Immunotherapy With Dinutuximab Beta in Combination With Chemotherapy for the Treatment of Patients With Primary Neuroblastoma Refractory to Standard Therapy and With Relapsed or Progressive Disease

Neuroblastoma (NBL) accounts for 8-10% of all childhood malignancies. It is the most common solid tumor outside the central nervous system in people <18 years of age. It occurs in 6-11 / 1 million children annually. In Poland, NBL is diagnosed annually in 60-70 patients, in 1/3 high-risk disease (HR). In 90% of children, NBL is diagnosed before the age of 5. The diagnosis is made on the basis of the histopathological assessment of the tumor tissue or the presence of NBL cells in the bone marrow together with elevated levels of catecholamines or their metabolites in the urine. The prognostic factors include the patient's age at diagnosis, stage of disease, tumor histopathology, DNA ploidy, MYCN gene status, chromosomal changes, and initial response to therapy. Due to the different course of the disease, the therapeutic decision is made after determining the risk group based on international criteria (International Neuroblastoma Risk Group Stage System, INRGSS and International Neuroblastoma Staging System, INSS). In the lowest-risk group, management is limited to observation or surgery, and in the intermediate-risk group, only standard low- and intermediate-intensity chemotherapy or combined with radiation therapy and surgery is performed. In contrast, HR-NBL uses intensive combination therapy, including standard induction chemotherapy, surgery, high-dose chemotherapy (HD-CHT) and autologous hematopoietic stem cell transplantation (auto-HSCT), radiotherapy and maintenance therapy with 13-cis retinoic acid and targeted immunotherapy with anti-GD2 antibodies. Treatment outcomes in NBL vary from spontaneous tumor regression in some infants to an OS rate of <50% despite intensive combination therapy in the HR-NBL group.

Inclusion criteria

• Diagnosis of NBL according to international criteria (International Neuroblastoma Risk Group, INRG).
• Patients 1-18 years of age with HR-NBL with primary refractory disease, disease progression or recurrence.
• Adequate function of vital organs (if abnormal, dysfunction below grade 4 according to the CTC AE WHO classification, except for disorders defined in the exclusion criteria).
• Life expectancy ≥6 months.
• Obtaining the informed written consent of the patient and/or statutory representative for the treatment.
• Female patients of childbearing potential must consent to the use of effective contraception; Breastfeeding patients must consent to the termination of breastfeeding.
• Patients who have previously received immunotherapy with DB or other anti-GD2 specific antibodies may be eligible for this study.

Exclusion criteria

• Patients with toxicities of ≥3 CTCAE WHO grade, except hearing impairment, hematological disorders, liver and kidney disorders.
• Patients with neurological toxicities of ≥2 CTCAE WHO grade.
• Active life-threatening infection until stabilization of the patient's condition.
• Pregnancy and / or lactation.
• Sexually active patients who refuse to use an effective method of contraception.
• Current treatment with experimental drugs or use of such treatment within 2 weeks before signing the informed consent to participate in the study.
• Radiotherapy within 3 weeks prior to the start of the study.
• Participation in another clinical trial within 6 months before signing the informed consent to participate in the trial (not applicable to clinical trials in 1st line of treatment in HR-NBL).
• Lack of informed written consent to treatment.