High Risk Neuroblastoma Study 1 (1.5) of SIOP-Europe (SIOPEN)
1 Month
21 Years
Both
Neuroblastoma
Trial Information
High Risk Neuroblastoma Study 1 (1.5) of SIOP-Europe (SIOPEN)
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.
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
-
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Event Free Survival (R1: MAT therapy)
Outcome Description:
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.
Outcome Time Frame:
Up to three years
Safety Issue:
No
Principal Investigator
Ruth L Ladenstein, MD, MBA, cPM
Investigator Role:
Principal Investigator
Investigator Affiliation:
St. Anna Kinderkrebsforschung
Authority:
Austria: Agency for Health and Food Safety
Study ID:
HR-NBL-1 (1.5)/SIOPEN
NCT ID:
NCT01704716
Start Date:
February 2002
Completion Date:
December 2014
Related Keywords:
- Neuroblastoma
- neuroblastoma
- immunotherapy
- MAT
- antibody treatment
- Neuroblastoma
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