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.

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-DE
• Lead Sponsor: Gustave Roussy

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2023-02-17
• Last Update Posted: 18 September 2023

Recruitment & Eligibility

• Status: A
• Sex: All
• Target Recruitment: 800

Inclusion Criteria

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**.
* 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 a

Exclusion Criteria

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 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) 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
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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

Study & Design

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