International and multicentric study that evaluates and compares 2 treatment strategies in 3 therapeutic phases (induction, high-dose chemotherapy and radiotherapy) for patients with high-risk neuroblastoma and introduces chemoimmunotherapy for patients with insufficient metastatic response after induction chemotherapy .

Phase 1

• Conditions: Very High Risk Neuroblastoma; MedDRA version: 20.0Level: PTClassification code 10029260Term: NeuroblastomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10029261Term: Neuroblastoma NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2019-001068-31-AT
• Lead Sponsor: Gustave Roussy Cancer Campus Grand Paris

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-03-06
• Last Update Posted: 5 August 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 800

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

R-I eligibility criteria:
1) 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
2) No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposide 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.
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 with MYCN amplification or focal high level MYC or MYCL amplification
2) Age < 21 years
3) Complete response (CR) or partial response (PR) at metastatic sites
- Bone marrow disease
- Other metastatic sites
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.

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 loca

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 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/1.73m² (toxicity = grade 2). If GFR < 60ml/min/1.73m², 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 nd R-RTx)
5) Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation.
7) Concomittant use with yellow fever vaccine and with live virus or bacterial vaccines.
8) Patient allergic to peanut or soya.

Non-inclusion criteria to R-HDC:
•Any negative answer concerning the R-HDC inclusion criteria

Non-inclusion criteria to chemoimmunotherapy arm:
•Any negative answer concerning the inclusion criteria of chemoimmunotherapy arm.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified