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

Neuroblastoma Clinical Trial

Official title:

High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01704716
• Other study ID #: HR-NBL-1.8 / SIOPEN
• Status: Recruiting
• Phase: Phase 3
• Start date: February 2002
• Est. completion date: September 2026

Study information

• Verified date: October 2020
• Source: St. Anna Kinderkrebsforschung
• Contact: Ruth L Ladenstein, MD, MBA, cPM
• Phone: 0043140470
• Email: ruth.ladenstein[@]ccri.at
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

In this protocol the term high-risk neuroblastoma refers to children with either

• disseminated disease (INSS stage 4: about 40 to 50% of all neuroblastoma) over the age of one or

• INSS stage 2 and 3 disease with amplification of the MycN proto-oncogene Between 10% and 20% of children with stage 3 and occasional patients with stage 2 disease are characterized by amplification of the MycN gene in their tumours. This biological characteristic has clearly been shown to be associated with a greater risk of relapse and death from disease progression. These patients may benefit from very aggressive treatment and, based on this hypothesis, they are included in this protocol. Infants (< 12 months at diagnosis) with MYCN amplified tumors are included.

Children with this type of presentation and age represent the largest neuroblastoma subgroup. Their prognosis remains poor in most cases and our ability to predict the clinical course and the outcome of the individual patient is modest.

Primary objectives:

R0 randomization: R0 was opened with the study activation in February 2002 and closed in November 2005. The randomized use of G-CSF during COJEC induction resulted in the recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia (Ladenstein R, Valteau-Couanet D, Brock P, et al. 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;3516-24).

R1 randomization: R1 was opened with the study activation in February 2002 and closed in 10/2010 following the results showing significant superiority of myeloablative therapy (MAT) with busulfan and melphalan over continuous infusion of carboplatin, etoposide and melphalan (CEM). BuMel is now the standard MAT (Ladenstein R, Pötschger U, Pearson ADJ, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomized, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017 Apr;500-14).

R2 randomization: R2 was activated in November 2006 (13-cis retinoic acid +/- chimeric ch14.18/CHO antibody), modified in July 2009 and suspended in August 2013. R2 randomization tested the hypothesis that immunotherapy with ch14.18/CHO and subcutaneous aldesleukin (IL-2, Proleukin®), following MAT and autologous stem cell transplantation, in addition to differentiation therapy with 13-cis retinoic acid, will improve 3-year EFS in patients with high-risk neuroblastoma (ASCO 2016: Ladenstein R, et al J Clin Oncol 34, 2016 (suppl; abstr 10500)).

R3 randomization: R3 was opened in June 2011 and tests the hypothesis that modified N7 induction regimen will improve the metastatic response rates or event free survival (EFS) as compared to Rapid COJEC. As of June 8th, 2017 R3 randomization reached the target of 630 randomized patients as planned. There was no difference in event free survival rate between both regimens (Rapid COJEC and modified N7), but modified N7 had a significantly higher grade 3 and 4 toxicity profile. Therefore, Rapid COJEC is maintained as the SIOPEN standard induction treatment with G-CSF support based on the results of the R0 randomization open from 2002 top 2005 This change has been implemented in amendment 8 of the protocol.

R4 randomization: R4 was activated in April 2014. The SIOPEN long term infusion (LTI) ch14.18/CHO trial successfully lowered the toxicity profile by prolonging the infusion time of the same total ch14.18/CHO antibody dose of 100 mg/m² to 10 days of continuous infusion in relapsed /refractory patients. Hence the HRNBL1/SIOPEN study committee wished to implement this more favorable immunotherapy dosing schedule for the time till the induction question R3 was answered and the HRNBL1/SIOPEN trial may be closed. Considering the high R2 dropout rate of patients unable to receive all immunotherapy cycles in the IL-2 s.c. combination treatment arm and not observing this effect in the current SIOPEN LTI trial, it is suggested to address the IL-2sc dose in the new R4. Therefore the potential synergistic effect of sc IL-2 will be addressed again with 50% of the original s.c. IL-2 dose. The IL-2sc dose will hence be reduced to 3 x 106 IU IL-2/m2/day s.c. in the HR-NBL1/SIOPEN R4 amendment instead of 6 x 106 IU IL-2/m2/day s.c as used in the SIOPEN LTI trial. In the second week of each IT course s.c.IL-2 will be given on days 2, 4, 6, 8, 10 in parallel to the ch14.18/CHO ctn infusion and not during the first 5 days in week 2 as scheduled in the SIOPEN LTI trial. R4 randomization is closed for patients diagnosed after June 8th, 2017, the closure date of R3 randomization. For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as continuous infusion (total dose 100 mg/m² over 10 days) as standard of care outside of controlled trials without scIL-2. The ch14.18/CHO monoclonal antibody received marketing authorization by EMA in May 2017 (dinutuximab beta, Qarziba®).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3300
• Est. completion date: September 2026
• Est. primary completion date: September 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 21 Years

Eligibility

Inclusion Criteria:

• • Established diagnosis of neuroblastoma according to the International Neuroblastoma Staging System (INSS).

• Age below 21 years.

• High risk neuroblastoma defined as either:

1. INSS stage 2, 3, 4, and 4s with MYCN amplification, or

2. 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.

Exclusion Criteria:

Any negative answer concerning the inclusion criteria of the study

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Related Conditions & MeSH terms

• Neuroblastoma

Intervention

Drug:
• Vincristine
given during Rapid COJEC and modified N7 therapy
• Aldesleukin
Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2
• ch14.18/CHO
ch14.18/CHO antibody is given during MRD treatment
• Carboplatin
Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)
• Etoposide
Etoposide is given during Induction Treatment (both R3 randomisation arms)
• Cisplatin
Cisplatin is given during Induction Treatment (both R3 randomisation arms)
• Cyclophosphamide
Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)
• Doxorubicin
Doxorubicin is given during Induction Treatment (R3 arm modified N7)
• G-CSF
G-CSF is given during Induction Treatment
• Busulfan
In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.
• Melphalan
Melphalan is given during MAT treatment

Locations

Country	Name	City	State
Australia	Women and Children´s Hospital	Adelaide
Australia	Lady Cilento Children´s Hospital	Brisbane
Australia	John Hunter Children's Hospital	Newcastle
Australia	Royal Children's Hospital Melbourne	Parkville
Australia	Sydney Children's Hospital	Sydney
Australia	Children´s Hospital Westmead	Westmead
Austria	Univ.-Klinik für Kinder- und Jugendheilkunde Graz	Graz
Austria	Univ.Klinik f. Kinder-u. Jugendheilkunde Innsbruck	Innsbruck
Austria	Landes- Kinderklinik Linz	Linz
Austria	St. Johanns Spital LKH Salzburg	Salzburg
Austria	St. Anna Kinderspital	Vienna	Austra
Belgium	Cliniques universitaires St-Luc	Brussels
Belgium	Hôpital des Enfants	Brussels
Belgium	University Hospital Gent	Gent
Belgium	UZ Gasthuisberg	Leuven
Belgium	CHR Citadelle	Lüttich
Belgium	Clinique de l'Espérance	Montegnee
Czechia	University Hospital Motol	Prague
Denmark	Aarhus Universitetshospital	Aarhus
Denmark	National State Hospital	Copenhagen
Denmark	University Hospital of Odense	Odense
Denmark	Skejby Hospital	Skejby
France	Hopital d'Enfants Dijon	Dijon
France	CHU de Grenoble	Grenoble
France	CHR Pellegrin	Le Pellerin
France	Centre Oscar Lambret de Lille	Lille
France	Hopitaux de Marseille La Timone	Marseille
France	CHR de Nantes	Nantes
France	Hôpital Trousseau Paris	Paris
France	Institut Curie	Paris
France	Hôpital American Memorial Hospital	Reims
France	CHU-Saint Etienne	Saint Etienne
France	Hôpital de Hautepierre	Strasbourg
France	Hôpital D'Enfants de Toulouse	Toulouse
France	Institut Gustave Roussy	Villejuif
Greece	"A&P Kyriakou" Children's Hospital	Athens
Greece	Aghia Sophia Children's Hospital	Athens
Greece	MITERA Hospital	Heraklion
Greece	PEPAGNH University Hospital	Heraklion
Hungary	Madarász Children Hospital Budapest	Budapest
Hungary	Semmelweis University of Budapest	Budapest
Hungary	University of Debrecen	Debrecen
Hungary	University of Pecs	Pécs
Hungary	University of Szeged	Szeged
Ireland	Dublin: OLHSC	Dublin
Israel	Rambam Medical Centre	Haifa
Israel	Schneider Children's Medical Center of Israel	Petah Tiqwa
Israel	Sheba Medical Center	Tel Aviv
Italy	Ospedale G. Salesi	Ancona
Italy	Universitr degli studi di Bari	Bari
Italy	Ospedali Riuniti	Bergamo
Italy	Ospedale S. Orsola	Bologna
Italy	Ospedale Regionale per le Microcitemie	Cagliari
Italy	Azienda Ospedaliera di Cosenza	Cosenza
Italy	Azienda Ospedaliera A. Meyer	Firenze
Italy	Istituto Giannina Gaslini	Genua
Italy	Istituto Nazionale Tumori di Milano	Milano
Italy	Azienda Ospedal. Univ. di Modena	Modena
Italy	Sec. Univ. degli Studi di Napoli - Policlinico	Napoli
Italy	Clinica di Oncoematologia Pediatrica Padova	Padova
Italy	Ospedale dei Bambini, Palermo	Palermo
Italy	Azienda Ospedaliera Universitaria di Parma-Oncoematologia Pediatrica	Parma
Italy	Policlinico San Matteo	Pavia
Italy	Ospedale Civile Spirito Santo	Pescara
Italy	Ospedale "Infermi "	Rimini
Italy	Policlinico Borgo Roma	Roma
Italy	Ospedale Bambino Gesu	Rome
Italy	Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	O.I.R.M. - S. Anna	Torino
Italy	Istituto per l'Infanzia "Burlo Garofolo"	Trieste
Norway	Haukeland University Hospital	Bergen
Norway	Rikshospitalet	Oslo
Norway	University Hospital of North-Norway	Tromso
Poland	Medical University of Bialystok	Bialystok
Poland	Medical University of Bydgoszcz	Bydgoszcz
Poland	Childrens' Hospital in Chorzów	Chorzów
Poland	Medical University in Gdansk	Gdansk
Poland	Upper Silesian Centre of Child and Mother's Care	Katowice
Poland	University Children's Hospital	Kraków
Poland	Children's University Hospital in Lublin	Lublin
Poland	University of Medical Sciences Poznan	Poznan
Poland	Institute Mother and Child	Warschau
Poland	Wroclaw Medical University	Wroclaw
Portugal	Ipofg-Crl	Lissabon
Slovakia	University Hospital F. D. Roosevelt	Banská Bystrica
Slovenia	University Children's Hospital Ljubljana	Ljubljana
Spain	H. General de Alicante	Alicante
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital de Cruces	Bilbao
Spain	Complejo Hospitalario de Jaen	Jaen
Spain	H . Materno-Infantil Teresa Herrera	La Coruna
Spain	H. Monteprincipe	Madrid
Spain	Hospital 12 de Octubre	Madrid
Spain	H Central de Asturias	Oviedo
Spain	H. C. U. de Salamanca	Salamanca
Spain	H. de Donostia Ntra. Sra. de Aranzazu	San Sebastián
Spain	H. General de Galicia	Santiago De Compostela
Spain	Hospital Virgen del Rocio	Sevilla
Spain	Carlos Haya	Valencia
Spain	Hospital Infantil La Fe	Valencia
Spain	H Clinico-Universitario	Zaragoza
Sweden	Queen Silvia's Children's Hospital	Göteburg
Sweden	Childrens Hospital Linkoping	Linkoping
Switzerland	University Children's Hospital	Geneva
Switzerland	CHUV	Lausanne
United Kingdom	Aberdeen: Royal Aberdeen Children's Hospital	Aberdeen
United Kingdom	Royal Belfast Hospital for Sick Children	Belfast
United Kingdom	Birmingham Children's Hospital	Birmingham
United Kingdom	Bristol Royal Hospital for Children	Bristol
United Kingdom	Addenbrooke's NHS Trust	Cambridge
United Kingdom	Llandough Hospital	Cardiff
United Kingdom	Edinburgh Royal Hospital for Sick Children	Edinburgh
United Kingdom	Glasgow Royal Hospital for Sick Children	Glasgow
United Kingdom	Leeds: St James's University Hospital	Leeds
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Liverpool: Alder Hey Children's Hospital	Liverpool
United Kingdom	Great Ormond Street Hospital	London
United Kingdom	St Bartholomew's Hospital	London
United Kingdom	UCLH University College London Hospital	London
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	Newcastle: Royal Victoria Infirmary	Newcastle
United Kingdom	Nottingham: Queen's Medical Centre	Nottingham
United Kingdom	Oxford: John Radcliffe Hospital	Oxford
United Kingdom	Sheffield Children's Hospital	Sheffield
United Kingdom	Southampton General Hospital	Southhampton
United Kingdom	Royal Marsden Hospital	Sutton

Sponsors (1)

Lead Sponsor	Collaborator
St. Anna Kinderkrebsforschung

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Czechia,  Denmark,  France,  Greece,  Hungary,  Ireland,  Israel,  Italy,  Norway,  Poland,  Portugal,  Slovakia,  Slovenia,  Spain,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (7)

Berbegall AP, Bogen D, Pötschger 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. — View Citation

Ladenstein R, Pötschger 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, — View Citation

Ladenstein R, Pötschger 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 — View Citation

Ladenstein R, Pötschger 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, Pe — View Citation

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, Pötschger U, Pearson A. Randomized Trial of prophylactic gr — View Citation

Morgenstern DA, Pötschger 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 stratif — View Citation

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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