High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN) (HR-NBL2)

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.

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. The first randomization (R-I) will compare the efficacy of two induction chemotherapies (RAPID COJEC and GPOH regimens) in a phase III setting. The primary endpoint will be the 3-year EFS from date of randomization . The R-I randomization will be stratified on age, stage, MYCN status and countries. The second randomization (R-HDC) will compare the efficacy of single HDC with Bu-Mel versus tandem HDC with Thiotepa followed by Bu-Mel. The primary endpoint is 3-year EFS calculated from the date of the R-HDC randomization. The R-HDC randomization will be stratified on the age, stage, MYCN status, induction chemotherapy regimen, response to induction phase and countries. The impact of local treatment in this phase III setting will be assessed, according to the presence or not of a macroscopic residual disease after surgery and HDC. In case of macroscopic residual disease, 21.6 Gy radiotherapy to the preoperative tumor bed will be randomized (R-RTx) versus the same treatment plus a sequential boost of additional 14.4 Gy to the residual tumor. The primary endpoint of R-RTx is 3-year EFS from the date of the R-RTx randomization. The R-RTx randomization will be stratified on age, stage, MYCN status, induction chemotherapy regimen, HDC regimen and countries. In case of no macroscopic residual disease, 21.6 Gy radiotherapy will be delivered to the preoperative tumor bed.

R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years.

R-HDC: consolidation regimen Bu-Mel vs Thiotepa + Bu-Mel The 3-year EFS in the Bu-Mel arm (with immunotherapy) is estimated to be 55%. This study aims to show an improvement of 12% for the Thiotepa + Bu-Mel arm (3-year EFS of 67%). With a recruitment of 448 patients (224 in each arm) over a period of 3 years and a minimum follow-up of 2 years, the power to show a 12% difference is 80% (two-sided logrank test and α=5%).

< 9kg: 1.0 mg/kg/dose 9 kg to < 16 kg : 1.2 mg/kg/dose 16 kg to 23 kg : 1.1 mg/kg/dose >23 kg to 34 kg: 0.95 mg/kg/dose >34 kg: 0.8 mg/kg/dose Infusion IV over 2 hours Administration every 6 hours for a total of 16 doses

Patients >12 kg are dosed based on the BSA: 10 mg/m^2/day Patients ≤ 12 kg are dosed according to their body weight: 0.33 mg/kg/day

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: Established diagnosis of neuroblastoma according to the SIOPEN-modified 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. No previous chemotherapy or up to 21days one cycle of chemotherapy for patients with localized neuroblastoma with MYCN amplification or patients with metastatic neuroblastoma treated in emergency 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". Female patients who are lactating must agree to stop breast-feeding. Written informed consent to enter the R-I randomization from patient or parents/legal representative, patient, and age-appropriate assent. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements. 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 organ toxicity, exclusion criteria at diagnosis, 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 (rapid COJEC or GPOH) 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: - 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 Age < 21 years 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. Acceptable organ function and performance status Performance status ≥ 50%. Hematological status: ANC > 0.5x10^9/L, platelets > 20x 10^9/L Cardiac function (< grade 2) Normal chest X-ray and oxygen saturation. Absence of any toxicity ≥ grade 3. Sufficient collected stem cells available; minimum required: 6 x 10^6 CD34+ cells/kg body weight stored in 3 separate fractions. Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-HDC randomization. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements. 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 10^6 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 will be eligible for subsequent randomization. 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-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: No evidence of disease progression after HDC/ASCR. Interval between the last ASCR and radiotherapy start between 60 and 90 days. Performance status greater or equal 50%. Hematological status: ANC > 0.5x10^9/L, platelets > 20x10^9/L. Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-RTx randomization. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements. 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 Exclusion Criteria: Non-inclusion criteria specific to the R-I randomization (RAPID COJEC/GPOH) : Urinary tract obstruction ≥ grade 3 Heart failure or myocarditis ≥ grade 2, any arrhythmia or myocardial infection Peripheral motor or sensory neuropathy ≥ grade 3 demyelinating form of Charcot-Marie-Tooth syndrome hearing impairment ≥ grade 2 Concurrent prophylactic use of phenytoin cardiorespiratory disease that contraindicates hyperhydration Non-inclusion criteria common to all randomizations (R-I, R-HDC and R-RTx) : 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. 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. Renal function: Creatinine clearance and/or GFR < 60 ml/min/1.73m^2 (toxicity ≥ grade 2). If GFR < 60 ml/min/1.73m^2, call national principal investigator to discuss about the treatment Dyspnea at rest and/or pulse oximetry < 95% in air. Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent. Participating in another clinical study with an IMP while on study treatment. Concomitant use with yellow fever vaccine and with live virus or bacterial vaccines. Patient allergic to peanut or soya. Chronic inflammatory bowel disease and/or bowel obstruction. Pregnant or breastfeeding women. Known hypersensitivity to the active substance or to any of the excipients of study drugs known 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 eligible for RHDC