / all
    20 / 20
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Haemorrhage
         subjects affected / exposed
    7 / 145 (4.83%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    1 / 1
    Mood altered
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cranial neuropathy
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Personality change
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cognitive disturbance
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    CNS Ischemia
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Motor neuropathy
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    4 / 145 (2.76%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain GI abdomen
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Hearing
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anorexia nervosa
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Perforated small bowel
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Small bowel obstruction
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 145 (1.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Mucositis
         subjects affected / exposed
    7 / 145 (4.83%)
         occurrences causally related to treatment / all
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage
         subjects affected / exposed
    4 / 145 (2.76%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    Reproductive system and breast disorders
    Haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Testicular pain
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Radionecrosis spinal cord
         subjects affected / exposed
    1 / 145 (0.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection NOS
         subjects affected / exposed
    17 / 145 (11.72%)
         occurrences causally related to treatment / all
    17 / 17
         deaths causally related to treatment / all
    4 / 4
    Febrile neutropenia
         subjects affected / exposed
    14 / 145 (9.66%)
         occurrences causally related to treatment / all
    14 / 14
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    145 / 145 (100.00%)
    Investigations
    Hypokalaemia
         subjects affected / exposed
    8 / 145 (5.52%)
         occurrences all number
    8
    Cardiac disorders
    Cardiac NOS
         subjects affected / exposed
    11 / 145 (7.59%)
         occurrences all number
    11
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    15 / 145 (10.34%)
         occurrences all number
    15
    Neutropenia
         subjects affected / exposed
    140 / 145 (96.55%)
         occurrences all number
    140
    Anaemia
         subjects affected / exposed
    38 / 145 (26.21%)
         occurrences all number
    38
    Thrombocytopenia
         subjects affected / exposed
    136 / 145 (93.79%)
         occurrences all number
    136
    Nervous system disorders
    Neurological not specified
         subjects affected / exposed
    11 / 145 (7.59%)
         occurrences all number
    11
    Headache
         subjects affected / exposed
    8 / 145 (5.52%)
         occurrences all number
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 145 (6.21%)
         occurrences all number
    9
    Fever
         subjects affected / exposed
    29 / 145 (20.00%)
         occurrences all number
    29
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    16 / 145 (11.03%)
         occurrences all number
    16
    Diarrhoea
         subjects affected / exposed
    14 / 145 (9.66%)
         occurrences all number
    14
    Anorexia
         subjects affected / exposed
    13 / 145 (8.97%)
         occurrences all number
    13
    Vomiting
         subjects affected / exposed
    9 / 145 (6.21%)
         occurrences all number
    9
    Mucositis
         subjects affected / exposed
    47 / 145 (32.41%)
         occurrences all number
    47
    Infections and infestations
    Febrile neutropenia
         subjects affected / exposed
    27 / 145 (18.62%)
         occurrences all number
    27
    Infection NOS
         subjects affected / exposed
    95 / 145 (65.52%)
         occurrences all number
    95
    Sepsis
         subjects affected / exposed
    3 / 145 (2.07%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jul 2006
    An amendment to the protocol containing the following changes: • For each of the IVAC courses the Depocyte is given on day 5 not on day 1 • Consequently Dexamethasone is moved to day 5-10 instead of day 1-5 • The Depocyte will be given on day 5 as a part of treatment of patients with CNS disease
    19 Oct 2006
    The protocol was amended as follows: • International Prognostic Index has replaced the Age Adjusted IPI in Appendix 1 and reference made to this changed throughout the protocol • The Declaration of Helsinki was added, appendix 11 • Reference to Rasburicase removed • Information on who will be supplying what drugs was added • Rituximab amended to be given on day 11 as opposed to day 10 • Section on safety reporting has had additions made to it, providing more comprehensive information to sites as well as a flow diagram on assessing and notifying the Lymphoma Trials Office of events • A reference has been removed • Appendix 3 addition of information prophylaxis has been added • Patient Information Sheet, reference to ‘age adjusted’ has been removed as well as reference to Rasburicase • Consent form part I and II, reference to ‘age adjusted’ has been removed • GP letter, reference to ‘age adjusted’ has been removed. • Contact details have changed for Cathy Burton.
    28 Aug 2007
    The protocol, PIS, consent form and GP letter were amended as below: • International Prognostic Index replaced the Age Adjusted IPI in Appendix 1 and reference made to this was changed throughout the protocol • The Declaration of Helsinki was added, appendix 11 • Reference to Rasburicase was removed • Information on who will be supplying what drugs was added • Rituximab was amended to be given on day 11 as opposed to day 10 • Section on safety reporting had additions made to it, providing more comprehensive information to sites as well as a flow diagram on assessing and notifying the Lymphoma Trials Office of events • Pg 42, a reference was removed • Appendix 3 addition of information on prophylaxis was added • Patient Information Sheet reference to ‘age adjusted’ was removed as well as reference to Rasburicase • Consent form part I and II reference to ‘age adjusted’ was removed • GP letter reference to ‘age adjusted’ was removed • Contact details changed for Cathy Burton
    20 Aug 2008
    An Urgent Safety Measure (USM) led to an amendment to the protocol, PIS and consent form. This was following a decision to remove Depocyte (liposomal cytarabine) from the protocol treatment schedule due to safety concerns over it's use with high dose chemotherapy, Depocyte was replaced in the protocol amendment with a proven safe and effective option. The PIS was also amended to include an update to the the number of times patients would receive intrathecal treatment.
    19 May 2009
    The title of the study and the protocol was amended to include Burkitt's Lymphoma (BL). The decision to include BL patients into the trial was based upon published data which suggested promising results had been reported using CODOX-M/IVAC in this group of patients at the time. The protocol amendment included: • Change of primary outcome measure and endpoint to progression free survival • More information given on non-haematological toxicity & dose modification (section 8.2) • Statistical Consideration section was changed to reflect the change in endpoint and inclusion of Burkitt’s lymphoma patients (section 13) • Additional information added to Appendix 5, recommending that Septrin be stopped once week prior to the administration of high dose methotrexate to avoid any potential drug reactions • Appendix 6 included an extensive list of toxicities expected with chemotherapy drugs • PIS , consent form and GP letter removed as appendices and provided as stand alone documents • The inclusion of BL patients was added to the PIS and GP letter, the title of the consent form was changed on the consent form, GP letter and the PIS. The PIS was also updated to include the advice by Roche over the concern of patients developing Progressive Leukoencephalopathy (PML) having been treated with rituximab.
    09 Aug 2010
    The protocol was amended to include the following changes: • Change of protocol cover page and authorisation signature page • Additional information to the site selection section (section 3.0) • Addition of a section on Informed consent (section 4.0) • Change in the patient selection section; baseline investigations and eligibility criteria. Maximum age of inclusion was increased from 60 years as stated in the original application to 65 years of age. Echocardiogram or nuclear medicine scan (MUGA) was made mandatory for patients aged from 61 to 65 years. (sections 5.1 and 5.3.1) • Addition of sections on pregnancy /birth control and long term infertility (sections 5.3.3 and 5.3.4) • Additional sections on trial monitoring and oversight, withdrawal of patients and trial closure (sections 14.0, 15.0 & 16.0,) • Additional information to the ethical and regulatory approvals section (section 18.0) • Additional sections on sponsorship & indemnity, funding and publication policy (section 19.0, 20.0 and 21.0) • Removal of the expected toxicities for each chemotherapy drug from the appendix, and the addition of expected adverse events for the treatment regimen. The expected adverse events for each drug will be based on the individual SmPCs (appendix 9) The PIS and consent form were also updated to reflect the changes to the protocol.
    28 Jan 2011
    The protocol was amended following an urgent safety measure (USM) which lead to amending the treatment schedule so vincristine was no longer scheduled on the same day as the intrathecal drugs.
    06 Jun 2011
    The protocol was amended to include: • Update of the Trial Synopsis to include patients with positive serology for HIV • Inclusion of a section on the training requirements for site staff • Additional information for patients pre-treated with steroids • Addition of patients with positive serology for HIV with criteria to be satisfied in the ‘inclusion criteria’ • Addition of Neulasta to the list of IMPs as stated in the CT application • Update of rituximab administration to fall in line with the information given in its SPC • Update of the dose modification for renal impairment toxicity • Update to the data management, pharmacovigilance, trial monitoring and oversight sections of the protocol • Addition of a reference to the existing list • Update to the appendix on Methotrexate administration and uroprotection • Update to the appendix on protocol version history
    14 Oct 2015
    The protocol was amended to clarify timelines for adverse event reporting. The wording was amended to state' adverse events that occur between informed consent and 30 days days post trial treatment must be recorded in the patient notes and the trial CRFs'.

    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.
    See 'general information about the trial' section.
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