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    Clinical Trial Results:
    Dose densified chemoimmunotherapy with early CNS prophylaxis in patients less than 65 years with high risk (aaIPI≥2) Diffuse Large B-Cell Lymphoma. (NLG-LBC05, CHIC)

    Summary
    EudraCT number
    		 2010-023125-38
    Trial protocol
    		 SE   FI   NO   DK  
    Global end of trial date
    14 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Nov 2024
    First version publication date
    20 Nov 2024
    Other versions
    Summary report(s)
    		 CHIC, Summary of results

    Trial information

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    Trial identification
    Sponsor protocol code
    NLG-LBC05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01325194
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CHIC: NLG-LB05
    Sponsors
    Sponsor organisation name
    Hospital district of Helsinki and Uusimaa
    Sponsor organisation address
    Haartmaninkatu 4, Helsinki, Finland, 00290
    Public contact
    Sirpa Leppä, Nordic Lymphoma Group, +358 504270820, sirpa.leppa@helsinki.fi
    Scientific contact
    Sirpa Leppä, Nordic Lymphoma Group, +358 504270820, sirpa.leppa@helsinki.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
    14 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Time to treatment failure from date of registration. CNS relapse rate at 1,5 years.
    Protection of trial subjects
    Patient protection The responsible investigators will ensure that this study is conducted in agreement with either the declaration of Helsinki (Tokyo, Venice and Hong Kong amendments), or the laws and the regulations of the countries, whichever provide the greatest protection of the patient. The protocol has been written, and the study will be conducted according to the guidelines for Good Clinical Practice issued by the European Union. As a pre-requirement for implementation, the protocol will have to be approved by the local, regional or national Ethical Review Boards according to the existing national and local regulatory requirements.
    Background therapy
    		 A mainstay of therapy has been CHOP chemotherapy regimen, which is as effective as and less toxic than more intensive regimens (2-4). With a CHOP-like therapy, approximately 50% of all patients are cured. Recently, combination of rituximab, a monoclonal antibody targeting CD20, with CHOP has led to a marked improvement of survival.
    Evidence for comparator
    		 This was a phase II study without a direct comparator. Instead the study results were compared to the recent CRY 04 study . Previous reduced CNS relapse rate in a phase II study with a historical control does not prove the importance of prophylaxis and should ideally be confirmed in an adequately sized phase III study. However, such a study cannot be performed within the Nordic community within a reasonable time. Internationally it was not possible to agree upon a treatment plan for a multicentre prospective randomized study due lack of conformity concerning treatment recommendations for this treatment group.
    Actual start date of recruitment
    14 Mar 2011
    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: 46
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Denmark: 33
    Country: Number of subjects enrolled
    Finland: 55
    Worldwide total number of subjects
    139
    EEA total number of subjects
    139
    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)
    139
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started 14.3.2011, stopped 31.12.2014

    Pre-assignment
    Screening details
    		 Main inclusion criteria: •Age ≥ 18 - < 65 years • Histologically confirmed CD20+ diffuse large B-cell lymphoma •Advanced stage

    Pre-assignment period milestones
    Number of subjects started
    		 139
    Number of subjects completed
    		 139

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Arm title
    		 Phase II single arm study
    Arm description
    		 Patients are given a pre-phase medication consisting of dexamethasone, rituximab and vincristine, followed by two cycles of high dose methotrexate with CHOP/CHOD and rituximab, and four cycles of CHOEP/CHOED with rituximab. In addition, one course of high dose cytarabine and rituximab, and three courses of liposomal cytarabine (DepoCyte®) are given. The courses should be given with a two week interval if possible.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Methotrexate 3 g/m2 i.v. as a 3 hour infusion. Folic acid rescue (leucovorin) is given after 24 hours,

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 750 mg/m2 i.v. day 1

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 50 mg/m2 i.v. day 1

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine 1.4 mg/m2 (max. 2.0 mg) i.v. day 1

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 100 mg po days 1-5 OR Dexamethasone 10 mg x 2 daily p.o. (alternatively betamethasone 8 mg x 2daily p.o.) days 1-5 in courses including DepoCyte

    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
    Rituximab 375 mg/m2 i.v. day 1

    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
    Etoposide 100 mg/m2 i.v. day 1-3

    Investigational medicinal product name
    Pegfilgastrim
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Long lasting G-CSF (pegfilgrastim, Neulasta®) 48 hours after chemotherapy course 1 and 2, 24 hours after the 3-day CHOEP courses and the 2-day High dose AraC courses.

    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
    Cytarabine 3 g/m2 i.v. x 2 for 2 days (in total four times). Cytarabine is given as a 1-hour infusion every 12-hour in 500 ml glucose 5%.

    Investigational medicinal product name
    DepoCyte
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    DepoCyte 50 mg by intraspinal route.

    Number of subjects in period 1
    		Phase II single arm study
    Started
    139
    Completed
    126
    Not completed
    13
         Adverse event, non-fatal
    9
         Lack of efficacy
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 139 139
    Age categorical
    Adults, 18-64 years
    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)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        Adults 18-64
    		 139 139
    Age continuous
    Units: years
        median (full range (min-max))
    		 56 (20 to 64) -
    Gender categorical
    51 women, 88 men were included in the study
    Units: Subjects
        Female
    		 51 51
        Male
    		 88 88
    Large B-cell lymphoma
    Units: Subjects
        DLBCL
    		 113 113
        TCRB
    		 5 5
        PMBCL
    		 8 8
        Intravascular
    		 1 1
        Follicular lymphoma, grade 3B
    		 5 5
        Not reviewed, not recorded
    		 7 7
    Subject analysis sets

    Subject analysis set title
    Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The main analysis included those registered patients that started the protocol treatment. TTF as well as the secondary endpoints Overall Survival and Time to Progression, will be presented using Kaplan-Meier curves and the effect of clinical and biological prognostic factors will be analysed by means of Cox regression. Toxicity and incidence of CNS-relapse will be shown in descriptive tables. The study results will be compared to the recent CRY 04 study. The aims of the study are to at least achieve the 3-year TTF of the CRY04 study and with a substantial reduction of the CNS relapse rate with the use of early systemic and intrathecal CNS prophylaxis. A reduced CNS relapse rate in a phase II study with a historical control will not prove the importance of prophylaxis and should ideally be confirmed in an adequately sized phase III study.

    Subject analysis sets values
    		 Analysis
    Number of subjects
    139
    Age categorical
    Adults, 18-64 years
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
        Adults 18-64
    139
    Age continuous
    Units: years
        median (full range (min-max))
    56 (20 to 64)
    Gender categorical
    51 women, 88 men were included in the study
    Units: Subjects
        Female
    51
        Male
    88
    Large B-cell lymphoma
    Units: Subjects
        DLBCL
    113
        TCRB
    5
        PMBCL
    8
        Intravascular
    1
        Follicular lymphoma, grade 3B
    5
        Not reviewed, not recorded
    7

    End points

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    End points reporting groups
    Reporting group title
    Phase II single arm study
    Reporting group description
    		 Patients are given a pre-phase medication consisting of dexamethasone, rituximab and vincristine, followed by two cycles of high dose methotrexate with CHOP/CHOD and rituximab, and four cycles of CHOEP/CHOED with rituximab. In addition, one course of high dose cytarabine and rituximab, and three courses of liposomal cytarabine (DepoCyte®) are given. The courses should be given with a two week interval if possible.

    Subject analysis set title
    Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The main analysis included those registered patients that started the protocol treatment. TTF as well as the secondary endpoints Overall Survival and Time to Progression, will be presented using Kaplan-Meier curves and the effect of clinical and biological prognostic factors will be analysed by means of Cox regression. Toxicity and incidence of CNS-relapse will be shown in descriptive tables. The study results will be compared to the recent CRY 04 study. The aims of the study are to at least achieve the 3-year TTF of the CRY04 study and with a substantial reduction of the CNS relapse rate with the use of early systemic and intrathecal CNS prophylaxis. A reduced CNS relapse rate in a phase II study with a historical control will not prove the importance of prophylaxis and should ideally be confirmed in an adequately sized phase III study.

    Primary: Three – year - time to treatment failure (TTF)

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    End point title
    		 Three – year - time to treatment failure (TTF)
    End point description
    End point type
    Primary
    End point timeframe
    Time to treatment failure 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. Otherwise
    End point values
    		 Phase II single arm study Analysis
    Number of subjects analysed
    139
    139
    Units: months
        number (not applicable)
    139
    139
    Statistical analysis title
    		 TTF
    Statistical analysis description
    Time to treatment failure 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. 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 1 day.
    Comparison groups
    Phase II single arm study v Analysis
    Number of subjects included in analysis
    278
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.03 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.96
    Notes
    [1] - survival
    [2] - Comparison is done with historical control.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events with excerpts occurring during the treatment period and until the end of the last treatment administration
    Adverse event reporting additional description
    Serious adverse events will be reported until 30 days after the last course of chemotherapy.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCA
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    AEs (> grade 2)
    Reporting group description
    		 -

    Serious adverse events
    		 AEs (> grade 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 139 (6.47%)
         number of deaths (all causes)
    23
         number of deaths resulting from adverse events
    4
    Vascular disorders
    Subdural hematoma
         subjects affected / exposed
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    GI hemorrage
         subjects affected / exposed
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infections and infestations
    Multiorgan failure
         subjects affected / exposed
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Septisemia
         subjects affected / exposed
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Unspecified toxicity
         subjects affected / exposed
    4 / 139 (2.88%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    Progressive multifocal neuroencephalopathy
         subjects affected / exposed
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 AEs (> grade 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 139 (56.83%)
    Blood and lymphatic system disorders
    Neutropenia
    Additional description: In the case of this trial, treatment consist of dose densified immunochemotherapy which results in adverse events such as hematological toxicity. Therefore we consider this part irrelevant.
         subjects affected / exposed
    79 / 139 (56.83%)
         occurrences all number
    560

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2011
    (5.1.2011 first approval for the study) Amendment 01 1. New inclusion criterion for Danish and Swedish centres: Epidural lymphoma. 2. New exclusion criterion: Conditions that may be compatible with impaired cerebrospinal fluid flow. 3. Addition of two rituximab courses (one extra during pre-phase on day -4 and one during 7th course with high-dose cytarabine). 4. Increased dose of dexamethasone during CHOD or CHOED courses. Dexamethasone can be substituted with equipotent amount of betamethasone. 5. Option to delay second R-CHOP course with 1-2 days. 6. Common Terminology Criteria for Adverse Events v.3.0 (CTCAE) (Appendix 3). 7. Revised methotrexate excretion table (Appendix 4). 8.Sampling of cerebrospinal fluid for freezing
    20 Sep 2012
    Amendment 02 1. Administration of DepoCyte omitted from the protocol. 2. CHOED courses changed to CHOEP (Dxm changed to Prednisone in courses 1, 3 and 5). 3. Number of study population increased from 170. 4. Inclusion criteria for Danish centres have been revised to be the same as in Finland and Norway. 5. List of local PIs in Denmark has been updated (Appendix 1 on page 34).
    01 Sep 2013
    Amendment 03 1. Administration of DepoCyte is reimplemented to the protocol in Denmark, Finland and Norway as in protocol version 3. 2. CHOEP courses changed to CHOED (Prednisone changed to Dxm in courses 1, 3 and 5). 3. Revised methotrexate excretion table (Appendix 4). 4.Study will be continued until the end of 2014. New planned sample size is 130. 5. Prephase can be initiated before registration if clinically needed. 6. Treatment and particularly possible DepoCyte associated side effects are recorded using a specific patient questionnaire after cycles 1, 3 and 5 at the beginning of the following cycle. 7. Contact information for the protocol secretariat to register patients and report SAEs has been changed. 8. List of local PIs and study centres in Sweden has been updated (Appendix 1 on page 33).

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32380536
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