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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01704716




Registration number
NCT01704716
Ethics application status
Date submitted
5/10/2012
Date registered
11/10/2012
Date last updated
23/10/2020

Titles & IDs
Public title
High Risk Neuroblastoma Study 1.8 of SIOP-Europe (SIOPEN)
Scientific title
High Risk Neuroblastoma Study 1 of SIOP-Europe (SIOPEN)
Secondary ID [1] 0 0
HR-NBL-1.8 / SIOPEN
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuroblastoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Neuroendocrine tumour (NET)
Cancer 0 0 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Vincristine
Treatment: Drugs - Aldesleukin
Treatment: Drugs - ch14.18/CHO
Treatment: Drugs - Carboplatin
Treatment: Drugs - Etoposide
Treatment: Drugs - Cisplatin
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Doxorubicin
Treatment: Drugs - G-CSF
Treatment: Drugs - Busulfan
Treatment: Drugs - Melphalan

Experimental: R0: COJEC plus G-CSF - 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 Patients randomised to Rapid COJEC alone will receive induction Treatment without G-CSF

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 Aldesleukin - Patients randomised to receive ch14.18/CHO plus Aldesleukin

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).

Active comparator: R4: cnt inf ch14.18/CHO - ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO

Experimental: R4: cnt inf ch14.18/CHO plus Aldesleukin - ch14.18/CHO is given as continuous Infusion over 10 days at a cumulative dose of 100mg/m2. Patients receive 5 cycles of ch14.18/CHO.

In addition, Aldesleukin is given at a dose of 3 x 10e6 on days 1 to 5 and on days 9, 11, 13, 15, and 17 during ch14.18/CHO infusion


Treatment: Drugs: Vincristine
given during Rapid COJEC and modified N7 therapy

Treatment: Drugs: Aldesleukin
Aldesleukin is given during MRD Treatment for patients randomised to the arm with IL-2

Treatment: Drugs: ch14.18/CHO
ch14.18/CHO antibody is given during MRD treatment

Treatment: Drugs: Carboplatin
Carboplatin is given during induction Treatment (R3 randomisation: Rapid COJEC arm)

Treatment: Drugs: Etoposide
Etoposide is given during Induction Treatment (both R3 randomisation arms)

Treatment: Drugs: Cisplatin
Cisplatin is given during Induction Treatment (both R3 randomisation arms)

Treatment: Drugs: Cyclophosphamide
Cyclophosphamid is given during Induction Treatment (both R3 randomisation arms)

Treatment: Drugs: Doxorubicin
Doxorubicin is given during Induction Treatment (R3 arm modified N7)

Treatment: Drugs: G-CSF
G-CSF is given during Induction Treatment

Treatment: Drugs: Busulfan
In case i.v. busulfan is not available, the use of oral busulfan is permitted, although not recommended.

Treatment: Drugs: Melphalan
Melphalan is given during MAT treatment
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event Free Survival (R1: MAT therapy)
Timepoint [1] 0 0
Up to three years
Primary outcome [2] 0 0
Event Free Survival (immunotherapy)
Timepoint [2] 0 0
Up to three years
Primary outcome [3] 0 0
Complete metastatic response (R3: Induction therapy)
Timepoint [3] 0 0
Up to 95 days
Primary outcome [4] 0 0
Event free survival (R3: Induction therapy)
Timepoint [4] 0 0
Up to three years

Eligibility
Key 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.
Minimum age
1 Month
Maximum age
21 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any negative answer concerning the inclusion criteria of the study

-

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/02/2002
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/09/2026
Actual
Sample size
Target
3300
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Women and Children´s Hospital - Adelaide
Recruitment hospital [2] 0 0
Lady Cilento Children´s Hospital - Brisbane
Recruitment hospital [3] 0 0
John Hunter Children's Hospital - Newcastle
Recruitment hospital [4] 0 0
Royal Children's Hospital Melbourne - Parkville
Recruitment hospital [5] 0 0
Sydney Children's Hospital - Sydney
Recruitment hospital [6] 0 0
Children´s Hospital Westmead - Westmead
Recruitment postcode(s) [1] 0 0
- Adelaide
Recruitment postcode(s) [2] 0 0
- Brisbane
Recruitment postcode(s) [3] 0 0
- Newcastle
Recruitment postcode(s) [4] 0 0
- Parkville
Recruitment postcode(s) [5] 0 0
- Sydney
Recruitment postcode(s) [6] 0 0
- Westmead
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Austra
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Austria
State/province [2] 0 0
Graz
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Austria
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Innsbruck
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Austria
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Linz
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Austria
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Salzburg
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Belgium
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Brussels
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Belgium
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Gent
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Belgium
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Leuven
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Belgium
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Lüttich
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Belgium
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Montegnee
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Czechia
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Prague
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Denmark
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Aarhus
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Denmark
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Copenhagen
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Denmark
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Odense
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Denmark
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Skejby
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France
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Dijon
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France
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Grenoble
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France
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Le Pellerin
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France
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Lille
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France
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Marseille
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France
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Nantes
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France
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Paris
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France
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Reims
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France
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Saint Etienne
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France
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Strasbourg
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Toulouse
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Villejuif
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Athens
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Greece
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Heraklion
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Hungary
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Budapest
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Hungary
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Debrecen
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Hungary
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Pécs
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Hungary
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Szeged
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Ireland
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Dublin
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Israel
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Haifa
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Israel
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Petah Tiqwa
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Israel
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Tel Aviv
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Italy
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Ancona
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Italy
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Bari
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Italy
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Bergamo
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Italy
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Bologna
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Cagliari
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Cosenza
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Italy
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Firenze
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Italy
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Genua
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Italy
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Milano
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Italy
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Modena
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Napoli
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Italy
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Padova
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Italy
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Palermo
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Italy
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Parma
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Italy
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Pavia
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Pescara
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Italy
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Rimini
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Roma
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Rome
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Italy
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San Giovanni Rotondo
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Torino
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Italy
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Trieste
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Norway
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Bergen
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Norway
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Oslo
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Norway
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Tromso
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Bialystok
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Bydgoszcz
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Chorzów
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Gdansk
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Katowice
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Kraków
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Lublin
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Warschau
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Wroclaw
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Portugal
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Lissabon
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Banská Bystrica
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Slovenia
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Ljubljana
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Alicante
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Barcelona
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Bilbao
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Sevilla
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Spain
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Valencia
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Zaragoza
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Sweden
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Göteburg
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Sweden
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Linkoping
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Switzerland
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Geneva
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Switzerland
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Lausanne
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United Kingdom
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Aberdeen
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Belfast
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United Kingdom
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Birmingham
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United Kingdom
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Bristol
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United Kingdom
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Cambridge
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United Kingdom
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Cardiff
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United Kingdom
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Edinburgh
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United Kingdom
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Glasgow
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United Kingdom
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Leeds
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United Kingdom
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Leicester
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United Kingdom
State/province [103] 0 0
Liverpool
Country [104] 0 0
United Kingdom
State/province [104] 0 0
London
Country [105] 0 0
United Kingdom
State/province [105] 0 0
Manchester
Country [106] 0 0
United Kingdom
State/province [106] 0 0
Newcastle
Country [107] 0 0
United Kingdom
State/province [107] 0 0
Nottingham
Country [108] 0 0
United Kingdom
State/province [108] 0 0
Oxford
Country [109] 0 0
United Kingdom
State/province [109] 0 0
Sheffield
Country [110] 0 0
United Kingdom
State/province [110] 0 0
Southhampton
Country [111] 0 0
United Kingdom
State/province [111] 0 0
Sutton

Funding & Sponsors
Primary sponsor type
Other
Name
St. Anna Kinderkrebsforschung
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT01704716
Trial related presentations / publications
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.
Ladenstein R, Potschger 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, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D; SIOP Europe Neuroblastoma Group (SIOPEN). Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):500-514. doi: 10.1016/S1470-2045(17)30070-0. Epub 2017 Mar 2.
Ladenstein R, Potschger 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, Pearson ADJ, Lode HN. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Dec;19(12):1617-1629. doi: 10.1016/S1470-2045(18)30578-3. Epub 2018 Nov 12.
Morgenstern DA, Potschger 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 stratification of high-risk metastatic neuroblastoma: A report from the HR-NBL-1/SIOPEN study. Pediatr Blood Cancer. 2018 Nov;65(11):e27363. doi: 10.1002/pbc.27363. Epub 2018 Jul 17.
Berbegall AP, Bogen D, Potschger 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. Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study. Br J Cancer. 2018 May;118(11):1502-1512. doi: 10.1038/s41416-018-0098-6. Epub 2018 May 14.
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.
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.
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.
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.
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.
Public notes

Contacts
Principal investigator
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Ruth L Ladenstein, MD, MBA, cPM
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St. Anna Kinderkrebsforschung
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Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
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Ruth L Ladenstein, MD, MBA, cPM
Address 0 0
Country 0 0
Phone 0 0
0043140470
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Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01704716