Study to optimise the treatment for high risk neuroblastoma patients

• Register: EUCTR
• Last refreshed on: 2 March 2022
• Main ID: EUCTR2006-001489-17-SI
• Date of registration: 12/07/2013
• Prospective Registration: Yes
• Primary sponsor: University medical center Ljubljana
• Public title: Study to optimise the treatment for high risk neuroblastoma patients
• Scientific title: High risk neuroblastoma study 1.5 of SIOP-Europe (SIOPEN) - HR-NBL-1.5
• Date of first enrolment: 23/12/2013
• Target sample size: 2230
• Recruitment status: Not Recruiting
• 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: no; 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, Czech Republic, Denmark, Finland, France, Greece, Hungary, Ireland, Israel, Italy, Norway, Poland, Portugal, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom

Contacts

• Name: Maja Cesen Mazic
• Affiliation: University medical center Ljubljana

• Name: Maja Cesen Mazic
• Affiliation: University medical center Ljubljana

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
weeks from diagnosis.
- Provisional follow up of 5 years.
- National and local ethical committee approval.
The date of eligibility is defined as the date at which all criteria for entry
into the study have been checked by the co-ordinating centre along with
the referring physician. The date of diagnosis will be the starting point
for subsequent follow up.




Are the trial subjects under 18? yes
Number of subjects for this age range: 2200
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
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, R2
and R3 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)

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

Trade Name: Proleukin 18x10^6 IU
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: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1.1-

Trade Name: Endoxan 1000 mg powder for solution for infusion
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50180
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Trade Name: Adriablastina 2mg/ml solution for infusion
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DOXORUBICIN
CAS Number: 23214-92-8
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Trade Name: Vincristine Hospira
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: VINCRISTINE
CAS Number: 57227
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Trade Name: Cisplatin Pliva 0,5mg/ml
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CISPLATIN
CAS Number: 15663271
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 0,5-

Trade Name: Eposin 20mg/ml concentrate for solution for infusion
Pharmaceutical Form: Concentrate for solution

Primary Outcome(s)

Primary end point(s): Randomisation 3:
Two co-primary endpoints will be investigated:
1) Metastatic response after induction
• No skeletal uptake on MIBG
• Negative Bone marrow aspirates and trephines
• Absence of other metastatic sites
2) Event Free Survival
• 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.
Randomisation 2: Immunotherapy-Question (Ch14.18 antiGD2 mAb 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,
• 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. The aim is to test the effect of
immunotherapy on 3-year EFS.

Timepoint(s) of evaluation of this end point: ?The final analysis will be performed 18 months for R1 and R2 and 6 months for R3 after the inclusion of the last patient.

Secondary Objective: To evaluate BM response to Rapid COJEC and to modified N7.
To evaluate response to Rapid COJEC and modified N7 induction
therapies with mIBG for standardised scoring of skeletal response
To determine the effect of response of metastatic disease to induction
therapy, on EFS and OS
To investigate the relationship between complete surgical resection of
the primary tumour, and OS
To collect data on selected, validated biological features and to
determine the effect of these on EFS, the incidence of
relapse/progression and OS
To compare the toxicity, in particular episodes of febrile neutropenia and
grade 3-4 infection associated with induction therapy with Rapid COJEC
and modified N7
To sample PK data to calculate the effect of AUC as achieved according
to dosing guidelines
To monitor drug levels of MAT and to relate them to patients' outcome
and toxicity
To collect data on selected, validated biological features and to
determine the effect of these on EFS and OS

Main Objective: • To test the hypothesis that the modified N7 induction regimen will
improve the metastatic response or event free survival rate in a higher
number of patients as compared to Rapid COJEC.
• To test the hypothesis that immunotherapy with chimeric 14.18 anti-
GD2 monoclonal antibody produced in Chinese hamster ovary (CHO)
cells (ch14.18/CHO) and subcutaneous aldesleukin (IL-2, (Proleukin®)),
following MAT and autologous SCR, in addition to differentiation therapy
with isotretinoin (13-cis-RA), will improve 3-year 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).

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: ?The final analysis will be performed 18 months for R1 and R2 and 6 months for R3 after the inclusion of the last patient.

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)

Secondary ID(s)

SIOPENRNET003

2006-001489-17-AT

Source(s) of Monetary Support

University medical center Ljubljana

Ethics review

Status: Approved
Approval date: 11/04/2013
Contact: