HR-NBL-2

High-risk neuroblastoma represents the largest neuroblastoma subgroup. The prognosis of these patients has been progressively improved over the years through an intensified induction regimen, surgery of the primary tumor, high-dose chemotherapy (HDC) followed by autologous stem cell rescue (ASCR), radiotherapy and immunotherapy. As a result of this strategy, the current 3-year eventfree survival (EFS) is now around 40% from date of randomization and 55% for those patients who complete all the different parts of the treatment. However, a further improvement in patient outcome is warranted.

Primary objectives

R-I:
Comparison of the EFS rate of 2 induction regimens, GPOH and RAPID COJEC, in patients with high-risk neuroblastoma.
R-HDC
Comparison of the EFS rate of single HDC with busulphan and melphalan (Bu-Mel) versus tandem HDC with Thiotepa followed by Bu-Mel in patients with high-risk neuroblastoma
R-RTx:
Comparison of the EFS rate of 21.6 Gy radiotherapy to the preoperative tumor bed versus 21.6 Gy radiotherapy and a sequential boost up to 36 Gy to the residual tumor in patients with macroscopic residual disease after HDC and surgery.

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 R-I randomization will be stratified on age, stage, MYCN status and countries. If the parents or the patient refuse randomization, the patient receives the standard treatment (GPOH in Germany). Treatment after induction chemotherapy will depend on the assessment of the metastatic response after induction chemotherapy.#
  With sufficient metastatic response: Partial metastatic response (greater than 50 % reduction in metastases) and SIOPEN score ≤ 3 for patients with an mIBG-avid tumor or at least a 50 % reduction in FDG-storing lesions in the PET scan for non-mIBG-avid tumors), patients will continue with RHDC and R-RTx.
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 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 R-RTx randomization will be stratified on age, stage, MYCN status, induction chemotherapy regimen, HDC regimen and countries.
In the event of an insufficient response of the metastases to induction chemotherapy: (Insufficient metastatic response with less than 50 % reduction in metastases or SIOPEN score > 3), patients are additionally treated with 3 courses of irinotecan-temozolomide (TEMIRI). Randomization for R-HDC will not take place in this case. This is followed by tandem consolidation with Thiotepa and then Bu-Mel, with each treatment followed by a hematopoietic stem cell transplant (HSC).

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

R-I Inclusion 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 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.
• 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).
• 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 dations related to contraception and pregnancy testing in clin Appendix 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 requrements.
• Patients should be able and willing to comply with study visits and procedures as per protocol.

In case of partent`s/patient`s refusal to R-I, or renal or liver toxicity, patients can still be enrolled in HR-NBL2 trial with partent`s/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.

R-HDC inclusion 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 under 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
• Other metastatic sites: complete response after induction chemotherapy +/- surgery.
• Acceptable organ function and performance status: Performance status ≥ 50 %, Hematological status: ANC > 0.5x109/L, platelets > 20x 109/L, Cardiac function (under grade 2), Normal chest X-ray and oxygen saturation, Absence of any toxicity ≥ grade 3.
• Sufficient collected stem cells available; minimum required: 6 x 106 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 partent´s or 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.

R-RTx - inclusion criteria

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:

• 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 >0.5x109/L, platelets > 20x109/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 partent´s or 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.

Main exclusion-criteria specific for the randomization R-I (RAPID COJEC/GPOH):

• Urinary outflow obstructionsevere arrhythmia, heart failure, previous cardiac infarct, acute
• inflammatory heart disease
• severe peripheral neuropathy
• demyelinating form of Charcot-Marie-Tooth syndrome
• hearing impairment
• Concurrent prophylactic use of phenytoin
• cardiorespiratory disease that contraindicates hyperhydration

Exclusion-criteria specific for the randomization R-HDC

• Patienten mit einem unzureichenden metastatischen Ansprechen am Ende der Induktionstherapie (SIOPEN-Score >3 oder Ansprechen von weniger als 50 % des SIOPEN mIBG-Score oder bei einem nicht mIBG-aviden Tumor eine Abnahme der sichtbaren Läsionen um weniger als 50 % oder mehr als 3 verbleibende Läsionen auf dem FDG PET-Scan) sind nicht für die R-HDC geeignet.

Main exclusion-criteria for all randomizations (R-I, R-HDC und RRTx):

• In Germany, patients aged less than 18 months with stage M and without MYCN amplification will not be enrolled in the HR-NBL2 trial
• In Germany, patients who are accommodated in an institution due to the order of a court or an authority will not be enrolled in the HR-NBL2 trial.
• 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 under 60 ml/min/1.73m² (toxicity ≥ grade 2). If GFR under 60ml/min/1.73m², call national principal
• investigator to discuss about the treatment.
• Dyspnea at rest and/or pulse oximetry under 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.
• Concomittant 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
• 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