Dinutuximab-beta and Chemotherapy in Newly Diagnosed High-Risk Neuroblastoma

This is a prospective, single-arm, pilot study aiming to evaluate the tolerability, safety, and clinical efficacy of incorporating GD2-directed immunotherapy (Dinutuximab-beta) into the frontline induction chemotherapy for high-risk neuroblastoma.

Patients with newly diagnosed high-risk neuroblastoma will receive Dinutuximab-beta administered as a 10-day continuous intravenous infusion (10 mg/m²/day) during Cycles 2 to 6 of the standard 6-cycle induction chemotherapy. The chemotherapy backbone includes cyclophosphamide, vincristine, doxorubicin/epirubicin, etoposide, and cisplatin.

The study is designed with a safety monitoring phase for the initial cohort to evaluate unacceptable toxicities closely. Following the completion of the 6-cycle induction therapy, patients will be assessed for clinical response based on the revised International Neuroblastoma Response Criteria (INRC) before proceeding to standard consolidation therapy, which includes high-dose chemotherapy with stem cell rescue, radiotherapy, and maintenance therapy. Exploratory evaluations will also be conducted to monitor minimal residual disease (MRD), assess event-free and overall survival, and explore the correlation between immune biomarkers and clinical outcomes.

Inclusion criteria

• Must be 1 to 30 years of age at the time of initial diagnosis.
• Must have histological verification of neuroblastoma or ganglioneuroblastoma, OR demonstration of neuroblastoma cells in the bone marrow with elevated urinary VMA at the time of initial diagnosis.
• Must have newly diagnosed high-risk neuroblastoma according to the revised COG NBL risk classifier (version 2), defined as meeting at least ONE of the following:

• INRG Stage M: MYCN amplification (> 4-fold increase), OR age 12 to < 18 months without MYCN amplification but with unfavorable histology/DI = 1/SCA, OR age > 18 months regardless of biologic features.
• INRG Stage MS: MYCN amplification, OR age 12 to < 18 months without MYCN amplification but with unfavorable histology/DI = 1/SCA.
• INRG Stage L2: MYCN amplification, OR age 18 months to < 5 years without MYCN amplification but with unfavorable histology, OR age ≥ 5 years without MYCN amplification but with unfavorable histology (undifferentiated or poorly differentiated tumor).
• INRG Stage L1: Tumor with incomplete resection and MYCN amplification.
• Patients > 18 months of age initially diagnosed with INRG Stage L1, L2, or MS who are subsequently upgraded to high-risk disease.
• Must have had no prior systemic therapy, or have only completed the first cycle of induction chemotherapy under the TPOG N2020-HR protocol.
• Must have measurable disease, defined as at least ONE of the following (Note: Patients with elevated VMA only are NOT eligible):

• Measurable tumor on MRI or CT scan within 3 weeks prior to study entry (≥ 10 mm in at least one dimension) that is MIBG avid or demonstrates increased FDG/FDOPA uptake on PET scan.
• MIBG or FDG/FDOPA PET scan within 2 weeks prior to study entry with positive uptake at a minimum of one site.
• ECOG Performance Status of 0, 1, or 2.
• Adequate organ function, including:

• Renal: Creatinine clearance or estimated GFR ≥ 60 mL/min/1.73 m², or serum creatinine ≤ upper limit of normal (ULN) based on age/gender.
• Liver: Total bilirubin ≤ 1.5 x ULN for age AND SGPT (ALT) ≤ 5.0 x ULN (if liver tumor is present) or ≤ 3.0 x ULN (if no liver tumor).
• CNS: No clinical or radiological evidence of active CNS disease (well-controlled seizures allowed), and CNS toxicity ≤ Grade 2.
• Cardiac: Shortening fraction ≥ 27% or Ejection fraction ≥ 50% by ECHO or gated radionuclide study.
• Pulmonary: No dyspnea at rest, no exercise intolerance, no chronic oxygen requirement, and room air pulse oximetry > 94%.
• Must be enrolled on the TPOG N2020-GD2 protocol with completed informed consent forms, and be willing to proceed to standard therapy of high-risk neuroblastoma with a 10-year follow-up.

Exclusion criteria

• Participation in other interventional clinical trials within 1 month.
• Inability to obey the trial instructions.
• Patients with bone marrow failure syndromes.
• Current requirement for immunosuppressive medications (e.g., tacrolimus, cyclosporine, systemic corticosteroids for reasons other than prevention/treatment of acute allergic reactions or adrenal replacement therapy).
• Females who are pregnant or breastfeeding (A pregnancy test is required for female patients of childbearing potential).

• Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• The subject or their partner is planning to conceive
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method during study therapy and for two months after the last dose of (ch14.18/CHO) (dinutuximab-β) are not eligible.