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: Solution for infusion
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 sol

Gender:
Female: yes
Male: yes

Inclusion criteria:
1) Established diagnosis of neuroblastoma according to the SIOPENmodified
International Neuroblastoma Risk Group (INRG) criteria,
High-risk neuroblastoma defined as:
-Stage M neuroblastoma above 365 days of age at diagnosis (no upper
age limit) and Ms neuroblastoma 12-18 months old, any MYCN status*
or -L2, M or Ms neuroblastoma any age with MYCN amplification, or focal
high level MYC or MYCL amplification**.
* In Germany, patients aged less than 18 months with stage M and
without MYCN amplification will not be enrolled in HR-NBL2 trial.
2) No previous chemotherapy or up to 21 days after one cycle of
chemotherapy for patients with localized neuroblastoma with MYCN
amplification or patients with metastatic neuroblastoma treated in
emergency).
3) Females of childbearing potential must have a negative serum or
urine pregnancy test within 7 days prior to initiation of treatment.
Sexually active patients must agree to use acceptable and appropriate
contraception while on HRNBL2 study drug and for one year after
stopping the study. Acceptable contraception is defined in CTFG
Guidelines "Recommendations related to contraception and pregnancy
testing in clinical trials" (Appendix 12). Female patients who are
lactating must agree to stop breast-feeding.
4) Written informed consent to enter the R-I randomization from patient
or parents/legal representative, patient, and age-appropriate assent.
5) Patient affiliated to a social security regimen or beneficiary of the
same according to local requrements.
6) Patients should be able and willing to comply with study visits and
procedures as per protocol.
R-HDC eligibility criteria:
1) Stage M neuroblastoma above 365 days of age at diagnosis, any MYCN
status, EXCEPT patients with stage M or Ms 12-18 months old with
numerical chromosomal alterations only, and in complete metastatic
response at the end of induction: in this case, patients will have surgery
but will not be eligible for R-HDC and will not be able to pursue the trial.
OR
- L2, M or Ms neuroblastoma any age with MYCN amplification or focal
high level MYC or MYCL amplification**
** see section 8 (Biology) for details
2) Age < 21 years
3) Complete response (CR) or partial response (PR) at metastatic sites:
? Bone disease: MIBG uptake (or FDG-PET uptake for MIBG-nonavid
tumors) completely resolved or SIOPEN score = 3 and at least 50%
reduction in mIBG score (or = 3 bone lesions and at least 50% reduction
in number of FDG-PET-avid bone lesions for MIBG-nonavid tumors).
? Bone marrow disease: CR and/or minimal disease (MD) according to
International Neuroblastoma Response Criteria [61;15]
? Other metastatic sites: complete response after induction
chemotherapy +/- surgery.
4) Acceptable organ function and performance status
? Performance status = 50%.
? Hematological status: ANC>0.5x109/L, platelets > 20x 109/L
? Cardiac function (< grade 2)
? Normal chest X-ray and oxygen saturation.
? Absence of any toxicity = grade 3.
5) Sufficient collected stem cells available; minimum required: 6 x 106
CD34+ cells/kg body weight stored in 3 separate fractions.
6) Written informed consent, including agreement of patient or
parents/legal guardian for minors, to enter the R-HDC randomization.
7) Patient affiliated to a social security regimen or beneficiary of the
same according to local requirements.
8) Patients should be able and willing to comply with study visits and
procedures as per protocol.
R-RTx if the following criteria are met:
1) No evidence of di
Exclusion criteria:
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 R-RTx):
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. However, these patients may be kept on study and be considered to receive standard treatment of the respective therapy phase, and may be potentially eligible for subsequent randomisations.
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) Concomitant 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 hypersensitivity to the active substance or to any of the excipients of study drugs
13) Concomitant use with St John?s Wort (Hypericum Perforatum).
Non-inclusion criteria to R-HDC:
Patients with insufficient metastatic response at the end of induction 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, will not be elegible for R-HDC