Study to optimise the treatment for high risk neuroblastoma patients

• Register: EUCTR
• Last refreshed on: 23 July 2018
• Main ID: EUCTR2006-001489-17-PL
• Date of registration: 22/05/2014
• Prospective Registration: Yes
• Primary sponsor: Jagiellonian University Medical College
• Public title: Study to optimise the treatment for high risk neuroblastoma patients
• Scientific title: High risk neuroblastoma study 1.8 of SIOP-Europe - SIOPEN – (HR-NB-L1.8/SIOPEN) - HR-NBL-1.8
• Date of first enrolment: 25/07/2014
• Target sample size: 3300
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-001489-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: Rapid Cojec Induction; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, China, Czech Republic, Denmark, Finland, France, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, Norway, Poland, Portugal, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom

Contacts

• Name: prof. Walentyna Balwierz
• Affiliation: Klinika Onkologii i Hematologii Dzieciecej

• Name: prof. Walentyna Balwierz
• Affiliation: Klinika Onkologii i Hematologii Dzieciecej

Key inclusion & exclusion 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:
a) INSS stages 2, 3, 4 and 4s with MYCN amplification, or
b) INSS stage 4 without MYCN amplification aged = 12 months
- Patients who have received no previous chemotherapy except for 1 cycle of etoposide and carboplatin (Vp/Carbo). In this situation patients will receive Rapid COJEC induction and the first COJEC cycle may be replaced by the first cycle of Vp/Carbo.
- 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.
- Registration of all eligibility criteria with the data centre within 6 weeks from diagnosis.
- 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.
- Provisional follow up of 5 years.
- National and local ethical committee approval.

Are the trial subjects under 18? yes
Number of subjects for this age range: 3300
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 12
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Any negative answer concerning the inclusion criteria of the study and R4 will render the patient ineligible for the corresponding therapy phase.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

High Risk Neuroblastoma

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Dinutuximab beta
Product Name: Dinutuximab beta
Pharmaceutical Form: Concentrate and solvent for solution for infusion
INN or Proposed INN: dinutuximab beta
Other descriptive name: ch14.18/CHO
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 4.5-

Pharmaceutical Form: Powder for injection
INN or Proposed INN: Aldesleukin
CAS Number: 110942-02-4
Current Sponsor code: Proleukin
Other descriptive name: ALDESLEUKIN
Concentration unit: million IU million international units
Concentration type: equal
Concentration number: 3-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: The final analysis will be performed 1 year for R4 after the inclusion of the last patient.

Secondary Objective: •To test the molecular - biological profile of disseminating tumour cells
(DTCs) obtained via liquid biopsies in comparison with molecular -
biological profiles in BM and primary tumour at diagnosis and respective
specified response and follow up time points to validate the value of
liquid biopsies for future follow up and to correlate above parameters
with EFS and OS.
•To evaluate BM response to Rapid COJEC (after the fourth and eight
cycles with ICH-GD2, AIPF and QRT-PCR.
•To determine the effect of response of metastatic disease to induction therapy
therapy on EFS and overall survival (OS) with mIBG/SPECT SIOPEN
stand scoring of skeletal response
•To investigate the relationship between complete surgical resection of
the primary tumour on EFS and OS within the scope of established
standard treatments.

Main Objective: - To test the hypothesis that the addition of subcutaneous aldesleukin
(IL-2, (Proleukin®)) to immunotherapy with Dinutuximab beta EUSA
given as continuous infusion in addition to differentiation therapy with
isotretinoin (13-cis-RA) following myeloablative therapy (MAT) and
autologous stem cell rescue, will improve EFS in patients with high-risk
neuroblastoma (stage 4 disease or stages 2 and 3 with MYCN
amplification, all over the age of one, or infants with MYCN
amplification) (R4 randomisation).
- To correlate molecular biological features with metastatic and primary
tumour response, event free and overall survival (EFS, OS) as well as
with respective treatment elements and phases.

Primary end point(s): Randomisation 4:
The primary endpoint is Event Free Survival calculated from the date of the R4- 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.

Secondary Outcome(s)

Secondary end point(s): Secondary endpoints of the main trial
- Overall survival
Calculated from date of randomisation to death from any cause. Patients lost to follow-up without an event will be censored at the date of their last follow-up evaluation.
- Cumulative incidence of relapse/progression and deaths without relapse/progression
- The cumulative incidence of treatment related mortality and of disease related mortality
- Response
Overall response (incl. primary tumour after induction), skeletal response on MIBG, BM-response,
- Toxicity
in particular comparison of the frequency of episodes of febrile neutropenia and grade 3-4 infections during induction (modified N7 vs. Cojec)
- Response rates, survival, EFS and the cumulative incidence of relapse/progressions will be related to potential prognostic factors including:
- Biological factors (MYCN amplification, SCAs, expression signature) of neuroblastoma cells in the bone marrow and/or the primary tumour.
- Serological factors (serum concentrations at diagnosis of LDH, ferritin, neuron specific enolase).
- Urinary catecholamines at diagnosis (VMA, HVA, Dopamine)

Timepoint(s) of evaluation of this end point: The final analysis will be performed after the inclusion of the last patient.

Secondary ID(s)

2006-001489-17-AT

SIOPENRNET003

Source(s) of Monetary Support

Jagiellonian University Collegium Medicum