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    Clinical Trial Results:
    EuroNet-Paediatric Hodgkin’s Lymphoma Group First international Inter-Group Study for classical Hodgkin’s Lymphoma in Children and Adolescents

    Summary
    EudraCT number
    2006-000995-33
    Trial protocol
    DE   CZ   GB   SE   AT   FR   IE   ES   DK   PL   BE   NL   SI  
    Global end of trial date
    30 Oct 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Jun 2021
    First version publication date
    10 Jun 2021
    Other versions
    Summary report(s)
    Final report

    Trial information

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    Trial identification
    Sponsor protocol code
    EuroNet-PHL-C1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Martin-Luther-University of Halle-Wittenberg
    Sponsor organisation address
    Magdeburger Str. 27, Halle (Saale), Germany, 06097
    Public contact
    Prof Dr Dieter Körholz (Coordinating chairperson), UK Giessen und Marburg GmbH; Standort Giessen - Zentrum f. Kinderheilkunde u. Jugendmedizin, Dieter.Koerholz@paediat.med.uni-giessen.de
    Scientific contact
    Prof Dr Dieter Körholz (Coordinating chairperson), UK Giessen und Marburg GmbH; Standort Giessen - Zentrum f. Kinderheilkunde u. Jugendmedizin, Dieter.Koerholz@paediat.med.uni-giessen.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
    07 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. Are 5 year event free survival (EFS) rate estimates in patients with adequate response after 2 OEPA treated without radiotherapy consistent with a target EFS rate of 90% in all treatment groups? 2. Can Procarbazine be safely replaced by Dacarbazine in therapy groups TG-2 and TG-3 without a deterioration of EFS (randomised comparison of COPDAC and COPP)? 3. Description of treatment outcome to a standardised risk adapted relapse strategy
    Protection of trial subjects
    Patients werde closely monitored by the trating staff with regard to safety during the course of the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Jan 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
    Netherlands: 33
    Country: Number of subjects enrolled
    Norway: 39
    Country: Number of subjects enrolled
    Poland: 98
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Spain: 105
    Country: Number of subjects enrolled
    Sweden: 56
    Country: Number of subjects enrolled
    United Kingdom: 289
    Country: Number of subjects enrolled
    Austria: 87
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Czechia: 52
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    France: 487
    Country: Number of subjects enrolled
    Germany: 693
    Country: Number of subjects enrolled
    Ireland: 41
    Country: Number of subjects enrolled
    Slovakia: 35
    Country: Number of subjects enrolled
    Switzerland: 45
    Worldwide total number of subjects
    2102
    EEA total number of subjects
    1768
    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)
    455
    Adolescents (12-17 years)
    1647
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Within this clinical trial N=2131 patients have been recruited in 188 trial centres in 16 European countries. The first patient within this clinical trial has been recruited on 2007-01-31, the last patient on 2013-01-29. Accrual to the study closed on 2013-01-29.

    Pre-assignment
    Screening details
    Screening included: confirmation of the diagnosis by the local pathologist; FDG-PET scan before start of treatment; confirmation of local pathology result by reference pathologist; medical history; previous and concomitant disease status; clinical, laboratory and functional examinations; pubertal assessment, if appl.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    TG-1
    Arm description
    TG-1 (treatment group 1): patients of stages I A/B and II A without bulk>=200 ml and without ESR>=30mm/hr All patients receive two cycles of OEPA. Patients in TG-1 with adequate response (response groups AR1 and AR2) receive no further therapy. Patients with inadequate response (IR and IRU) receive involved field radiotherapy .
    Arm type
    stratification group

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OEPA scheme Prednisone/prednisolone 60 mg/m2/day p.o. divided into 3 doses day 1 – 15

    Investigational medicinal product name
    Vincristine sulphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    OEPA scheme Vincristine 1.5 mg/m2 i.v., max. SD 2 mg day 1 + 8 + 15

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    OEPA scheme Doxorubicine 40 mg/m2 as 1-6 hour infusion day 1 + 15

    Investigational medicinal product name
    Etoposide/Etopophos
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    OEPA scheme Etoposide/Etopophos 125 mg/m² as 1-2 hour infusion day 1 – 5

    Arm title
    TG-2
    Arm description
    TG-2 (treatment group 2): patients of stages IEA/B, IIEA, II B or III A and patients of stages I A/B and II A with bulk>=200 ml and/or ESR>=30mm/hr All patients receive two cycles of OEPA. After initial staging and assignment to treatment groups 2 or 3, patients are randomised between COPP and COPDAC. Following completion of 2 cycles of OEPA and after early response assessment including FDG-PET, patients in TG-2 receive two cycles, patients in TG-3 four cycles of either COPP or COPDAC. Patients in TG-2 / TG-3 with adequate response in early response assessment (response groups AR1 and AR2) receive no radiotherapy.
    Arm type
    stratification group

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    COPP scheme Procarbazine 100 mg/m²/day, p.o. divided into 2 – 3 doses day 1 – 15

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    COPP / COPDAC scheme Cyclophosphamide 500 mg/m2, 60-min. inf. day 1 + 8

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    COPDAC scheme Dacarbazine 250 mg/m2 as 15 - 30-min. inf. day 1 – 3

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OEPA scheme Prednisone/prednisolone 60 mg/m2/day p.o. divided into 3 doses day 1 – 15

    Investigational medicinal product name
    Vincristine sulphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    OEPA scheme Vincristine 1.5 mg/m2 i.v., max. SD 2 mg day 1 + 8 + 15

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    OEPA scheme Doxorubicine 40 mg/m2 as 1-6 hour infusion day 1 + 15

    Investigational medicinal product name
    Etoposide/Etopophos
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    OEPA scheme Etoposide/Etopophos 125 mg/m² as 1-2 hour infusion day 1 – 5

    Arm title
    TG-3
    Arm description
    TG-3 (treatment group 3): patients of stages IIEB, IIIEA/B, III B or IV A/B All patients receive two cycles of OEPA. After initial staging and assignment to treatment groups 2 or 3, patients are randomised between COPP and COPDAC. Following completion of 2 cycles of OEPA and after early response assessment including FDG-PET, patients in TG-2 receive two cycles, patients in TG-3 four cycles of either COPP or COPDAC. Patients in TG-2 / TG-3 with adequate response in early response assessment (response groups AR1 and AR2) receive no radiotherapy.
    Arm type
    stratification group

    Investigational medicinal product name
    Procarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    COPP scheme Procarbazine 100 mg/m²/day, p.o. divided into 2 – 3 doses day 1 – 15

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    COPP / COPDAC scheme Cyclophosphamide 500 mg/m2, 60-min. inf. day 1 + 8

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    COPDAC scheme Dacarbazine 250 mg/m2 as 15 - 30-min. inf. day 1 – 3

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    OEPA scheme Prednisone/prednisolone 60 mg/m2/day p.o. divided into 3 doses day 1 – 15

    Investigational medicinal product name
    Vincristine sulphate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    OEPA scheme Vincristine 1.5 mg/m2 i.v., max. SD 2 mg day 1 + 8 + 15

    Investigational medicinal product name
    Doxorubicine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    OEPA scheme Doxorubicine 40 mg/m2 as 1-6 hour infusion day 1 + 15

    Investigational medicinal product name
    Etoposide/Etopophos
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    OEPA scheme Etoposide/Etopophos 125 mg/m² as 1-2 hour infusion day 1 – 5

    Number of subjects in period 1
    TG-1 TG-2 TG-3
    Started
    714
    479
    909
    Completed
    713
    478
    904
    Not completed
    1
    1
    5
         disease progression
    -
    -
    4
         early death
    -
    1
    -
         Consent withdrawn by subject
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TG-1
    Reporting group description
    TG-1 (treatment group 1): patients of stages I A/B and II A without bulk>=200 ml and without ESR>=30mm/hr All patients receive two cycles of OEPA. Patients in TG-1 with adequate response (response groups AR1 and AR2) receive no further therapy. Patients with inadequate response (IR and IRU) receive involved field radiotherapy .

    Reporting group title
    TG-2
    Reporting group description
    TG-2 (treatment group 2): patients of stages IEA/B, IIEA, II B or III A and patients of stages I A/B and II A with bulk>=200 ml and/or ESR>=30mm/hr All patients receive two cycles of OEPA. After initial staging and assignment to treatment groups 2 or 3, patients are randomised between COPP and COPDAC. Following completion of 2 cycles of OEPA and after early response assessment including FDG-PET, patients in TG-2 receive two cycles, patients in TG-3 four cycles of either COPP or COPDAC. Patients in TG-2 / TG-3 with adequate response in early response assessment (response groups AR1 and AR2) receive no radiotherapy.

    Reporting group title
    TG-3
    Reporting group description
    TG-3 (treatment group 3): patients of stages IIEB, IIIEA/B, III B or IV A/B All patients receive two cycles of OEPA. After initial staging and assignment to treatment groups 2 or 3, patients are randomised between COPP and COPDAC. Following completion of 2 cycles of OEPA and after early response assessment including FDG-PET, patients in TG-2 receive two cycles, patients in TG-3 four cycles of either COPP or COPDAC. Patients in TG-2 / TG-3 with adequate response in early response assessment (response groups AR1 and AR2) receive no radiotherapy.

    Reporting group values
    TG-1 TG-2 TG-3 Total
    Number of subjects
    714 479 909 2102
    Age categorical
    Units: Subjects
        Age under 13
    236 142 243 621
        Age over 13
    478 337 666 1481
    Gender categorical
    Units: Subjects
        Female
    390 236 383 1009
        Male
    324 243 526 1093
    Stage
    Units: Subjects
        Stage I
    45 3 0 48
        Stage II
    668 315 133 1116
        Stage III
    1 159 247 407
        Stage IV
    0 2 529 531

    End points

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    End points reporting groups
    Reporting group title
    TG-1
    Reporting group description
    TG-1 (treatment group 1): patients of stages I A/B and II A without bulk>=200 ml and without ESR>=30mm/hr All patients receive two cycles of OEPA. Patients in TG-1 with adequate response (response groups AR1 and AR2) receive no further therapy. Patients with inadequate response (IR and IRU) receive involved field radiotherapy .

    Reporting group title
    TG-2
    Reporting group description
    TG-2 (treatment group 2): patients of stages IEA/B, IIEA, II B or III A and patients of stages I A/B and II A with bulk>=200 ml and/or ESR>=30mm/hr All patients receive two cycles of OEPA. After initial staging and assignment to treatment groups 2 or 3, patients are randomised between COPP and COPDAC. Following completion of 2 cycles of OEPA and after early response assessment including FDG-PET, patients in TG-2 receive two cycles, patients in TG-3 four cycles of either COPP or COPDAC. Patients in TG-2 / TG-3 with adequate response in early response assessment (response groups AR1 and AR2) receive no radiotherapy.

    Reporting group title
    TG-3
    Reporting group description
    TG-3 (treatment group 3): patients of stages IIEB, IIIEA/B, III B or IV A/B All patients receive two cycles of OEPA. After initial staging and assignment to treatment groups 2 or 3, patients are randomised between COPP and COPDAC. Following completion of 2 cycles of OEPA and after early response assessment including FDG-PET, patients in TG-2 receive two cycles, patients in TG-3 four cycles of either COPP or COPDAC. Patients in TG-2 / TG-3 with adequate response in early response assessment (response groups AR1 and AR2) receive no radiotherapy.

    Primary: Event free survival (EFS)

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    End point title
    Event free survival (EFS) [1]
    End point description
    EFS = time from registration until the first of the following events: - progression/relapse of disease - occurrence of a secondary malignancy - death by any cause
    End point type
    Primary
    End point timeframe
    60 months
    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: See attached final trial report
    End point values
    TG-1 TG-2 TG-3
    Number of subjects analysed
    713
    478
    904
    Units: months
        number (confidence interval 95%)
    87.4 (85.0 to 89.9)
    91.7 (89.2 to 94.2)
    85.5 (83.2 to 87.9)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival (OS) = time period from registration until death of any cause
    End point type
    Secondary
    End point timeframe
    60 months
    End point values
    TG-1 TG-2 TG-3
    Number of subjects analysed
    713
    478
    904
    Units: months
        number (confidence interval 95%)
    99.1 (98.4 to 99.8)
    98.9 (98.0 to 99.9)
    97.9 (97.0 to 98.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    3 months after application of last trial therapy
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Frequency threshold for reporting non-serious adverse events: 5%
    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: See attached final trial report

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2007
    1. Data of the interim analysis of the GPOH-HD2002 pilot study support that COPDAC is an effective and safe treatment option. Relevant safety information is updated. 2. Treatment of study patients who refuse randomisation. (In the event of refusal of randomisation between COPP and COPDAC the recommendation of the trial chairpersons is that COPP is considered as the standard arm. In these situations these patients will remain on the study. These patients will be informative concerning the STAR question and add to the safety data. Patients should not be treated on the COPDAC arm outside the study.) 3. SAE reporting: Time horizon and clarification in order avoid unnecessary SAE – reporting. (SAE reporting is restricted to events occurring within 3 month after the end of the study treatment; addition of expected toxicities for each IMP and RT) 4. Administrative data (update of contact data, correction of typos)
    17 Nov 2009
    1. Clarification of discrepancies between patient information and informed consent declaration concerning time of archiving 2. Change of members in the central review team and in the panel of referenpathologists. 3. Title of patient information and informed consent for relapse treatment is adjusted to the protocol. The inclusion criteria do not contain an age limit for patients with relapse of childhood and adolescent Hodgkin`s Lymphoma 4. Clarification in patient information for primary and relapse treatment that depending on the treatment center either prednisone or prednisolon will be used as prescribed in the final version of the treatment protocol 5. Clarification of antibacterial prophylaxis since the use of these drugs is differently handled in the various countries and institutions. However, this will not affect the study results, since all patients will receive a necessary prophylaxis. 6. The protocol prescribes either Prednisone or Prednisolone. In the abbreviation section only prednisone was listed, Therefore prednisolone was added for formal correctness. 7. Administrative data (update of contact data)
    22 Feb 2012
    1. Stop randomisation COPP vs COPDAC: Further to a Clinical Board Meeting of EuroNet-PHL and the Annual EuroNet-PHL Clinicians Meeting (from 09.02.2012 to 11.02.2012), a decision was made to end the randomisation between COPP and COPDAC for eligible Patients in the EuroNet-PHL-C1 trial. This decision was made on the basis of the results of the second interim data analysis which showed emerging evidence that COPP and COPDAC are similarly efficacious. In view of the evidence that emerged from the interim data analysis of EuroNet PHL-C1 the Clinical Board and associated parties saw a change in the risk-benefit assessment for the trial and decided that randomisation should be stopped on 13.02.2012. Although the data was immature, it was clear that the sample size was sufficient to answer the randomised question on efficacy and that furthermore it was essential to avoid the potentially detrimental effects of COPP on male fertility. All Patients in EuroNet-PHL-C1 (in TG-2 and TG-3) should now receive COPDAC. The trial remained open to recruitment (outside of Germany) because that data was required to fully answer the other important questions in the protocol relating to the STAR approach to treatment and whether it is safe to omit radiotherapy. 2. Administrative data: Update of contact data
    13 Apr 2015
    1. Addition of global scientific side projects: a) DETERMINATION OF ANTI MULLERIAN AND OTHER GONADAL HORMONES IN FEMALE PATIENTS OF THE EURONET-PHL-C1 PATIENTS; b) QUALITY CONTROL IN RADIOTHERAPY; c) INCIDENCE OF OSTEONECROSES IN CHILDREN AND ADOLESCENTS TREATED WITHIN THE EURONET-PHL-C1 TRIAL 2. Addition of country-specific scientific side projects: a) IDENTIFICATION OF A PROGNOSTIC GENE EXPRESSION SIGNATURE IN PEDIATRIC HODGKIN’S LYMPHOMA IN CONTEXT OF THE EURONET-PHL-C1 TRIAL; b) IDENTIFICATION OF DISTINCTIVE PATHOLOGIC FEATURES OF PEDIATRIC HODGKIN’S LYMPHOMAS WITH ABNORMAL CHEMO RESPONSE IN CONTEXT OF THE EURONET-PHL-C1 TRIAL c) ASSESSMENT OF LATE EFFECTS IN PATIENTS TREATED ACCORDING TO EURONET-PHL-C1

    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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