High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)

NCT01704716 | Recruiting Phase 3 DMC

• 1 other identifier: HR-NBL-1.8 / SIOPEN
• Study Type: interventional
• Target: 3,300
• Locations: 18 countries
• Sites: 120

Brief Summary

This is a randomized study of the European SIOP Neuroblastoma Group (SIOPEN) in high-risk neuroblastoma (stages 2, 3, 4 and 4s MYCN-amplified neuroblastoma, stage 4 MYCN non amplified \> 12 months at diagnosis). The protocol consists of a rapid, dose intensive induction chemotherapy, peripheral blood stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour and immunotherapy (R4 randomization - isotretinoin and ch14.18/CHO (Dinutuximab beta, Qarziba ®).), with or without s.c. aldesleukin (IL-2)). Patients diagnosed after the closure of R3 randomization will not be R4 randomized. For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as continuous infusion as standard of care outside of controlled trials. ch14.18/CHO received marketing authorization by EMA in May 2017 (Qarziba ®). In the induction phase, all patients receive Rapid COJEC following the result of the R3 randomization which was closed on June 8th, 2017 after inclusion of 630 patients as planned. Following induction treatment peripheral blood stem cell harvest (PBSCH) is performed and complete excision of the primary tumour will be attempted. Patients with an inadequate metastatic response to allow BuMel MAT followed by PBSCR at the end of induction should receive 2 TVD (Topotecan, Vincristine, Doxorubicin) cycles. After Rapid COJEC induction, localized patients will proceed to consolidation. Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without segmental chromosomal alterations (SCAs) are thought to have a good prognosis and will stop treatment after induction therapy and surgery to the primary tumour. Consolidation consists of BuMel MAT based on the results of the R1 randomization followed by peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour. The R2 immunotherapy randomization using ch14.18/CHO as 8 hour infusion on 5 consecutive days ( total dose (100mg/m²) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) is closed. The amended R4 immunotherapy randomization using ch14.18/CHO as continuous infusion (total dose 100mg/m² over 10 days) with or without aldesleukin (IL-2) alternated with isotretinoin (13-cis-RA) has accrued according to plan with results pending awaiting data maturity and DMC approval.

Conditions

Neuroblastoma

Keywords

neuroblastoma; immunotherapy; MAT; antibody treatment

Outcome Measures

Primary Outcomes (4)

• Event Free Survival (R1: MAT therapy)

  The primary endpoint was the event free survival (EFS) calculated from the date of the first R1 randomisation. The following was considered as event: * disease progression or relapse * death from any cause * second neoplasm Patients lost to follow up without event were considered at the date of their last follow up evaluation. R1 has been closed in October 2010 following the results of R1 randomisation showing significant superiority for myeloablative therapy (MAT) with busulfan and melphalan (BuMel) in patients with high risk neuroblastoma over MAT with continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT.

  Up to three years

• Event Free Survival (immunotherapy)

  R2 randomisation comparing immunotherapy with ch14.18/CHO and 13-cis retinoic acid versus 13-cis retinoic acid alone was activated in November 2006. It was amended in July 2009 and compares immunotherapy with anti GD2 antibody ch14.18/CHO with or without aldesleukin (IL-2). Immunotherapy randomisation has been amended in 2014 (R4 randomisation). The ch14.18/CHO antibody is given as continuous Infusion and the randomisation has lasted until the necessary number of patients for R3 randomisation was reached The primary endpoint is 3-year event free survival calculated from the date of the second randomisation. The following will be considered as events: * disease progression or relapse * death from any cause * second neoplasm Patients lost to follow up without event will be censored at the date of their last follow-up evaluation.

  Up to three years

• Complete metastatic response (R3: Induction therapy)

  R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7. Complete metastatic response after induction is defined as: * no skeletal uptake on mIBG * Negative bone marrow aspirates (by cytomorphology) and trephines * Absence of other metastatic sites

  Up to 95 days

• Event free survival (R3: Induction therapy)

  R3 randomisation compares two different induction therapy regimen, Rapid COJEC and modified N7. The primary endpoint is event free survival calculated from the date of the R3-randomisation. The following will be calculated as events: * disease progression or relapse * death from any cause * second neoplasm Patients lost to follow up without event will be censored at the date of their last follow up evaluation

  Up to three years

Study Arms (10)

R0: COJEC plus G-CSF

EXPERIMENTAL

Patients randomised to G-CSF during induction treatment (Rapid COJEC) received a single daily subcutaneous injection of 5 microgram/kg/day G-CSF (filgrastim) beginning 24 hours after the last chemotherapy dose.

Drug: Carboplatin; Drug: Etoposide; Drug: Cisplatin; Drug: Cyclophosphamide; Drug: G-CSF

R0: COJEC

ACTIVE COMPARATOR

Induction treatment (COJEC) without filgrastim Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF

Drug: Vincristine; Drug: Carboplatin; Drug: Etoposide; Drug: Cisplatin; Drug: Cyclophosphamide

R1: BuMel MAT

ACTIVE COMPARATOR

The BuMel MAT regimen consists of oral administration of busulphan and the short i.v. infusion of melphalan. In July 2007 (amendment 3) oral busulfan was changed to i.v. Busulfan (Busilvex)

Drug: Busulfan; Drug: Melphalan

R1: CEM MAT

EXPERIMENTAL

The CEM MAT regimen uses three drugs: the dose of Carboplatin must be based on renal function with a target area under the concentration versus time curve (AUC) of 16.4 mg/ml.min, etoposide 350 mg/m2/course and melphalan 210 mg/m2/course

Drug: Carboplatin; Drug: Etoposide; Drug: Melphalan

R2: ch14.18/CHO

ACTIVE COMPARATOR

ch14.18/CHO is given at a dose of 20 mg/m2/day over five days every four weeks for five courses

Drug: ch14.18/CHO

R2: ch14.18/CHO plus Aldesleukin

EXPERIMENTAL

Patients randomised to receive ch14.18/CHO plus Aldesleukin

Drug: Aldesleukin; Drug: ch14.18/CHO

R3: COJEC Induction

ACTIVE COMPARATOR

Rapid COJEC induction treatment is applied over ten weeks; three different courses are given every ten days: Course A (given on days 0 and 40): vincristine, carboplatin, and etoposide Course B (given on days 10, 30, 50, and 70): vincristine and cisplatin Course C (given on days 20 and 60): vincristine, etoposide, and cyclophosphamide

Drug: Vincristine; Drug: Carboplatin; Drug: Etoposide; Drug: Cisplatin; Drug: Cyclophosphamide

R3: Modified N7

EXPERIMENTAL

The modified N7 induction is a dose intense induction chemotherapy regimen including two putatively non cross-resistent drug combinations: high-dose cyclophosphamide plus doxorubicin/vincristine (CAV) and high-dose cisplatin/etoposide (P/E).

Drug: Vincristine; Drug: Etoposide; Drug: Cisplatin; Drug: Cyclophosphamide; Drug: Doxorubicin

R4: cnt inf ch14.18/CHO

ACTIVE COMPARATOR

ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO

Drug: ch14.18/CHO

R4: cnt inf ch14.18/CHO plus Aldesleukin

EXPERIMENTAL

ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO. In addition, Aldesleukin is given at a dose of 3 x 10e6 on days 1 to 5 and on days 9, 11, 13, 15, and 17 during ch14.18/CHO infusion

Drug: Aldesleukin; Drug: ch14.18/CHO

Interventions

Vincristine DRUG

given during Rapid COJEC and modified N7 therapy

R0: COJEC; R3: COJEC Induction; R3: Modified N7

Aldesleukin DRUG

Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2

Also known as: Interleukin 2, IL-2, IL2

R2: ch14.18/CHO plus Aldesleukin; R4: cnt inf ch14.18/CHO plus Aldesleukin

ch14.18/CHO DRUG

ch14.18/CHO antibody is given during MRD treatment

Also known as: anti GD2 antibody, Dinutuximab beta EUSA, Qarziba®

R2: ch14.18/CHO; R2: ch14.18/CHO plus Aldesleukin; R4: cnt inf ch14.18/CHO; R4: cnt inf ch14.18/CHO plus Aldesleukin

Carboplatin DRUG

Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)

Also known as: Paraplatin

R0: COJEC; R0: COJEC plus G-CSF; R1: CEM MAT; R3: COJEC Induction

Etoposide DRUG

Etoposide is given during Induction Treatment (both R3 randomisation arms)

Also known as: VP16

R0: COJEC; R0: COJEC plus G-CSF; R1: CEM MAT; R3: COJEC Induction; R3: Modified N7

Cisplatin DRUG

Cisplatin is given during Induction Treatment (both R3 randomisation arms)

Also known as: CDDP

R0: COJEC; R0: COJEC plus G-CSF; R3: COJEC Induction; R3: Modified N7

Cyclophosphamide DRUG

Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)

Also known as: Endoxan

R0: COJEC; R0: COJEC plus G-CSF; R3: COJEC Induction; R3: Modified N7

Doxorubicin DRUG

Doxorubicin is given during Induction Treatment (R3 arm modified N7)

Also known as: Adriamycin

R3: Modified N7

G-CSF DRUG

G-CSF is given during Induction Treatment

Also known as: Filgrastim

R0: COJEC plus G-CSF

Busulfan DRUG

In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.

Also known as: Busilvex, Myleran, Busulphan

R1: BuMel MAT

Melphalan DRUG

Melphalan is given during MAT treatment

Also known as: Alkeran

R1: BuMel MAT; R1: CEM MAT

Eligibility Criteria

• Age: 1 Month - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Established diagnosis of neuroblastoma according to the International Neuroblastoma Staging System (INSS).
• Age below 21 years.
• High risk neuroblastoma defined as either:
• INSS stage 2, 3, 4, and 4s with MYCN amplification, or
• INSS stage 4 without MYCN amplification aged \> 12 months at diagnosis
• Patients who have received no previous chemotherapy except for one cycle of etoposide and carboplatin (VP16/Carbo). In this situation patients will receive Rapid COJEC induction and the first Rapid COJEC cycle may be replaced by the first cycle VP16/Carbo (etoposide / carboplatin).
• Written informed consent, including agreement of parents or legal guardian for minors, to enter a randomised study if the criteria for randomisation are met.
• Tumour cell material available for determination of biological prognostic factors.
• Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
• Registration of all eligibility criteria with the data centre within 6 weeks from diagnosis.
• Provisional follow up of 5 years.
• National and local ethical committee approval.

Sponsors & Collaborators

• St. Anna Kinderkrebsforschung: lead

Study Sites (126)

Women and Children´s Hospital

Adelaide, Australia

RECRUITING

Lady Cilento Children´s Hospital

Brisbane, Australia

RECRUITING

John Hunter Children's Hospital

Newcastle, Australia

RECRUITING

Royal Children's Hospital Melbourne

Parkville, Australia

RECRUITING

Sydney Children's Hospital

Sydney, Australia

RECRUITING

Children´s Hospital Westmead

Westmead, Australia

RECRUITING

St. Anna Kinderspital

Vienna, Austra, 1090, Austria

RECRUITING

Univ.-Klinik für Kinder- und Jugendheilkunde Graz

Graz, Austria

RECRUITING

Univ.Klinik f. Kinder-u. Jugendheilkunde Innsbruck

Innsbruck, Austria

RECRUITING

Landes- Kinderklinik Linz

Linz, Austria

RECRUITING

St. Johanns Spital LKH Salzburg

Salzburg, Austria

RECRUITING

Cliniques universitaires St-Luc

Brussels, Belgium

RECRUITING

Hôpital des Enfants

Brussels, Belgium

RECRUITING

University Hospital Gent

Ghent, Belgium

RECRUITING

UZ Gasthuisberg

Leuven, Belgium

RECRUITING

CHR Citadelle

Liège, Belgium

RECRUITING

Clinique de l'Espérance

Montegnée, Belgium

RECRUITING

University Hospital Motol

Prague, Czechia

RECRUITING

Aarhus Universitetshospital

Aarhus, Denmark

RECRUITING

National State Hospital

Copenhagen, Denmark

RECRUITING

University Hospital of Odense

Odense, Denmark

RECRUITING

Skejby Hospital

Skejby, Denmark

RECRUITING

Hopital d'Enfants Dijon

Dijon, France

RECRUITING

CHU de Grenoble

Grenoble, France

RECRUITING

CHR Pellegrin

Le Pellerin, France

RECRUITING

Centre Oscar Lambret de Lille

Lille, France

RECRUITING

Hopitaux de Marseille La Timone

Marseille, France

RECRUITING

CHR de Nantes

Nantes, France

RECRUITING

Hôpital Trousseau Paris

Paris, France

RECRUITING

Institut Curie

Paris, France

RECRUITING

Hôpital American Memorial Hospital

Reims, France

RECRUITING

CHU-Saint Etienne

Saint-Etienne, France

RECRUITING

Hôpital de Hautepierre

Strasbourg, France

RECRUITING

Hôpital D'Enfants de Toulouse

Toulouse, France

RECRUITING

Institut Gustave Roussy

Villejuif, France

RECRUITING

"A&P Kyriakou" Children's Hospital

Athens, Greece

RECRUITING

Aghia Sophia Children's Hospital

Athens, Greece

RECRUITING

MITERA Hospital

Heraklion, Greece

RECRUITING

PEPAGNH University Hospital

Heraklion, Greece

RECRUITING

Madarász Children Hospital Budapest

Budapest, Hungary

RECRUITING

Semmelweis University of Budapest

Budapest, Hungary

RECRUITING

University of Debrecen

Debrecen, Hungary

RECRUITING

University of Pecs

Pécs, Hungary

RECRUITING

University of Szeged

Szeged, Hungary

RECRUITING

Dublin: OLHSC

Dublin, Ireland

RECRUITING

Rambam Medical Centre

Haifa, Israel

RECRUITING

Schneider Children's Medical Center of Israel

Petah Tikva, Israel

RECRUITING

Sheba Medical Center

Tel Aviv, Israel

RECRUITING

Ospedale G. Salesi

Ancona, Italy

RECRUITING

Universitŕ degli studi di Bari

Bari, Italy

RECRUITING

Ospedali Riuniti

Bergamo, Italy

RECRUITING

Ospedale S. Orsola

Bologna, Italy

RECRUITING

Ospedale Regionale per le Microcitemie

Cagliari, Italy

RECRUITING

Azienda Ospedaliera di Cosenza

Cosenza, Italy

RECRUITING

Azienda Ospedaliera A. Meyer

Florence, Italy

RECRUITING

Istituto Giannina Gaslini

Genoa, Italy

RECRUITING

Istituto Nazionale Tumori di Milano

Milan, Italy

RECRUITING

Azienda Ospedal. Univ. di Modena

Modena, Italy

RECRUITING

Sec. Univ. degli Studi di Napoli - Policlinico

Napoli, Italy

RECRUITING

Clinica di Oncoematologia Pediatrica Padova

Padua, Italy

RECRUITING

Ospedale dei Bambini, Palermo

Palermo, Italy

RECRUITING

Azienda Ospedaliera Universitaria di Parma-Oncoematologia Pediatrica

Parma, Italy

RECRUITING

Policlinico San Matteo

Pavia, Italy

RECRUITING

Ospedale Civile Spirito Santo

Pescara, Italy

RECRUITING

Ospedale "Infermi "

Rimini, Italy

RECRUITING

Policlinico Borgo Roma

Roma, Italy

RECRUITING

Ospedale Bambino Gesu

Rome, Italy

RECRUITING

Casa Sollievo della Sofferenza

San Giovanni Rotondo, Italy

RECRUITING

O.I.R.M. - S. Anna

Torino, Italy

RECRUITING

Istituto per l'Infanzia "Burlo Garofolo"

Trieste, Italy

RECRUITING

Haukeland University Hospital

Bergen, Norway

RECRUITING

Rikshospitalet

Oslo, Norway

RECRUITING

University Hospital of North-Norway

Tromsø, Norway

RECRUITING

Medical University of Bialystok

Bialystok, Poland

RECRUITING

Medical University of Bydgoszcz

Bydgoszcz, Poland

RECRUITING

Childrens' Hospital in Chorzów

Chorzów, Poland

RECRUITING

Medical University in Gdansk

Gdansk, Poland

RECRUITING

Upper Silesian Centre of Child and Mother's Care

Katowice, Poland

RECRUITING

University Children's Hospital

Krakow, Poland

RECRUITING

Children's University Hospital in Lublin

Lublin, Poland

RECRUITING

University of Medical Sciences Poznan

Poznan, Poland

RECRUITING

Institute Mother and Child

Warsaw, Poland

RECRUITING

Wroclaw Medical University

Wroclaw, Poland

RECRUITING

Ipofg-Crl

Lisbon, Portugal

RECRUITING

University Hospital F. D. Roosevelt

Banská Bystrica, Slovakia

RECRUITING

University Children's Hospital Ljubljana

Ljubljana, 10000, Slovenia

RECRUITING

H . Materno-Infantil Teresa Herrera

A Coruña, Spain

RECRUITING

H. General de Alicante

Alicante, Spain

RECRUITING

Hospital Vall d'Hebron

Barcelona, Spain

RECRUITING

Hospital de Cruces

Bilbao, Spain

RECRUITING

Complejo Hospitalario de Jaen

Jaén, Spain

RECRUITING

H. Monteprincipe

Madrid, Spain

RECRUITING

Hospital 12 de Octubre

Madrid, Spain

RECRUITING

H Central de Asturias

Oviedo, Spain

RECRUITING

H. C. U. de Salamanca

Salamanca, Spain

RECRUITING

H. de Donostia Ntra. Sra. de Aranzazu

San Sebastián, Spain

RECRUITING

H. General de Galicia

Santiago de Compostela, Spain

RECRUITING

Hospital Virgen del Rocio

Seville, Spain

RECRUITING

Carlos Haya

Valencia, Spain

RECRUITING

Hospital Infantil La Fe

Valencia, Spain

RECRUITING

H Clinico-Universitario

Zaragoza, Spain

RECRUITING

Queen Silvia's Children's Hospital

Göteburg, Sweden

RECRUITING

Childrens Hospital Linkoping

Linköping, Sweden

RECRUITING

University Children's Hospital

Geneva, Switzerland

RECRUITING

CHUV

Lausanne, Switzerland

RECRUITING

Aberdeen: Royal Aberdeen Children's Hospital

Aberdeen, United Kingdom

RECRUITING

Royal Belfast Hospital for Sick Children

Belfast, United Kingdom

RECRUITING

Birmingham Children's Hospital

Birmingham, United Kingdom

RECRUITING

Bristol Royal Hospital for Children

Bristol, United Kingdom

RECRUITING

Addenbrooke's NHS Trust

Cambridge, United Kingdom

RECRUITING

Llandough Hospital

Cardiff, United Kingdom

RECRUITING

Edinburgh Royal Hospital for Sick Children

Edinburgh, United Kingdom

RECRUITING

Glasgow Royal Hospital for Sick Children

Glasgow, United Kingdom

RECRUITING

Leeds: St James's University Hospital

Leeds, United Kingdom

RECRUITING

Leicester Royal Infirmary

Leicester, United Kingdom

RECRUITING

Liverpool: Alder Hey Children's Hospital

Liverpool, United Kingdom

RECRUITING

Great Ormond Street Hospital

London, United Kingdom

RECRUITING

St Bartholomew's Hospital

London, United Kingdom

RECRUITING

UCLH University College London Hospital

London, United Kingdom

RECRUITING

Royal Manchester Children's Hospital

Manchester, United Kingdom

RECRUITING

Newcastle: Royal Victoria Infirmary

Newcastle, United Kingdom

RECRUITING

Nottingham: Queen's Medical Centre

Nottingham, United Kingdom

RECRUITING

Oxford: John Radcliffe Hospital

Oxford, United Kingdom

RECRUITING

Sheffield Children's Hospital

Sheffield, United Kingdom

RECRUITING

Southampton General Hospital

Southhampton, United Kingdom

RECRUITING

Royal Marsden Hospital

Sutton, United Kingdom

RECRUITING

Related Publications (10)

• Ladenstein R, Valteau-Couanet D, Brock P, Yaniv I, Castel V, Laureys G, Malis J, Papadakis V, Lacerda A, Ruud E, Kogner P, Garami M, Balwierz W, Schroeder H, Beck-Popovic M, Schreier G, Machin D, Potschger U, Pearson A. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul 20;28(21):3516-24. doi: 10.1200/JCO.2009.27.3524. Epub 2010 Jun 21.

  PMID: 20567002 RESULT

• Ladenstein R, Potschger U, Pearson ADJ, Brock P, Luksch R, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, de Lacerda AF, Beck-Popovic M, Bician P, Garami M, Trahair T, Canete A, Ambros PF, Holmes K, Gaze M, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D; SIOP Europe Neuroblastoma Group (SIOPEN). Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):500-514. doi: 10.1016/S1470-2045(17)30070-0. Epub 2017 Mar 2.

  PMID: 28259608 RESULT

• Ladenstein R, Potschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chan GCF, Ruud E, Schroeder H, Beck Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1617-1629. doi: 10.1016/S1470-2045(18)30578-3. Epub 2018 Nov 12.

  PMID: 30442501 RESULT

• Morgenstern DA, Potschger U, Moreno L, Papadakis V, Owens C, Ash S, Pasqualini C, Luksch R, Garaventa A, Canete A, Elliot M, Wieczorek A, Laureys G, Kogner P, Malis J, Ruud E, Beck-Popovic M, Schleiermacher G, Valteau-Couanet D, Ladenstein R. Risk stratification of high-risk metastatic neuroblastoma: A report from the HR-NBL-1/SIOPEN study. Pediatr Blood Cancer. 2018 Nov;65(11):e27363. doi: 10.1002/pbc.27363. Epub 2018 Jul 17.

  PMID: 30015396 RESULT

• Berbegall AP, Bogen D, Potschger U, Beiske K, Bown N, Combaret V, Defferrari R, Jeison M, Mazzocco K, Varesio L, Vicha A, Ash S, Castel V, Coze C, Ladenstein R, Owens C, Papadakis V, Ruud E, Amann G, Sementa AR, Navarro S, Ambros PF, Noguera R, Ambros IM. Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study. Br J Cancer. 2018 May;118(11):1502-1512. doi: 10.1038/s41416-018-0098-6. Epub 2018 May 14.

  PMID: 29755120 RESULT

• Mueller I, Ehlert K, Endres S, Pill L, Siebert N, Kietz S, Brock P, Garaventa A, Valteau-Couanet D, Janzek E, Hosten N, Zinke A, Barthlen W, Varol E, Loibner H, Ladenstein R, Lode HN. Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. MAbs. 2018 Jan;10(1):55-61. doi: 10.1080/19420862.2017.1402997. Epub 2017 Dec 5.

  PMID: 29120699 RESULT

• Ladenstein R, Potschger U, Valteau-Couanet D, Luksch R, Castel V, Ash S, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chi Fung Chan G, Ruud E, Schroeder H, Beck-Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN. Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1). Cancers (Basel). 2020 Jan 28;12(2):309. doi: 10.3390/cancers12020309.

  PMID: 32013055 RESULT

• Bellini A, Potschger U, Bernard V, Lapouble E, Baulande S, Ambros PF, Auger N, Beiske K, Bernkopf M, Betts DR, Bhalshankar J, Bown N, de Preter K, Clement N, Combaret V, Font de Mora J, George SL, Jimenez I, Jeison M, Marques B, Martinsson T, Mazzocco K, Morini M, Muhlethaler-Mottet A, Noguera R, Pierron G, Rossing M, Taschner-Mandl S, Van Roy N, Vicha A, Chesler L, Balwierz W, Castel V, Elliott M, Kogner P, Laureys G, Luksch R, Malis J, Popovic-Beck M, Ash S, Delattre O, Valteau-Couanet D, Tweddle DA, Ladenstein R, Schleiermacher G. Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). J Clin Oncol. 2021 Oct 20;39(30):3377-3390. doi: 10.1200/JCO.21.00086. Epub 2021 Jun 11.

  PMID: 34115544 DERIVED

• Holmes K, Potschger U, Pearson ADJ, Sarnacki S, Cecchetto G, Gomez-Chacon J, Squire R, Freud E, Bysiek A, Matthyssens LE, Metzelder M, Monclair T, Stenman J, Rygl M, Rasmussen L, Joseph JM, Irtan S, Avanzini S, Godzinski J, Bjornland K, Elliott M, Luksch R, Castel V, Ash S, Balwierz W, Laureys G, Ruud E, Papadakis V, Malis J, Owens C, Schroeder H, Beck-Popovic M, Trahair T, Forjaz de Lacerda A, Ambros PF, Gaze MN, McHugh K, Valteau-Couanet D, Ladenstein RL; International Society of Paediatric Oncology Europe Neuroblastoma Group (SIOPEN). Influence of Surgical Excision on the Survival of Patients With Stage 4 High-Risk Neuroblastoma: A Report From the HR-NBL1/SIOPEN Study. J Clin Oncol. 2020 Sep 1;38(25):2902-2915. doi: 10.1200/JCO.19.03117. Epub 2020 Jul 8.

  PMID: 32639845 DERIVED

• Viprey VF, Gregory WM, Corrias MV, Tchirkov A, Swerts K, Vicha A, Dallorso S, Brock P, Luksch R, Valteau-Couanet D, Papadakis V, Laureys G, Pearson AD, Ladenstein R, Burchill SA. Neuroblastoma mRNAs predict outcome in children with stage 4 neuroblastoma: a European HR-NBL1/SIOPEN study. J Clin Oncol. 2014 Apr 1;32(10):1074-83. doi: 10.1200/JCO.2013.53.3604. Epub 2014 Mar 3.

  PMID: 24590653 DERIVED

MeSH Terms

Conditions

Neuroblastoma

Interventions

Vincristine; aldesleukin; Interleukin-2; humanized 3F8 anti-GD2 monoclonal antibody; Carboplatin; Etoposide; Cisplatin; Cyclophosphamide; Doxorubicin; Granulocyte Colony-Stimulating Factor; Filgrastim; Busulfan; Melphalan

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Coordination Complexes; Organic Chemicals; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids

Study Officials

• Ruth L Ladenstein, MD, MBA, cPM

  St. Anna Kinderkrebsforschung

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ruth L Ladenstein, MD, MBA, cPM

CONTACT

0043140470; ruth.ladenstein@ccri.at

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2012
• First Posted: October 11, 2012
• Study Start: February 1, 2002
• Primary Completion: September 30, 2021
• Study Completion (Estimated): September 1, 2026
• Last Updated: October 23, 2020

Record last verified: 2020-10

Locations

PL (10); GR (4); ES (15); CH (2); DK (4); IE (1); GB (21); AU (6); BE (6); IL (3); SE (2); SL (1); CZ (1); FR (13); HU (5); PT (1); IT (22); NO (3)