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    Clinical Trial Results:
    BIO-CHIC-Study BIOmarker driven and dose intensified CHemoImmunotherapy with early CNS prophylaxis in patients less than 65 years with high risk diffuse large B-cell lymphoma

    Summary
    EudraCT number
    		 2015-002846-30
    Trial protocol
    		 FI   DK   NO   SE  
    Global end of trial date
    30 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jun 2026
    First version publication date
    06 Jun 2026
    Other versions
    Summary report(s)
    		 BIO-CHIC results summary

    Trial information

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    Trial identification
    Sponsor protocol code
    NLG-LBC-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01325194
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HUS , Comprehensive Cancer Center
    Sponsor organisation address
    Haartmaninkatu 4, Helsinki, Finland, 00290
    Public contact
    Sirpa Leppä, HUH Comprehensive Cancer Centre, 358 504270820, sirpa.leppa@hus.fi
    Scientific contact
    Sirpa Leppä, HUH Comprehensive Cancer Centre, 358 504270820, sirpa.leppa@hus.fi
    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
    30 Jan 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Failure free survival rate (FFS) of the patients with biological risk factors compared to similar patients from the historical CRY-04 and CHIC studies, with spesific focus on three years survival.
    Protection of trial subjects
    Supportive care: Medication to prevent nausea G-CSF to reduce neutropenia and to reduce the risk of neutropenic infection Pneumocystis prophylaxis Blood transfusions in case of gr 3 anemia and gr 4 trombocytopenia
    Background therapy
    		 As listed above
    Evidence for comparator
    		 No comparator
    Actual start date of recruitment
    03 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 35
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Denmark: 34
    Country: Number of subjects enrolled
    Finland: 55
    Worldwide total number of subjects
    127
    EEA total number of subjects
    127
    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)
    127
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started in 6.6.2017 and ended 2.2.2021

    Pre-assignment
    Screening details
    		 127 patients were included. 4 were not eligible due to unsuccessful stratification, resulting 123 patient intend-to-treat population.

    Period 1
    Period 1 title
    Prephase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All patients
    Arm description
    		 -
    Arm type
    		 all

    Investigational medicinal product name
    Prednison
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg 3-6 days

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1mg x1

    Number of subjects in period 1
    		All patients
    Started
    127
    Completed
    127
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Biologically high risk group, GROUP B
    Arm description
    		 Patients with at least one of the following factor o Myc translocation (FISH) o Myc/Bcl2 double hits (FISH) o P53 deletion (FISH) o Myc+ and Bcl2+ (IHC; double expressors, DE) o P53+ (ICH) o CD5+ (IHC)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Continuous infusion for 96 h, 1,6mg/ m2, 6 cycles

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/m2, 7 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750mg m2, 6 cycles

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    continuous infusion for 96h, 40mg/m2, 6 cycles

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Continuous infusion for 96 h, 200mg/ m2, 4 cycles

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3g/m2 in two cycles

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    12g/m2 one cycle

    Arm title
    		 Biologically low risk group, GROUP A
    Arm description
    		 o Myc translocation (FISH) o Myc/Bcl2 double hits (FISH) o P53 deletion (FISH) o Myc+ and Bcl2+ (IHC; double expressors, DE) o P53+ (ICH) o CD5+ (IHC) Patients without the above listed factors
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/ m2on D1 for 4 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    750mg/m2 for 4 cycles

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50mg/m2 for 4 cycles

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4mg/m2 on D1 for 4 cycles

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100mg/m2 on Days 1-3 for 4 cycles

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg for 5 days, for 4 cycles

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is not a treatment period. Period 2 is the treatment period.
    Number of subjects in period 2 [2] [3]
    		Biologically high risk group, GROUP B Biologically low risk group, GROUP A
    Started
    61
    62
    Completed
    56
    57
    Not completed
    5
    5
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    2
    2
         Lymphoma progression
    2
    2
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Screening failures: 4 patients
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Stratification failure in 4 patients, in addition 6 patients (3 in high risk group, 3in low risk groups) discontinued the study due to AE or refractory disease.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 High risk and low risk groups

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 123 123
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 123 123
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 53 53
        Male
    		 70 70

    End points

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    End points reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 -
    Reporting group title
    Biologically high risk group, GROUP B
    Reporting group description
    		 Patients with at least one of the following factor o Myc translocation (FISH) o Myc/Bcl2 double hits (FISH) o P53 deletion (FISH) o Myc+ and Bcl2+ (IHC; double expressors, DE) o P53+ (ICH) o CD5+ (IHC)

    Reporting group title
    Biologically low risk group, GROUP A
    Reporting group description
    		 o Myc translocation (FISH) o Myc/Bcl2 double hits (FISH) o P53 deletion (FISH) o Myc+ and Bcl2+ (IHC; double expressors, DE) o P53+ (ICH) o CD5+ (IHC) Patients without the above listed factors

    Primary: Time to treatment failure

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    End point title
    		 Time to treatment failure
    End point description
    Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first. Secondary hematologic malignancies (leukemia and MDS) are included as events in this category. Otherwise, patients will be censored at the last date they were known to be alive. For patients not responding at any time point on study treatment, TTF is defined as one day.
    End point type
    Primary
    End point timeframe
    Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first.
    End point values
    		 Biologically high risk group, GROUP B Biologically low risk group, GROUP A
    Number of subjects analysed
    61
    62
    Units: % at 3 years
    61
    62
    Statistical analysis title
    		 Kaplan-Meier and log rank
    Comparison groups
    Biologically high risk group, GROUP B v Biologically low risk group, GROUP A
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 > 0.3
    Method
    		 Logrank
    Confidence interval
    Notes
    [1] - Different risk groups (no purpose to compare these)

    Secondary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    The time from the registration date to the date of progression or death from any cause
    End point type
    Secondary
    End point timeframe
    The time from the registration date to the date of progression or death from any cause
    End point values
    		 Biologically high risk group, GROUP B Biologically low risk group, GROUP A
    Number of subjects analysed
    61
    62
    Units: % at 3 years
    61
    62
    Statistical analysis title
    		 Kaplan-Meier and log rank
    Comparison groups
    Biologically low risk group, GROUP A v Biologically high risk group, GROUP B
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.27
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - Different risk groups (no purpose to compare)

    Secondary: Overall survival (all causes of death)

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    End point title
    		 Overall survival (all causes of death)
    End point description
    The time from the registration date to the date of death. Patients still alive or lost to follow-up are censored at the last date they were known to be alive.
    End point type
    Secondary
    End point timeframe
    The time from the registration date to the date of death. Patients still alive or lost to follow-up are censored at the last date they were known to be alive.
    End point values
    		 Biologically high risk group, GROUP B Biologically low risk group, GROUP A
    Number of subjects analysed
    61
    62
    Units: % at 3 years
    61
    62
    Statistical analysis title
    		 Kaplan-Meier and log rank
    Comparison groups
    Biologically high risk group, GROUP B v Biologically low risk group, GROUP A
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.51
    Method
    		 Logrank
    Confidence interval
    Notes
    [3] - Different risk groups (no purpose to compare)

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All adverse events occurring during the treatment period and within one month after the last treatment administration will be documented in the applicable eCRF section.
    Adverse event reporting additional description
    Total of 143 SAEs were reported during the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Infection gradus 4
    Reporting group description
    		 Infection gradus 4

    Reporting group title
    Renal gradus 3
    Reporting group description
    		 -

    Reporting group title
    Gastrointestinal gradus 4
    Reporting group description
    		 Both low and high risk patients.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Protocol only requested to record AEs higher than gr 2.
    Serious adverse events
    		 Infection gradus 4 Renal gradus 3 Gastrointestinal gradus 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 123 (1.63%)
    3 / 123 (2.44%)
    3 / 123 (2.44%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 123 (1.63%)
    3 / 123 (2.44%)
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Infection gradus 4 Renal gradus 3 Gastrointestinal gradus 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 123 (0.00%)
    0 / 123 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2017
    • Primary End point was defined as PTTF (time to treatment failure) instead of FFS:n (failure free survival). • High riski group definition was amended to include Myc+ and/ or BCL2+ • Exclusion criteria list was refined • Monitoring Plan was included in the protocol (Appendix 8) • Contact details updated • Due to a delay in the start of the study, the enrollment period has been extended
    14 Mar 2017
    PO etoposide is allowed in cycles 4-6 on D2 and D3 as a part of CHOEP regimen
    27 Oct 2017
    Only minor changes and updates added.
    18 Apr 2018
    This amendment was made solely to comply with the requirements of the Swedish authorities. -A signature page has been added to the protocol - The administrative procedure has been clarified · The process of ICF has been clarified
    14 Jun 2019
    -Contact information of CTU has been updated -Recruitment time has been extended to 31.12.2020 - Use of rituximab biosimilars is allowed -Vincristine can be given on day -4 (+/- 3 days) during prophase -Plasma samples will be collected to STECK tubes. -GDPR rules concerning subjects rights have been included to the patient information form. -PI in Roskilde has changed -Contact information of the PI in Tampere has been corrected Oulu site has been closed Typos have been corrected

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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