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).
ConditionNeuroblastoma
InterventionDrug: 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
PhasePhase 3
SponsorSt. Anna Kinderkrebsforschung
Responsible PartySt. Anna Kinderkrebsforschung
ClinicalTrials.gov IdentifierNCT01704716
First ReceivedOctober 5, 2012
Last UpdatedOctober 10, 2012
Last verifiedOctober 2012

Tracking Information[ + expand ][ + ]

First Received DateOctober 5, 2012
Last Updated DateOctober 10, 2012
Start DateFebruary 2002
Estimated Primary Completion DateDecember 2014
Current Primary Outcome Measures
  • Event Free Survival (R1: MAT therapy) [Time Frame: Up to three years] [Designated as safety issue: No]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.
  • Event Free Survival (R2: immunotherapy) [Time Frame: Up to three years] [Designated as safety issue: No]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 now compares immunotherapy with anti GD2 antibody ch14.18/CHO with or without aldesleukin (IL-2).
    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.
  • Complete metastatic response (R3: Induction therapy) [Time Frame: Up to 95 days] [Designated as safety issue: No]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
  • Event free survival (R3: Induction therapy) [Time Frame: Up to three years] [Designated as safety issue: No]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
Current Secondary Outcome MeasuresNot Provided

Descriptive Information[ + expand ][ + ]

Brief TitleHigh Risk Neuroblastoma Study 1 (1.5) of SIOP-Europe (SIOPEN)
Official TitleHigh 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 TypeInterventional
Study PhasePhase 3
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionNeuroblastoma
InterventionDrug: 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:
  • Busilvex
  • Myleran
  • Busulphan
Drug: Melphalan
Study Arm (s)
  • Experimental: R0: COJEC plus G-CSF (supportive care question)
    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.
  • Active Comparator: R0: COJEC
    Induction treatment (COJEC) without filgrastim
  • Active Comparator: R1: BuMel MAT
    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)
  • Experimental: R1: CEM MAT
    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
  • Active Comparator: R2: ch14.18/CHO
    ch14.18/CHO is given at a dose of 20 mg/m2/day over five days every four weeks for five courses
  • Experimental: R2: ch14.18/CHO plus IL-2
    Patients randomised to receive ch14.18/CHO plus IL-2
  • Active Comparator: R3: COJEC Induction
    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
  • Experimental: R3: Modified N7
    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).

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment2000
Estimated Completion DateDecember 2014
Estimated Primary Completion DateDecember 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

-
GenderBoth
Ages1 Month
Accepts Healthy VolunteersNo
ContactsContact: Ruth L Ladenstein, MD, MBA, cPM
0043140470
ruth.ladenstein@ccri.at
Location CountriesAustralia, 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
Other Study ID NumbersHR-NBL-1 (1.5)/SIOPEN
Has Data Monitoring CommitteeYes
Information Provided BySt. Anna Kinderkrebsforschung
Study SponsorSt. Anna Kinderkrebsforschung
CollaboratorsNot Provided
Investigators Principal Investigator: Ruth L Ladenstein, MD, MBA, cPM St. Anna Kinderkrebsforschung
Verification DateOctober 2012

Locations[ + expand ][ + ]

Sydney Children's Hospital
Sydney, Australia
Recruiting
St. Anna Kinderspital
Vienna, Austra, Austria, 1090
Contact: Ruth Ladenstein, MD, MBA, cPM | 00431404704750 | ruth.ladenstein@ccri.at
Recruiting
Univ.-Klinik für Kinder- und Jugendheilkunde Graz
Graz, Austria
Contact: , MD
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
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