High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)
HR-NBL2
3 other identifiers
interventional
800
18 countries
134
Brief Summary
This is an international multicenter, open-label, randomized phase III trial including three sequential randomizations to assess efficacy of induction and consolidation chemotherapies and radiotherapy for patients with high-risk neuroblastoma.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Nov 2019
Longer than P75 for phase_3
134 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
November 5, 2019
CompletedFirst Submitted
Initial submission to the registry
January 6, 2020
CompletedFirst Posted
Study publicly available on registry
January 9, 2020
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 1, 2026
ExpectedStudy Completion
Last participant's last visit for all outcomes
November 1, 2032
June 26, 2025
June 1, 2025
7 years
January 6, 2020
June 25, 2025
Conditions
Outcome Measures
Primary Outcomes (1)
Event free survival (EFS)
Event free survival
Assessed at each end of randomization sequences up to one year
Study Arms (3)
phase induction-R-I
EXPERIMENTALR-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years. Patients with insufficient metastatic response at the end of induction chemotherapy, defined as SIOPEN score \> 3 or less than 50% reduction in mIBG score (or \> 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours), have a poorer prognosis. Chemoimmunotherapy arm Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy (TEMIRI/DB).
Phase high dose chemotherapy consolidation
EXPERIMENTALR-HDC: consolidation regimen Bu-Mel vs Thiotepa + Bu-Mel The 3-year EFS in the Bu-Mel arm (with immunotherapy) is estimated to be 55%. This study aims to show an improvement of 12% for the Thiotepa + Bu-Mel arm (3-year EFS of 67%). With a recruitment of 448 patients (224 in each arm) over a period of 3 years and a minimum follow-up of 2 years, the power to show a 12% difference is 80% (two-sided logrank test and α=5%).
Phase of radiotherapy
EXPERIMENTALR-RTx: 21.6 Gy radiotherapy vs 21.6 Gy + 14.4 Gy boost in patients with macroscopic residual disease
Interventions
\< 9kg: 1.0 mg/kg/dose 9 kg to \< 16 kg : 1.2 mg/kg/dose 16 kg to 23 kg : 1.1 mg/kg/dose \>23 kg to 34 kg: 0.95 mg/kg/dose \>34 kg: 0.8 mg/kg/dose Infusion IV over 2 hours Administration every 6 hours for a total of 16 doses
140 mg/m2/dose IV short infusion (15'), at least 24 h after the last busulfan dose
300 mg/m2/day over 2 hours
Patients \>12 kg are dosed based on the BSA: 10 mg/m\^2/day Patients ≤ 12 kg are dosed according to their body weight: 0.33 mg/kg/day
Cyclophosphamide has been demonstrated to have a cytostatic effect in many tumour types. The active metabolites of cyclophosphamide are alkylating agents which transfer alkyl groups to DNA during the process of cell division, thus preventing normal synthesis of DNA.
Eligibility Criteria
You may qualify if:
- Enrollment in HR-NBL2 will be performed:
- at diagnosis before the beginning of chemotherapy or
- up to 21 days after one course of Carboplatin-Etoposide for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification or patients with metastatic neuroblastoma treated in emergency or
- up to 21 days after one course of the current protocol for R-I randomisation (RAPID COJEC/GPOH) low/intermediate risk neuroblastoma in Germany/Netherlands for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification
- HR-NBL2 eligibility criteria:
- Established diagnosis of neuroblastoma according to the SIOPEN- modified International Neuroblastoma Risk Group (INRG) criteria, High-risk neuroblastoma defined as:
- Stage M neuroblastoma above 365 days of age at diagnosis (no upper age limit) and Ms neuroblastoma 12-18 months old, any MYCN status or
- L2, M or Ms neuroblastoma any age with MYCN amplification, or focal high level MYC or MYCL amplification.
- In Germany, patients aged less than 18 months with stage M and without MYCN amplification will not be enrolled in HR-NBL2 trial.
- No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposide chemotherapy for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification or patients with metastatic neuroblastoma treated in emergency or up to 21 days after one course of the current protocol for low/intermediate risk neuroblastoma in Germany/Netherlands for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification
- Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active patients must agree to use acceptable and appropriate contraception while on HR-NBL2 study and for one year after stopping the study. Acceptable contraception is defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials" (Appendix 11). Female patients who are lactating must agree to stop breast-feeding.
- Written informed consent to enter the HR-NBL2 protocol from patient or parents/legal representative, patient, and age-appropriate assent.
- Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
- Patients should be able and willing to comply with study visits and procedures as per protocol
- R-I eligibility criteria:
- +1 more criteria
You may not qualify if:
- R-HDC randomisation (Single HDC Bu-Mel/ Tandem HDC Thiotepa+Bu-Mel) Etoposide or one course of the current protocol for low/intermediate risk neuroblastoma in Germany/Netherlands). Patients will be treated with the standard induction regimen per country (Rapid COJEC or GPOH) and will be potentially eligible for subsequent randomisations.
- Randomisation for HDC strategy will be performed at the end of induction after the disease evaluation and after surgery of the primary tumour for those patients who will receive surgery before HDC.
- R-HDC eligibility criteria:
- \- Stage M neuroblastoma above 365 days of age at diagnosis, any MYCN status, EXCEPT patients with stage M or Ms 12-18 months old with numerical chromosomal alterations only, and in complete metastatic response at the end of induction: in this case, patients will have surgery and no further treatment.
- \- L2, M or Ms neuroblastoma, any age, with MYCN amplification, or focal high level MYC or MYCL amplification
- Age \< 21 years at the time of randomization
- Complete response (CR) or partial response (PR) at metastatic sites:
- Bone disease: mIBG uptake completely resolved or SIOPEN score ≤ 3 and at least 50% reduction in mIBG score (or ≤ 3 bone lesions and at least 50% reduction in number of FDG- PET-avid bone lesions for mIBG-nonavid tumours).
- Bone marrow disease: CR and/or minimal disease (MD) according to International Neuroblastoma Response Criteria
- Other metastatic sites: CR. (after induction chemotherapy +/- surgery), except for distant lymph nodes for which PR is accepted with a possible secondary surgery
- Acceptable organ function and performance status:
- Performance status ≥ 50%.
- Hematological status: ANC\>0.5x109/L, platelets \> 20x 109/L
- Cardiac function: (\< grade 2)
- Normal chest X-Ray and oxygen saturation.
- +49 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (142)
Sydney children Hospital
Sydney, Randwick, NSW, 2031, Australia
Children's Cancer Centre, Monash Children's Hospital
Clayton, VIC 3168, Australia
Oncology/Haematology Department, Perth Children's Hospital
Nedlands, WA, 6009, Australia
Children's Cancer & Haematology Services, John Hunter Children's Hospital
New Lambton Heights, NSW, 2305, Australia
Australian and New Zealand Children's Hematology/oncology Group
Sydney, NSW, 2031, Australia
sydney children Hospital
Sydney, NSW, 2031, Australia
Cancer Centre for Children, The Children's Hospital
Westmead, NSW, 2145,, Australia
Medical University Graz
Graz, Austria
Landeskrankenhaus-Universitätsklinikum Innsbruck
Innsbruck, Austria
Kepler Universitatsklinikum Linz
Linz, Austria
Universitastsklinikum Salzburg
Salzburg, Austria
St Anna'S Children Hospital
Vienna, A-1090, Austria
Hôpital Universitaire des Enfants Reine Fabiola (ULB)
Brussels, 1020, Belgium
Cliniques Universitaires Saint-Luc (UCL)
Brussels, 1200, Belgium
University Hospital Gent
Ghent, 9000, Belgium
University Hospitals Leuven
Leuven, 3000, Belgium
CHR Citadelle
Liège, 4000, Belgium
University Hospital Motol
Prague, Prague, 15006, Czechia
Klinika dětské onkologie FN Brno
Brno, 662 63, Czechia
Aarhus University Hospital
Aarhus, DK-8200, Denmark
Department of Paediatrics and Adolescent Medicine, Rigshospitalet
Copenhagen, DK-2100, Denmark
The Hans Christian Andersen Children's Hospital, University of Southern Denmark
Odense, DK-5000, Denmark
New Children's Hospital, Helsinki University Hospital, Helsinki and Uusimaa Hospital District
Helsinki, 00029, Finland
Kuopio University Hospital
Kuopio, Finland
Oulu University Hospital
Oulu, Finland
Tampere University Hospital
Tampere, Finland
Turku University Hospital
Turku, Finland
Gustave Roussy
Villejuif, Val De Marne, 94800, France
CHU d'AMIENS
Amiens, 80054, France
CHU angers
Angers, France
CHU-Pôle Médico-Chirurgical de l'Enfant et l'Adolescant
Besançon, France
CHU Bordeaux
Bordeaux, 33600, France
Groupe Hospitalier Pellegrin - Chu - Bordeaux
Bordeaux, France
CHU Brest
Brest, 29609, France
CHU Brest - Hôpital du Morvan
Brest, France
Centre François Baclesse
Caen, France
CHU de Caen
Caen, France
CHU Estaing
Clermont-Ferrand, France
Centre Georges-François Leclerc
Dijon, France
Hopital d'enfants Marechal de lattre
Dijon, France
Hôpital Couple-Enfant CHU de Grenoble
Grenoble, France
Chu de La Reunion - St Denis
La Réunion, France
centre Oscar lambert
Lille, France
Hôpital de la Mère et de l'Enfant - CHU Limoges
Limoges, France
Centre Léon Berard
Lyon, France
hopital la Timone
Marseille, France
CHRU Nancy-Hôpital Brabois Enfant
Nancy, France
Institut de cancérologie de Loraine
Nancy, France
Centre Antoine Lacassagne
Nice, France
CHU Nice-Hôpital d'Archet
Nice, France
Hôpital Armand Trousseau
Paris, France
institut Curie
Paris, France
CHU Poitiers
Poitiers, France
Hôpital Américain -CHU Reims
Reims, France
Centre Eugène Marquis
Rennes, France
CHU Rennes
Rennes, France
Hôpital des Enfants - CHU Rouen
Rouen, France
CHU Saint Etienne
Saint-Etienne, France
Institut de cancérologie de l'Ouest - Sité René Gauducheau
Saint-Herblain, France
CHU Haute Pierre
Strasbourg, France
Institut de Cancérologie Strasbourg
Strasbourg, France
Hopital des enfants-CHU Toulouse
Toulouse, France
IUCT Oncopole
Toulouse, France
CHU Tours Hôpital Clocheville
Tours, France
charite universitatsmedizin Berlin
Berlin, 13353, Germany
Uniklinik Köln, Klinik und Poliklinik für Kinder und Jugendmedizin
Cologne, 50937, Germany
Children's General Hospital "I AGHIA SOFIA"
Athens, 11527, Greece
Children's General Hospital "P. & A. KYRIAKOU"
Athens, 11527, Greece
"MITERA" Private, General, Obstetrics - Gynaecology, Paediatric Clinic S.A.
Athens, 15123, Greece
Children's General Hospital "AGHIA SOFIA"
Athens, Greece
University General Hospital of Heraklion (UnGHH)
Heraklion, 71500, Greece
University General Hospital of Thessaloniki "AHEPA"
Thessaloniki, 54621, Greece
General Hospital of Thessaloniki "IPPOKRATIO"
Thessaloniki, 54642, Greece
RAMBAM Medical Center
Haifa, Israel
A.O.U Policlinico di Bari
Bari, 70124, Italy
Spedali civili Ospedale Dei Bambini Oncoematologia pediatrica e TMO
Brescia, 3995041, Italy
policlinico rodolico San marco
Catania, 95123, Italy
Azienda ospedaliero universtaria Anna Meyer
Florence, 50139, Italy
instituto Giannina Gaslini genova
Genova, 16147, Italy
IRCCS "Istituto Giannina Gaslini"
Genova, 16147, Italy
Azienda Policlinico di Modena
Modena, 41100, Italy
Azienda ospedaliero universitaria di Parma
Parma, 43126, Italy
Policlino San matteo di Pavia
Pavia, 27100, Italy
U.O Pediatria, SS Oncoematologia pediatrica
Rimini, 47900, Italy
IRCCS Burlo Garoflo oncoematologia
Trieste, 34137, Italy
U.O.C oncoematologia pediatrica ospedale Donna Bambino
Verona, 37126, Italy
Vilnius University Hospital Santaros Klinikos
Vilnius, 08406, Lithuania
National Cancer Institute
Vilnius, 08660, Lithuania
Universitair Medisch Centrum Groningen
Groningen, 9700, Netherlands
Princess Maxima center
Utrecht, 3584CS, Netherlands
Haukeland University Hospital
Haukeland, Norway
Oslo University Hospital
Oslo, 0424, Norway
University Hospital Northern Norway, Tromsoe
Tromsø, Norway
St Olavs Hospital,
Trondheim, Norway
Children's University Hospital Banská Bystrica
Banská Bystrica, 974 09, Slovakia
NÚDCH- National Institute of Children's Diseases,
Bratislava, 833 40, Slovakia
Children's University Hospital Košice
Košice, 040 11, Slovakia
University medical center Ljubljana, University Children's Hospital Ljubljana, Slovenia
Ljubljana, 1000, Slovenia
Hospital Universitario Son Espases
Balea, 07010, Spain
Hospital Universitario Vall D´Hebron
Barcelona, 08035, Spain
Hospital Universitario Cruces
Cruces, 48903, Spain
Hospital Clínico Universitario Virgen de la Arrixaca
El Palmar, 30120, Spain
Hospital Universitario Infantil Niño Jesús
Madrid, 28009, Spain
Hospital Universitario La Paz
Madrid, 28046, Spain
Hospital Regional Universitario de Málaga
Málaga, 29010, Spain
Hospital Universitario Donostia
San Sebastián, 20014, Spain
Hospital Clínico Universitario de Santiago
Santiago de Compostela, 15706, Spain
Hospital Universitario Virgen del Rocío
Seville, 41013, Spain
Hospital Universitario Politécnico de La FE
Valencia, Spain
Sahlgrenska University Hospital
Gothenburg, Sweden
Linköping University Hospital
Linköping, Sweden
Skåne University Hospital
Lund, Sweden
Karolinska University Hospital, Stockholm
Stockholm, Sweden
Norrland University Hospital
Umeå, Sweden
Uppsala University Hospital
Uppsala, Sweden
Kantonsspital Aarau AG Klinik für Kinder und Jugendliche
Aarau, CH-5001, Switzerland
Universitäts-Kinderspital beider Basel (UKBB)
Basel, CH-4031, Switzerland
Ospedale San Giovanni Pediatria, Emato-oncologia pediatrica
Bellinzona, CH-6500, Switzerland
Inselspital, Universitätsklinik für Kinderheilkunde
Bern, CH-3010, Switzerland
HUG Hôpitaux Universitaires de Genève Unité d'Hémato-Oncologie Pédiatrique
Geneva, CH-1205, Switzerland
CHUV - Centre Hospitalier Universitaire Vaudois
Lausanne, CH-1011, Switzerland
Luzerner Kantonsspital, Kinderspital pädiatrische Hämatologie/Onkologie
Lucerne, CH-6000, Switzerland
Ostschweizer Kinderspital Hämatologie/Onkologie Claudiusstrasse 6
Sankt Gallen, CH-9006, Switzerland
Division of Pediatric Oncology Universitäts-Kinderspital Zürich
Zurich, CH-8032, Switzerland
Royal Aberdeen Children's Hospital
Aberdeen, United Kingdom
Royal Belfast Hospital for Sick Children
Belfast, United Kingdom
Birmingham children's Hospital
Birmingham, B46NH, United Kingdom
University Hospitals Birmingham Queen Elisabeth Hospital(UHB)
Birmingham, B46NH, United Kingdom
University Hospitals Bristol and Weston NHS Foundation Trust
Bristol, BS1 3NU, United Kingdom
Addenbrookes Hospital, Cambridge
Cambridge, United Kingdom
Noah's Ark Children's Hospital for Wales - Cardiff
Cardiff, United Kingdom
Royal Hospital for Sick Children - Edinburgh
Edinburgh, United Kingdom
Royal Hospital for Children Glasgow
Glasgow, G34, United Kingdom
Leeds General Infirmary
Leeds, United Kingdom
Alder Hey Children's Hospital - Liverpool
Liverpool, United Kingdom
Great Ormond Street Hospital - London
London, United Kingdom
Royal Manchester Children's Hospital
Manchester, United Kingdom
Royal Victoria Infirmary, Newcastle
Newcastle, United Kingdom
Nottingham Children's Hospital
Nottingham, United Kingdom
Sheffield Children's Hospital
Sheffield, S102TH, United Kingdom
Southampton General Hospital
Southampton, United Kingdom
Royal Marsden Hospital
Sutton, SM2 5PT, United Kingdom
MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- STUDY CHAIR
Claudia Pasqualini, MD PhD
Gustave roussy, Paris, France
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 6, 2020
First Posted
January 9, 2020
Study Start
November 5, 2019
Primary Completion (Estimated)
November 1, 2026
Study Completion (Estimated)
November 1, 2032
Last Updated
June 26, 2025
Record last verified: 2025-06
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, ICF, CSR