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    Clinical Trial Results:
    Positronen-Emissionstomographie-gesteuerte Therapie aggressiver Non-Hodgkin-Lymphome (Positron emission tomography guided therapy of aggressive non-Hodgkin's lymphomas)

    Summary
    EudraCT number
    		 2006-001641-33
    Trial protocol
    		 DE  
    Global end of trial date
    31 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jun 2022
    First version publication date
    06 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PETAL-Studie
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00554164
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Essen
    Sponsor organisation address
    Hufelandstrasse 55, Essen, Germany, 45147
    Public contact
    Prof. Dr. Ulrich Dührsen, PETAL Study Group, 49 2102847374, ulrich.duehrsen@uk-essen.de
    Scientific contact
    Prof. Dr. Ulrich Dührsen, PETAL Study Group, 49 2102847374, ulrich.duehrsen@uk-essen.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    First-line therapy for patients with aggressive B-cell or T-cell non-Hodgkin lymphomas Comparison of treatment results in patients with CD20-positive aggressive non-Hodgkin lymphomas and a good response to 2 cycles of the R-CHOP protocol as assessed by positron emission tomography (interim PET) by randomisation between a further 4 cycles of the R-CHOP protocol or 4 cycles R-CHOP plus 2 additional applications of rituximab (R) Comparison of treatment results in aggressive non-Hodgkin lymphoma patients with a poor response to 2 cycles of the (R)-CHOP protocol as assessed by interim PET by randomisation between a further 6 cycles of the (R-)CHOP protocol or 6 blocks of the German Burkitt's lymphoma protocol (R restricted to CD20-positive lymphomas)
    Protection of trial subjects
    Documentation of adverse events according to CTCAE v3.0
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Nov 2007
    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
    Germany: 363
    Worldwide total number of subjects
    363
    EEA total number of subjects
    363
    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)
    156
    From 65 to 84 years
    207
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients age 18 to 80 with aggressive B-cell or T-cell non-Hodgkin lymphoma (except Burkitt, lymphoblastic or primary CNS lymphoma) with a positive baseline PET scan and without contraindication to standard first-line treatment First patient recruited - November 19, 2007 Last patient recruited - December 28, 2012

    Pre-assignment
    Screening details
    		 Randomisation was performed after the interim PET. Pre-assigned patients with a negative baseline PET (n=82), not reaching the interim PET (n=129) or presenting with a negative interim PET before or after the randomization period for interim PET-negative patients (n=499) were not treated within the randomized trial

    Pre-assignment period milestones
    Number of subjects started
    		 1073 [1]
    Number of subjects completed
    		 363

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Negative baseline PET: 82
    Reason: Number of subjects
    		 Histologic misdiagnosis: 41
    Reason: Number of subjects
    		 Protocol deviation: 33
    Reason: Number of subjects
    		 Technical/logistic PET issues: 13
    Reason: Number of subjects
    		 Physician decision: 7
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 Miscellaneous reasons: 32
    Reason: Number of subjects
    		 Not randomized (interim PET-negative patients): 499
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Randomization required a positive baseline PET and - after two standard treatment cycles - an interim PET based on which the pts were divided into interim PET-negative and interim PET-positive pts. These two groups were independently randomized. The result of the interim PET was not known at pre-assignment. The number of interim-PET negative pts. required for the trial was reached much earlier than that of interim PET-positive pts. Thus, most interim PET-negative pts. were not randomized.
    Period 1
    Period 1 title
    Interim PET-based randomization (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 4xR-CHOP
    Arm description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-negative patients with CD20-positive lymphomas randomized to the active comparator received a further 4 cycles of R-CHOP after the interim PET.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, day 1 of each cycle, 4 cycles, every two weeks

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2, day 1 of each cycle, 4 cycles, every 2 weeks

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2, day 1 of each cycle, 4 cycles, every 2 weeks

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg, day 1 of each cycle, 4 cycles, every 2 weeks

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg, days 1-5 of each cycle, 4 cycles, every 2 weeks

    Arm title
    		 4xR-CHOP+2xR
    Arm description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-negative patients with CD20-positive lymphomas randomized to the experimental arm received a further 4 cycles of R-CHOP plus 2 extra doses of rituximab after the interim PET.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2, day 1 of each cycle, 6 cycles, every 2 weeks

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2 day 1 of each cycle, 4 cycles, every 2 weeks

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2, day 1 of each cycle, 4 cycles, every 2 weeks

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg, day 1 of each cycle, 4 cycles, every 2 weeks

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg, days 1-5 of each cycle, 4 cycles, every 2 weeks

    Arm title
    		 6xR-CHOP
    Arm description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-positive patients randomized to the active comparator received a further 6 cycles of R-CHOP after the interim PET.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 (only for CD20-positive lymphomas), day 1 of each cycle, 6 cycles, every 2 weeks

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2, day 1 of each cycle, 6 cycles, every 2 weeks

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2, day 1 of each cycle, 6 cycles, every 2 weeks

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mg, day 1 of each cycle, 6 cycles, every 2 weeks

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg, day 1-5 of each cycle, 6 cycles, every 2 weeks

    Arm title
    		 6xBurkitt protocol
    Arm description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-positive patients randomized to the experimental arm received 6 blocks of the German Burkitt's lymphoma protocol after the interim PET.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 (only for CD20-positive lymphomas), day 1 of each cycle, 6 cycles, every 3 weeks

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Age ≤60 years: 1500 mg/m2, age < 60 years: 500 mg/m2, day 2 of each cycle, 6 cycles, every 3 weeks

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg, days 2-6 of each cycle, 6 cycles, every 3 weeks

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Age ≤60 years: 2 mg, day 2 of cycles 1, 2, 4 and 5 of six 3-weekly cycles Age >60 years: 1 mg, day 2 of cycles 2, 4 and 6 of six 3-weekly cycles

    Investigational medicinal product name
    Vindesine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Age ≤60 years: 5 mg, day 2 of cycles 3 and 6 of six 3-weekly cycles

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Age ≤60 years: 800 mg/m2, days 2-6 of cycles 1 and 4 of six 3-weekly cycles Age >60 years: 400 mg/m2, days 2-6 of cycles 1, 3 and 5 of six 3-weekly cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Age ≤60 years: 200 mg/m2, days 2-6 of cycles 2 and 5 of six 3-weekly cycles Age >60 years: 200 mg/m2, days 2-6 of cycles 2, 4 and 6 of six 3-weekly cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Age ≤60 years: 150 mg/m2 twice daily, days 5-6 of cycles 1 and 4 of six 3-weekly cycles; 2000 mg/m2 twice daily, day 6 of cycles 3 and 6 of six 3-weekly cycles Age >60 years: 60 mg/m2 twice daily, days 5-6 of cycles 1, 3 and 5 of six 3-weekly cycles

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Age ≤60 years: 100 mg/m2, days 5-6 of cycles 1 and 4 of six 3-weekly cycles; 250 mg/m2, days 5-6 of cycles 3 and 6 of six 3-weekly cycles Age >60 years: 60 mg/m2, days 5-6 of cycles 1, 3 and 5 of six 3-weekly cycles

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Age ≤60 years: 25 mg/m2, days 5-6 of cycles 2 and 5 of six 3-weekly cycles Age >60 years: 25 mg/m2, days 5-6 of cycles 2, 4 and 6 of six 3-weekly cycles

    Number of subjects in period 1
    		4xR-CHOP 4xR-CHOP+2xR 6xR-CHOP 6xBurkitt protocol
    Started
    129
    126
    52
    56
    Randomization
    129
    126
    52
    56
    Completed
    129
    126
    52
    56

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    4xR-CHOP
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-negative patients with CD20-positive lymphomas randomized to the active comparator received a further 4 cycles of R-CHOP after the interim PET.

    Reporting group title
    4xR-CHOP+2xR
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-negative patients with CD20-positive lymphomas randomized to the experimental arm received a further 4 cycles of R-CHOP plus 2 extra doses of rituximab after the interim PET.

    Reporting group title
    6xR-CHOP
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-positive patients randomized to the active comparator received a further 6 cycles of R-CHOP after the interim PET.

    Reporting group title
    6xBurkitt protocol
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-positive patients randomized to the experimental arm received 6 blocks of the German Burkitt's lymphoma protocol after the interim PET.

    Reporting group values
    		 4xR-CHOP 4xR-CHOP+2xR 6xR-CHOP 6xBurkitt protocol Total
    Number of subjects
    		 129 126 52 56 363
    Age categorical
    The age groups are: 18 to 60 years and >60 to 80 years
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 54 52 23 27 156
        From 65-84 years
    		 75 74 29 29 207
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 63 (18 to 80) 65 (20 to 78) 62 (21 to 77) 61 (24 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 56 56 20 21 153
        Male
    		 73 70 32 35 210
    International Prognostic Index
    Units: Subjects
        Low risk
    		 48 47 12 15 122
        Low-intermediate risk
    		 30 32 14 15 91
        High-intermediate risk
    		 29 30 16 14 89
        High risk
    		 21 17 9 11 58
        Not recorded
    		 1 0 1 1 3
    Lymphoma entity
    Units: Subjects
        Diffuse large B-cell lymphoma
    		 97 100 32 31 260
        Primary mediastinal B-cell lymphoma
    		 9 5 3 2 19
        Follicular lymphoma grade 3
    		 6 3 1 6 16
        Other aggressive B-cell lymphoma
    		 5 5 2 5 17
        T-cell lymphoma
    		 1 2 9 10 22
        Other entity
    		 11 11 5 2 29

    End points

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    End points reporting groups
    Reporting group title
    4xR-CHOP
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-negative patients with CD20-positive lymphomas randomized to the active comparator received a further 4 cycles of R-CHOP after the interim PET.

    Reporting group title
    4xR-CHOP+2xR
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-negative patients with CD20-positive lymphomas randomized to the experimental arm received a further 4 cycles of R-CHOP plus 2 extra doses of rituximab after the interim PET.

    Reporting group title
    6xR-CHOP
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-positive patients randomized to the active comparator received a further 6 cycles of R-CHOP after the interim PET.

    Reporting group title
    6xBurkitt protocol
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-positive patients randomized to the experimental arm received 6 blocks of the German Burkitt's lymphoma protocol after the interim PET.

    Primary: Event-free survival rate at 2 years

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    End point title
    		 Event-free survival rate at 2 years
    End point description
    Kaplan-Meier estimates of the proportion of event-free patients at 2 years Definition of event: Progression, relapse, change to a treatment not specified in the protocol, toxicity-related treatment discontinuation, death from any cause
    End point type
    Primary
    End point timeframe
    From randomization to last follow-up (median follow-up: 54 months)
    End point values
    		 4xR-CHOP 4xR-CHOP+2xR 6xR-CHOP 6xBurkitt protocol
    Number of subjects analysed
    129
    126
    52
    56
    Units: Proportion of patients
        number (confidence interval 95%)
    76.4 (68.0 to 84.2)
    73.5 (64.8 to 80.4)
    42.0 (28.2 to 55.2)
    31.6 (19.3 to 44.6)
    Attachments
    		 EFS and OS
    Statistical analysis title
    		 Event-free survival of interim PET-negative pts
    Statistical analysis description
    Kaplan-Meier analysis of the impact of treatment on event-free survival in patients with a negative interim PET scan after 2 cycles of R-CHOP
    Comparison groups
    4xR-CHOP v 4xR-CHOP+2xR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8216
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.689
         upper limit
    		 1.598
    Statistical analysis title
    		 Event-free survival of interim PET-positive pts
    Statistical analysis description
    Kaplan-Meier analysis of the impact of treatment on event-free survival in patients with a positive interim PET scan after 2 cycles of R-CHOP
    Comparison groups
    6xR-CHOP v 6xBurkitt protocol
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0924
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.502
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.931
         upper limit
    		 2.424

    Secondary: Overall survival rate at 2 years

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    End point title
    		 Overall survival rate at 2 years
    End point description
    Kaplan-Meier estimates of the proportion of patients surviving at 2 years
    End point type
    Secondary
    End point timeframe
    From randomization to last follow-up
    End point values
    		 4xR-CHOP 4xR-CHOP+2xR 6xR-CHOP 6xBurkitt protocol
    Number of subjects analysed
    129
    126
    52
    56
    Units: Proportion of patients
        number (confidence interval 95%)
    88.2 (81.2 to 92.7)
    87.2 (79.9 to 91.9)
    63.6 (48.5 to 75.3)
    55.4 (40.7 to 67.8)
    Statistical analysis title
    		 Overall survival of interim PET-negative pts
    Statistical analysis description
    Kaplan-Meier analysis of the impact of treatment on overall survival in patients with a negative interim PET scan after 2 cycles of R-CHOP
    Comparison groups
    4xR-CHOP+2xR v 4xR-CHOP
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6351
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.876
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.508
         upper limit
    		 1.513
    Statistical analysis title
    		 Overall survival of interim PET-positive pts
    Statistical analysis description
    Kaplan-Meier analysis of the impact of treatment on overall survival in patients with a positive interim PET scan after 2 cycles of R-CHOP
    Comparison groups
    6xR-CHOP v 6xBurkitt protocol
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3085
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.349
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.756
         upper limit
    		 2.406

    Secondary: Overall response rate

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    End point title
    		 Overall response rate
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment specified in the protocol
    End point values
    		 4xR-CHOP 4xR-CHOP+2xR 6xR-CHOP 6xBurkitt protocol
    Number of subjects analysed
    119
    120
    43
    35
    Units: Patients
    111
    109
    30
    24
    Statistical analysis title
    		 Overall response rate of interim PET-negative pts
    Comparison groups
    4xR-CHOP v 4xR-CHOP+2xR
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.485
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Overall response rate of interim PET-positive pts
    Comparison groups
    6xR-CHOP v 6xBurkitt protocol
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9094
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization to 6 weeks after the end of therapy Only for overall deaths: From randomization to death or last follow-up (median follow-up: 54 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    4xR-CHOP
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-negative patients with CD20-positive lymphomas randomized to the active comparator received a further 4 cycles of R-CHOP after the interim PET

    Reporting group title
    4xR-CHOP+2xR
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-negative patients with CD20-positive lymphomas randomized to the experimental arm received a further 4 cycles of R-CHOP plus 2 extra doses of rituximab after the interim PET

    Reporting group title
    6xR-CHOP
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-positive patients randomized to the active comparator received a further 6 cycles of R-CHOP after the interim PET

    Reporting group title
    6xBurkitt protocol
    Reporting group description
    		 Following 2 cycles of R-CHOP before the interim PET scan, interim PET-positive patients randomized to the experimental arm received 6 blocks of the German Burkitt's lymphoma protocol after the interim PET

    Serious adverse events
    		 4xR-CHOP 4xR-CHOP+2xR 6xR-CHOP 6xBurkitt protocol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 129 (40.31%)
    30 / 126 (23.81%)
    26 / 52 (50.00%)
    42 / 56 (75.00%)
         number of deaths (all causes)
    28
    23
    20
    27
         number of deaths resulting from adverse events
    5
    2
    2
    3
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    6 / 129 (4.65%)
    6 / 126 (4.76%)
    0 / 52 (0.00%)
    3 / 56 (5.36%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Treatment-related death
         subjects affected / exposed
    5 / 129 (3.88%)
    2 / 126 (1.59%)
    2 / 52 (3.85%)
    3 / 56 (5.36%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    5 / 5
    2 / 2
    2 / 2
    3 / 3
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    11 / 129 (8.53%)
    4 / 126 (3.17%)
    5 / 52 (9.62%)
    4 / 56 (7.14%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 4
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    10 / 129 (7.75%)
    9 / 126 (7.14%)
    1 / 52 (1.92%)
    8 / 56 (14.29%)
         occurrences causally related to treatment / all
    3 / 10
    4 / 9
    0 / 1
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    11 / 129 (8.53%)
    12 / 126 (9.52%)
    6 / 52 (11.54%)
    11 / 56 (19.64%)
         occurrences causally related to treatment / all
    11 / 11
    12 / 12
    6 / 6
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 129 (6.20%)
    11 / 126 (8.73%)
    6 / 52 (11.54%)
    7 / 56 (12.50%)
         occurrences causally related to treatment / all
    8 / 8
    11 / 11
    6 / 6
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucositis
         subjects affected / exposed
    3 / 129 (2.33%)
    1 / 126 (0.79%)
    2 / 52 (3.85%)
    12 / 56 (21.43%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    1 / 2
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    26 / 129 (20.16%)
    14 / 126 (11.11%)
    14 / 52 (26.92%)
    15 / 56 (26.79%)
         occurrences causally related to treatment / all
    10 / 26
    7 / 14
    7 / 14
    12 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorders
         subjects affected / exposed
    13 / 129 (10.08%)
    4 / 126 (3.17%)
    3 / 52 (5.77%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    2 / 13
    2 / 4
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal disorders
         subjects affected / exposed
    4 / 129 (3.10%)
    2 / 126 (1.59%)
    0 / 52 (0.00%)
    2 / 56 (3.57%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    2 / 129 (1.55%)
    2 / 126 (1.59%)
    1 / 52 (1.92%)
    3 / 56 (5.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    38 / 129 (29.46%)
    25 / 126 (19.84%)
    19 / 52 (36.54%)
    26 / 56 (46.43%)
         occurrences causally related to treatment / all
    38 / 38
    25 / 25
    19 / 19
    26 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolism disorders
         subjects affected / exposed
    8 / 129 (6.20%)
    5 / 126 (3.97%)
    5 / 52 (9.62%)
    9 / 56 (16.07%)
         occurrences causally related to treatment / all
    6 / 8
    2 / 5
    3 / 5
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 4xR-CHOP 4xR-CHOP+2xR 6xR-CHOP 6xBurkitt protocol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    129 / 129 (100.00%)
    126 / 126 (100.00%)
    52 / 52 (100.00%)
    56 / 56 (100.00%)
    Blood and lymphatic system disorders
    Anemia, grade 3 or 4
         subjects affected / exposed
    21 / 129 (16.28%)
    14 / 126 (11.11%)
    13 / 52 (25.00%)
    25 / 56 (44.64%)
         occurrences all number
    21
    14
    13
    25
    Leukopenia, grade 3 or 4
         subjects affected / exposed
    70 / 129 (54.26%)
    76 / 126 (60.32%)
    31 / 52 (59.62%)
    45 / 56 (80.36%)
         occurrences all number
    70
    76
    31
    45
    Neutropenia, grade 3 or 4
         subjects affected / exposed
    20 / 129 (15.50%)
    30 / 126 (23.81%)
    12 / 52 (23.08%)
    19 / 56 (33.93%)
         occurrences all number
    20
    30
    12
    19
    Thrombocytopenia, grade 3 or 4
         subjects affected / exposed
    19 / 129 (14.73%)
    10 / 126 (7.94%)
    11 / 52 (21.15%)
    33 / 56 (58.93%)
         occurrences all number
    19
    10
    11
    33
    Gastrointestinal disorders
    Mucositis, grade 3 or 4
         subjects affected / exposed
    2 / 129 (1.55%)
    3 / 126 (2.38%)
    6 / 52 (11.54%)
    21 / 56 (37.50%)
         occurrences all number
    2
    3
    6
    21
    Diarrhea, grade 3 or 4
         subjects affected / exposed
    4 / 129 (3.10%)
    1 / 126 (0.79%)
    5 / 52 (9.62%)
    3 / 56 (5.36%)
         occurrences all number
    4
    1
    5
    3
    Renal and urinary disorders
    Creatinine increase, grade 3 or 4
         subjects affected / exposed
    4 / 129 (3.10%)
    1 / 126 (0.79%)
    3 / 52 (5.77%)
    1 / 56 (1.79%)
         occurrences all number
    4
    1
    3
    1
    Infections and infestations
    Infection, grade 3 or 4
         subjects affected / exposed
    19 / 129 (14.73%)
    14 / 126 (11.11%)
    11 / 52 (21.15%)
    28 / 56 (50.00%)
         occurrences all number
    19
    14
    11
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Mar 2008
    Change of interim PET evaluation from a purely visual to a semi-quantitative SUV-based assessment
    01 Oct 2009
    Randomization of interim PET-negative patients between a further 4 cycles R-CHOP or 4 cycles R-CHOP plus 2 extra doses rituximab. After reaching the recruitment goal for this randomization, interim PET-negative patients were no longer subjected to randomization within the trial.
    16 Dec 2010
    Collection of serum samples for scientific investigations. Otherwise no protocol change.
    01 May 2011
    Extension of the study period until December 2012 to increase the recruitment of interim PET-positive patients

    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.
    The effect of 2 extra doses of rituximab on outcome in patients with CD20-positive lymphomas was only tested in interim PET-negative patients. The recruitment goal for interim PET-positive patients was not reached.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29750632
    http://www.ncbi.nlm.nih.gov/pubmed/30610279
    http://www.ncbi.nlm.nih.gov/pubmed/31427567
    http://www.ncbi.nlm.nih.gov/pubmed/31710995
    http://www.ncbi.nlm.nih.gov/pubmed/31890813
    http://www.ncbi.nlm.nih.gov/pubmed/32022621
    http://www.ncbi.nlm.nih.gov/pubmed/32067259
    http://www.ncbi.nlm.nih.gov/pubmed/32385164
    http://www.ncbi.nlm.nih.gov/pubmed/33246974
    http://www.ncbi.nlm.nih.gov/pubmed/34523055
    http://www.ncbi.nlm.nih.gov/pubmed/34708297
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