Clinical trial NCT01704716: High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)
Official title: High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Neuroblastoma
Keywords: neuroblastoma
immunotherapy
MAT
antibody treatment
Lead sponsor: St. Anna Kinderkrebsforschung
Sponsor class: OTHER
First posted: 2012-10-11
Enrollment: 3300
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed 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®).

Eligibility criteria: 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

-

Primary outcomes:
measure: Event Free Survival (R1: MAT therapy)
timeFrame: Up to three years
measure: Event Free Survival (immunotherapy)
timeFrame: Up to three years
measure: Complete metastatic response (R3: Induction therapy)
timeFrame: Up to 95 days
measure: Event free survival (R3: Induction therapy)
timeFrame: Up to three years
Secondary outcomes:
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Women and Children´s Hospital
city: Brisbane
country: Australia
facility: Lady Cilento Children´s Hospital
city: Newcastle
country: Australia
facility: John Hunter Children's Hospital
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne
city: Sydney
country: Australia
facility: Sydney Children's Hospital
city: Westmead
country: Australia
facility: Children´s Hospital Westmead
city: Vienna
country: Austria
facility: St. Anna Kinderspital
state: Austra
city: Graz
country: Austria
facility: Univ.-Klinik für Kinder- und Jugendheilkunde Graz
city: Innsbruck
country: Austria
facility: Univ.Klinik f. Kinder-u. Jugendheilkunde Innsbruck
city: Linz
country: Austria
facility: Landes- Kinderklinik Linz
city: Salzburg
country: Austria
facility: St. Johanns Spital LKH Salzburg
city: Brussels
country: Belgium
facility: Cliniques universitaires St-Luc
city: Brussels
country: Belgium
facility: Hôpital des Enfants
city: Gent
country: Belgium
facility: University Hospital Gent
city: Leuven
country: Belgium
facility: UZ Gasthuisberg
city: Lüttich
country: Belgium
facility: CHR Citadelle
city: Montegnee
country: Belgium
facility: Clinique de l'Espérance
city: Prague
country: Czechia
facility: University Hospital Motol
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital
city: Copenhagen
country: Denmark
facility: National State Hospital
city: Odense
country: Denmark
facility: University Hospital of Odense
city: Skejby
country: Denmark
facility: Skejby Hospital
city: Dijon
country: France
facility: Hopital d'Enfants Dijon
city: Grenoble
country: France
facility: CHU de Grenoble
city: Le Pellerin
country: France
facility: CHR Pellegrin
city: Lille
country: France
facility: Centre Oscar Lambret de Lille
city: Marseille
country: France
facility: Hopitaux de Marseille La Timone
city: Nantes
country: France
facility: CHR de Nantes
city: Paris
country: France
facility: Hôpital Trousseau Paris
city: Paris
country: France
facility: Institut Curie
city: Reims
country: France
facility: Hôpital American Memorial Hospital
city: Saint Etienne
country: France
facility: CHU-Saint Etienne
city: Strasbourg
country: France
facility: Hôpital de Hautepierre
city: Toulouse
country: France
facility: Hôpital D'Enfants de Toulouse
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Athens
country: Greece
facility: "A&P Kyriakou" Children's Hospital
city: Athens
country: Greece
facility: Aghia Sophia Children's Hospital
city: Heraklion
country: Greece
facility: MITERA Hospital
city: Heraklion
country: Greece
facility: PEPAGNH University Hospital
city: Budapest
country: Hungary
facility: Madarász Children Hospital Budapest
city: Budapest
country: Hungary
facility: Semmelweis University of Budapest
city: Debrecen
country: Hungary
facility: University of Debrecen
city: Pécs
country: Hungary
facility: University of Pecs
city: Szeged
country: Hungary
facility: University of Szeged
city: Dublin
country: Ireland
facility: Dublin: OLHSC
city: Haifa
country: Israel
facility: Rambam Medical Centre
city: Petah Tiqwa
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Tel Aviv
country: Israel
facility: Sheba Medical Center
city: Ancona
country: Italy
facility: Ospedale G. Salesi
city: Bari
country: Italy
facility: Universitŕ degli studi di Bari
city: Bergamo
country: Italy
facility: Ospedali Riuniti
city: Bologna
country: Italy
facility: Ospedale S. Orsola
city: Cagliari
country: Italy
facility: Ospedale Regionale per le Microcitemie
city: Cosenza
country: Italy
facility: Azienda Ospedaliera di Cosenza
city: Firenze
country: Italy
facility: Azienda Ospedaliera A. Meyer
city: Genua
country: Italy
facility: Istituto Giannina Gaslini
city: Milano
country: Italy
facility: Istituto Nazionale Tumori di Milano
city: Modena
country: Italy
facility: Azienda Ospedal. Univ. di Modena
city: Napoli
country: Italy
facility: Sec. Univ. degli Studi di Napoli - Policlinico
city: Padova
country: Italy
facility: Clinica di Oncoematologia Pediatrica Padova
city: Palermo
country: Italy
facility: Ospedale dei Bambini, Palermo
city: Parma
country: Italy
facility: Azienda Ospedaliera Universitaria di Parma-Oncoematologia Pediatrica
city: Pavia
country: Italy
facility: Policlinico San Matteo
city: Pescara
country: Italy
facility: Ospedale Civile Spirito Santo
city: Rimini
country: Italy
facility: Ospedale "Infermi "
city: Roma
country: Italy
facility: Policlinico Borgo Roma
city: Rome
country: Italy
facility: Ospedale Bambino Gesu
city: San Giovanni Rotondo
country: Italy
facility: Casa Sollievo della Sofferenza
city: Torino
country: Italy
facility: O.I.R.M. - S. Anna
city: Trieste
country: Italy
facility: Istituto per l'Infanzia "Burlo Garofolo"
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Rikshospitalet
city: Tromso
country: Norway
facility: University Hospital of North-Norway
city: Bialystok
country: Poland
facility: Medical University of Bialystok
city: Bydgoszcz
country: Poland
facility: Medical University of Bydgoszcz
city: Chorzów
country: Poland
facility: Childrens' Hospital in Chorzów
city: Gdansk
country: Poland
facility: Medical University in Gdansk
city: Katowice
country: Poland
facility: Upper Silesian Centre of Child and Mother's Care
city: Kraków
country: Poland
facility: University Children's Hospital
city: Lublin
country: Poland
facility: Children's University Hospital in Lublin
city: Poznan
country: Poland
facility: University of Medical Sciences Poznan
city: Warschau
country: Poland
facility: Institute Mother and Child
city: Wroclaw
country: Poland
facility: Wroclaw Medical University
city: Lissabon
country: Portugal
facility: Ipofg-Crl
city: Banská Bystrica
country: Slovakia
facility: University Hospital F. D. Roosevelt
city: Ljubljana
country: Slovenia
facility: University Children's Hospital Ljubljana
city: Alicante
country: Spain
facility: H. General de Alicante
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Bilbao
country: Spain
facility: Hospital de Cruces
city: Jaen
country: Spain
facility: Complejo Hospitalario de Jaen
city: La Coruna
country: Spain
facility: H . Materno-Infantil Teresa Herrera
city: Madrid
country: Spain
facility: H. Monteprincipe
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Oviedo
country: Spain
facility: H Central de Asturias
city: Salamanca
country: Spain
facility: H. C. U. de Salamanca
city: San Sebastián
country: Spain
facility: H. de Donostia Ntra. Sra. de Aranzazu
city: Santiago De Compostela
country: Spain
facility: H. General de Galicia
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocio
city: Valencia
country: Spain
facility: Carlos Haya
city: Valencia
country: Spain
facility: Hospital Infantil La Fe
city: Zaragoza
country: Spain
facility: H Clinico-Universitario
city: Göteburg
country: Sweden
facility: Queen Silvia's Children's Hospital
city: Linkoping
country: Sweden
facility: Childrens Hospital Linkoping
city: Geneva
country: Switzerland
facility: University Children's Hospital
city: Lausanne
country: Switzerland
facility: CHUV
city: Aberdeen
country: United Kingdom
facility: Aberdeen: Royal Aberdeen Children's Hospital
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: Cambridge
country: United Kingdom
facility: Addenbrooke's NHS Trust
city: Cardiff
country: United Kingdom
facility: Llandough Hospital
city: Edinburgh
country: United Kingdom
facility: Edinburgh Royal Hospital for Sick Children
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Hospital for Sick Children
city: Leeds
country: United Kingdom
facility: Leeds: St James's University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Liverpool: Alder Hey Children's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: UCLH University College London Hospital
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Newcastle
country: United Kingdom
facility: Newcastle: Royal Victoria Infirmary
city: Nottingham
country: United Kingdom
facility: Nottingham: Queen's Medical Centre
city: Oxford
country: United Kingdom
facility: Oxford: John Radcliffe Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Children's Hospital
city: Southhampton
country: United Kingdom
facility: Southampton General Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital
Study officials:
affiliation: St. Anna Kinderkrebsforschung
name: Ruth L Ladenstein, MD, MBA, cPM
role: PRINCIPAL_INVESTIGATOR
References:
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, 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.
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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 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.