Overview

This is an international multicenter, open-label, randomized phase III trial including three sequential randomizations to assess efficacy of induction and consolidation chemotherapies and radiotherapy for patients with high-risk neuroblastoma.

Eligibility

Inclusion Criteria:

At diagnosis (or up to 21 days after one cycle of chemotherapy for patients with localized neuroblastoma with MYCN amplification).

R-I eligibility criteria:

1. Established diagnosis of neuroblastoma according to the SIOPEN-modified nternational 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 with MYCN amplification, any age * 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 (except one cycle of Etoposide-Carboplatin or, in Germany and Nertherlands, one course of the current protocol for low/intermediate risk neuroblastoma).
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 study drug and for one year after stopping the study drug. Acceptable contraception is defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials" (Appendix 11). 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.

In case of parents'/patient's refusal to R-I, or renal or liver toxicity, patients can still be enrolled in HR-NBL2 trial with parents'/patient's consent within 3 weeks from the beginning of chemotherapy. Patients will be treated with the standard induction regimen per country and will be potentially eligible for subsequent randomizations.

Randomization for HDC strategy will be performed at the end of induction after the disease evaluation and after surgery of the primary tumor for those patients who will receive surgery before HDC.

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 with MYCN amplification 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 [Park JR, JCO 2017; Burchill S, Cancer 2017].
• 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: Shortening fraction 28% or ejection fraction 55% by echocardiogram, no clinical congestive heart failure. Normal pulmonary artery pressure.
• 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.

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 liver or renal toxicity, HDC will consist on the standard HD Bu-Mel and will be eligible for subsequent randomization.

An evaluation of the local disease will be performed after HDC and surgery:

• In case of no local macroscopic disease, all patients will receive 21-Gy radiotherapy to the pre-operative tumor bed
• In case of local macroscopic residual disease, patients will be eligible to R-RTx if the following criteria are met:
  1. No evidence of disease progression after HDC/ASCR.
  2. Interval between the last ASCR and radiotherapy start between 60 and 90 days.
  3. Performance status greater or equal 50%.
  4. Hematological status: ANC >0.5x109/L, platelets > 20x109/L.
  5. Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-RTx randomization.
  6. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
  7. Patients should be able and willing to comply with study visits and procedures as per protocol.

In case of parents'/patient's refusal of the randomization, the patient will receive 21.6 Gy radiotherapy to the pre-operative tumor bed and pursue the next step of the trial.

Exclusion Criteria:

Non-inclusion criteria specific to the R-I randomization (RAPID COJEC/GPOH) :

1. Urinary outflow obstruction
2. severe arrhythmia, heart failure, previous cardiac infarct, acute inflammatory heart disease
3. severe peripheral neuropathy
4. demyelinating form of Charcot-Marie-Tooth syndrome
5. hearing impairment
6. Concurrent prophylactic use of phenytoin
7. cardiorespiratory disease that contraindicates hyperhydration

Non-inclusion criteria common to all randomizations (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 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.the feasibility.
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 hypersensitivity to the active substance or to any of the excipients of study drugs known
13. Concomitant use with St John's Wort (Hypericum Perforatum).