High Risk Neuroblastoma Study 1 (1.5) of SIOP-Europe (SIOPEN)
Overview[ - collapse ][ - ]
Purpose | This is a randomised 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 (R3 randomisation - Rapid COJEC vs modified N7), peripheral blood stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy (BuMel) followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour and immunotherapy (R2 randomisation - isotretinoin and ch14.18/CHO, with or without aldesleukin (IL-2). In the induction phase, all patients with stage 4 neuroblastoma and those with stage 4s MYCN-amplified neuroblastoma will be randomised (R3) to Rapid COJEC or modified N7; localised patients receive Rapid COJEC (Rapid COJEC is given with G-CSF support based on the results of the R0 randomisation running between 2002 and 2005). Following induction treatment peripheral blood stem cell harvest (PBSCH) will be 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, localised patients will proceed to consolidation. Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without segmental chromosomal alterations (SCA) 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 (following the results of the R1 randomisation) followed by peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour. During the immunotherapy phase, patients will be randomised (R2) to immunotherapy with isotretinoin (13-cis-RA) and ch14.18/CHO, with or without aldesleukin (IL-2). |
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Condition | Neuroblastoma |
Intervention | Drug: Vincristine Drug: Aldesleukin Drug: ch14.18/CHO Drug: Carboplatin Drug: Etoposide Drug: Cisplatin Drug: Cyclophosphamide Drug: Doxorubicin Drug: G-CSF Drug: Busulfan i.v. Drug: Melphalan |
Phase | Phase 3 |
Sponsor | St. Anna Kinderkrebsforschung |
Responsible Party | St. Anna Kinderkrebsforschung |
ClinicalTrials.gov Identifier | NCT01704716 |
First Received | October 5, 2012 |
Last Updated | October 10, 2012 |
Last verified | October 2012 |
Tracking Information[ + expand ][ + ]
First Received Date | October 5, 2012 |
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Last Updated Date | October 10, 2012 |
Start Date | February 2002 |
Estimated Primary Completion Date | December 2014 |
Current Primary Outcome Measures |
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Current Secondary Outcome Measures | Not Provided |
Descriptive Information[ + expand ][ + ]
Brief Title | High Risk Neuroblastoma Study 1 (1.5) of SIOP-Europe (SIOPEN) |
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Official Title | High Risk Neuroblastoma Study 1 (1.5) of SIOP-Europe (SIOPEN) |
Brief Summary | This is a randomised 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 (R3 randomisation - Rapid COJEC vs modified N7), peripheral blood stem cell harvest, attempted complete excision of the primary tumour, myeloablative therapy (BuMel) followed by peripheral blood stem cell rescue, radiotherapy to the site of the primary tumour and immunotherapy (R2 randomisation - isotretinoin and ch14.18/CHO, with or without aldesleukin (IL-2). In the induction phase, all patients with stage 4 neuroblastoma and those with stage 4s MYCN-amplified neuroblastoma will be randomised (R3) to Rapid COJEC or modified N7; localised patients receive Rapid COJEC (Rapid COJEC is given with G-CSF support based on the results of the R0 randomisation running between 2002 and 2005). Following induction treatment peripheral blood stem cell harvest (PBSCH) will be 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, localised patients will proceed to consolidation. Patients aged 12-18 months at diagnosis, with stage 4 neuroblastoma, no MYCN amplification and without segmental chromosomal alterations (SCA) 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 (following the results of the R1 randomisation) followed by peripheral blood stem cell rescue (PBSCR) and radiotherapy to the site of the primary tumour. During the immunotherapy phase, patients will be randomised (R2) to immunotherapy with isotretinoin (13-cis-RA) and ch14.18/CHO, with or without aldesleukin (IL-2). |
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 characterised 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 tumours 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 randomisation: R0 was opened with the study activation in February 2002 and closed in November 2005. The randomised use of G-CSF during COJEC induction resulted in the recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia R1 randomisation: 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. R2 randomisation: R2 was activated in November 2006 (13-cis retinoic acid +/- chimeric ch14.18/CHO antibody) and modified in July 2009. R2 randomisation now tests the hypothesis that immunotherapy with chimeric 14.18/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. R3 randomisation: 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. |
Study Type | Interventional |
Study Phase | Phase 3 |
Study Design | Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment |
Condition | Neuroblastoma |
Intervention | Drug: Vincristine Drug: Aldesleukin Other Names: Interleukin 2, IL-2Drug: ch14.18/CHO Other Names: anti GD2 antbodyDrug: Carboplatin Drug: Etoposide Drug: Cisplatin Drug: Cyclophosphamide Drug: Doxorubicin Drug: G-CSF G-CSF is given in one arm of R0 randomisation during COJEC induction chemotherapy Other Names: FilgrastimDrug: Busulfan i.v. In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended. Other Names:
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Study Arm (s) |
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Recruitment Information[ + expand ][ + ]
Recruitment Status | Recruiting |
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Estimated Enrollment | 2000 |
Estimated Completion Date | December 2014 |
Estimated Primary Completion Date | December 2014 |
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 - |
Gender | Both |
Ages | 1 Month |
Accepts Healthy Volunteers | No |
Contacts | Contact: Ruth L Ladenstein, MD, MBA, cPM 0043140470 ruth.ladenstein@ccri.at |
Location Countries | Australia, Austria, Belgium, Czech Republic, Denmark, France, Greece, Hungary, Ireland, Israel, Italy, Norway, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland, United Kingdom |
Administrative Information[ + expand ][ + ]
NCT Number | NCT01704716 |
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Other Study ID Numbers | HR-NBL-1 (1.5)/SIOPEN |
Has Data Monitoring Committee | Yes |
Information Provided By | St. Anna Kinderkrebsforschung |
Study Sponsor | St. Anna Kinderkrebsforschung |
Collaborators | Not Provided |
Investigators | Principal Investigator: Ruth L Ladenstein, MD, MBA, cPM St. Anna Kinderkrebsforschung |
Verification Date | October 2012 |
Locations[ + expand ][ + ]
Sydney Children's Hospital | Sydney, Australia Recruiting |
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St. Anna Kinderspital | Vienna, Austra, Austria, 1090 Contact: Ruth Ladenstein, MD, MBA, cPM | 00431404704750 | ruth.ladenstein@ccri.atRecruiting |
Univ.-Klinik für Kinder- und Jugendheilkunde Graz | Graz, Austria Contact: , MDRecruiting |
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 | Gent, Belgium Recruiting |
UZ Gasthuisberg | Leuven, Belgium Recruiting |
CHR Citadelle | Lüttich, Belgium Recruiting |
Clinique de l'Espérance | Montegnee, Belgium Recruiting |
University Hospital Motol | Prague, Czech Republic 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 |
Institut Curie | Paris, France Recruiting |
Hôpital Trousseau Paris | Paris, France Recruiting |
Hôpital American Memorial Hospital | Reims, France Recruiting |
CHU-Saint Etienne | Saint Etienne, France Recruiting |
Hopital Hautepierre-CHU Strasbourg | Strasburg, 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 |
Madarász Children Hospital Budapest | Budapest, Hungary Recruiting |
Semmelweis University of Budapest | Budapest, Hungary Recruiting |
Dublin: OLHSC | Dublin, Ireland Recruiting |
Rambam Medical Centre | Haifa, Israel Recruiting |
Schneider Children's Medical Center of Israel | Petah Tiqwa, 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 | Firenze, Italy Recruiting |
Istituto Giannina Gaslini | Genua, Italy Recruiting |
Istituto Nazionale Tumori di Milano | Milano, 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 | Padova, 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 | Tromso, Norway Recruiting |
Medical University of Bialystok | Bialystok, Poland Recruiting |
Medical University of Bydgoszcz | Bydgoszcz, Poland Recruiting |
Childrens' Hospital in Chorzów | Chorzów, Poland Recruiting |
University Children's Hospital | Cracow, Poland Recruiting |
Medical University in Gdansk | Gdansk, Poland Recruiting |
Upper Silesian Centre of Child and Mother's Care | Katowice, Poland Recruiting |
Children's University Hospital in Lublin | Lublin, Poland Recruiting |
University of Medical Sciences Poznan | Poznan, Poland Recruiting |
Institute Mother and Child | Warschau, Poland Recruiting |
Wroclaw Medical University | Wroclaw, Poland Recruiting |
Ipofg-Crl | Lissabon, Portugal Recruiting |
University Hospital F. D. Roosevelt | Banská Bystrica, Slovakia Recruiting |
H. General de Alicante | Alicante, Spain Recruiting |
H. de Donostia Ntra. Sra. de Aranzazu | Aranzazu, Spain Recruiting |
Hospital Vall d`Hebron | Barcelona, Spain Recruiting |
Hospital de Cruces | Bilbao, Spain Recruiting |
H. General de Galicia | Galicia, Spain Recruiting |
Complejo Hospitalario de Jaen | Jaen, Spain Recruiting |
H . Materno-Infantil Teresa Herrera | La Coruna, Spain Recruiting |
Hospital 12 de Octubre | Madrid, Spain Recruiting |
H. Monteprincipe | Madrid, Spain Recruiting |
H Central de Asturias | Oviedo, Spain Recruiting |
H. C. U. de Salamanca | Salamanca, Spain Recruiting |
Hospital Virgen del Rocio | Sevilla, 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 | Linkoping, 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 |
UCLH University College London Hospital | London, United Kingdom Recruiting |
St Bartholomew's Hospital | London, United Kingdom Recruiting |
Great Ormond Street 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 |