HR-NBL2: High-risk neuroblastoma study 2.0 of SIOP-Europe-Neuroblastoma/SIOPEN

Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: Busulfan
Other descriptive name: Busulfan
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 0.5-

Pharmaceutical Form:
INN or Proposed INN: Carboplatin
Other descriptive name: Carboplatin
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Cyclophosphamide
CAS Number: 50-18-0
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Cisplatin
Other descriptive name: Cisplatin
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Dacarbazine
CAS Number: 4342-03-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Pharmaceutical Form: 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-

Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Etoposide
Other descriptive name: Etoposide
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Ifosfamide
CAS Number: 3778-73-2
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 80-

Pharmaceutical Form: Powder and solvent for solution for injection/i

Gender:
Female: yes
Male: yes

Inclusion criteria:
Enrollment in HR-NBL2 will be performed:
at diagnosis before the beginning of chemotherapy
or
up to 21 days after one course of Carboplatin-Etoposide for patients with
localized neuroblastoma or infants with metastatic neuroblastoma with
MYCN amplification or patients with metastatic neuroblastoma treated in
emergency
or
up to 21 days after one course of the current protocol for
low/intermediate risk neuroblastoma in Germany/Netherlands for
patients with localized neuroblastoma or infants with metastatic
neuroblastoma with MYCN amplification
HR-NBL2 eligibility criteria: (...)
R-I eligibility criteria: (...)
R-HDC eligibility criteria: (...)In case of parents'/patient's refusal, or
insufficient stem cells, collection for tandem HDC but with a minimum of
3 x 106 CD34+ cells/kg body weight, or in case of patients older than 21
years, or organ toxicity, HDC will consist on the standard HD Bu-Mel and
patients will be eligible for the subsequent randomisation.
R-RTx eligibility criteria:
An evaluation of the local disease will be performed after HDC/ASCR and
surgery:
- In case of no local macroscopic disease, all patients will receive 21,6-
Gy radiotherapy to the pre-operative tumour bed
- In case of local macroscopic residual disease, patients will be eligible
to R-RTx if the following criteria are met:
(...)
In case of parents'/patient's refusal of the randomisation, the patient
will receive 21.6 Gy radiotherapy to the pre-operative tumour bed.
Chemoimmunotherapy arm eligibility criteria:
1.Insufficient metastatic response at the end of induction
chemotherapy, defined as:
?SIOPEN score > 3 or less than 50% reduction in mIBG score (or > 3
bone lesions or less 50% reduction in number of FDG-PET-avid bone
lesions for mIBG-non avid tumours)
OR
?Bone marrow disease: SD according to International Neuroblastoma
Response Criteria OR
?Other metastatic sites: PR or SD. For distant lymph nodes : PR and
not resectable or SD.
2.Performance status = 50%.
3.Hematological status: ANC>0.75x109/L without G-CSF for at least 48
hours (or ANC = 0.50 x 109 /L in case of bone marrow involvement),
platelets > 50x 109/L and rising, without platelets transfusion for 72
hours.
4.AST or ALT =7.5 ULN and total bilirubin =1.5 ULN. In patients with
liver metastases, total bilirubin =2.5 ULN is allowed.
5.No active infection;
6.No grade >2 gastrointestinal toxicity.
7.No grade = 3 toxicity related to previous treatment.
8.Oxygen saturation > 94%
Are the trial subjects under 18? yes
Number of subjects for this age range: 790
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:
Non-inclusion criteria for HR-NBL2:
1.Any negative answer concerning the HR-NLB2 inclusion criteria
2.Patient under guardianship or deprived of his liberty by a judicial or
administrative decision or incapable of giving his consent.
3.Participating in another clinical study with an IMP while on study
treatment.
4.Chronic inflammatory bowel disease and/or bowel obstruction.
5.Pregnant or breastfeeding women.
6.Known hypersensitivity to the active substance or to any of the
excipients of the study drugs
7.Concomitant self-medication medicine that in the investigator
opinion could interact with study treatments, including herbal medicine
(e.g. St John's Wort (Hypericum Perforatum).
Non-inclusion criteria specific to the R-I randomisation (RAPID
COJEC/GPOH):
1.Urinary tract obstruction = grade 3
2.Heart failure or myocarditis = grade 2, any arrhythmia or myocardial
infection
3.Peripheral motor or sensory neuropathy = grade 3
4.Demyelinating form of Charcot-Marie-Tooth syndrome
5.Hearing impairment = grade 2
6.Concurrent prophylactic use of phenytoin
7.Cardiorespiratory disease that contraindicates hyperhydration
Non-inclusion criteria common to all randomisations (R-I, R-HDC, and RRTx
1) Any negative answer concerning the inclusion criteria of R-I or R-HDC
or R-RTx will render the patient ineligible for the corresponding therapy
phase randomization. However, these patients may remain on study and
be considered to receive standard treatment of the respective therapy
phase, and may be potentially eligible for subsequent randomizations.
2) Liver function: Alanine aminotransferase (ALT) > 3.0 x ULN and blood
bilirubin > 1.5 x ULN (toxicity = grade 2). In case of toxicity = grade 2,
call national principal investigator study coordinator to discuss the
feasibility.
3) Renal function: Creatinine clearance and/or GFR < 60 ml/min/1.73m?
(toxicity = grade 2). If GFR < 60ml/min/1.73m?, call national principal
investigator study coordinator to discuss about the treatment.
4) Dyspnea at rest and/or pulse oximetry <95% in air (only for R-HDC,a

1) Any negative answer concerning the inclusion criteria of R-I or R-HDC
or R-RTx will render the patient ineligible for the corresponding therapy
phase randomization. However, these patients may remain on study and
be considered to receive standard treatment of the respective therapy
phase, and may be potentially eligible for subsequent randomizations.
2) Liver function: Alanine aminotransferase (ALT) > 3.0 x ULN and blood
bilirubin > 1.5 x ULN (toxicity = grade 2). In case of toxicity = grade 2,
call national principal investigator study coordinator to discuss the
feasibility.
3) Renal function: Creatinine clearance and/or GFR < 60 ml/min/1.73m?
(toxicity = grade 2). If GFR < 60ml/min/1.73m?, call national principal
investigator to discuss about the treatment.
4) Dyspnea at rest and/or pulse oximetry <95% in air.
5) Any uncontrolled intercurrent illness or infection that in the
investigator opinion would impair study participation.
6) Patient under guardianship or deprived of his liberty by a judicial or
administrative decision or incapable of giving his consent.
7) Participating in another clinical study with an IMP while on study
treatment.
8) Concomittant use with yellow fever vaccine and with live virus or
bacterial vaccines.
9) Patient allergic to peanut or soya.
10) Chronic inflammatory bowel disease and/or bowel obstruction.
11) Pregnant or breastfeeding women.
12) Known hyperse