Estudo de Fase II de Chidamida-Dinutuximab Beta-Irinotecano-Temozolomida para Neuroblastoma Refratário/Recorrente em Crianças

Inclusion Criteria:

1. Age 0-18 years at enrolment.
2. Histologically diagnosed neuroblastoma defined as high-risk according to the International Neuroblastoma Risk Group classification or Chinese consensus/guideline risk classification.
3. Relapsed or refractory neuroblastoma. Relapse is defined as any recurrence of neuroblastoma. Refractory disease is defined as inadequate response to prior therapy, including partial response, minor response or stable disease, followed by progression.
4. Prior exposure to histone deacetylase inhibitors, DNA methylation inhibitors or GD2 monoclonal antibodies does not preclude eligibility.
5. Presence of evaluable disease.
6. Performance status of Lansky score >=50%, Karnofsky score >=50% or ECOG performance status <=3.
7. Life expectancy >=12 weeks.
8. Adequate bone marrow function: for patients without bone marrow disease, platelet count >=75 x 10^9/L, absolute neutrophil count >=0.75 x 10^9/L and haemoglobin >=8 g/dL with transfusion permitted; for patients with bone marrow disease, platelet count >=50 x 10^9/L, absolute neutrophil count >=0.5 x 10^9/L and haemoglobin >=8 g/dL with transfusion permitted.
9. Renal function without clinically significant proteinuria. If urine dipstick protein is >=2+, protein:creatinine ratio must be <0.5 or 24-hour protein excretion must be <0.5 g.
10. Serum creatinine <=1.5 x upper limit of normal or calculated glomerular filtration rate >=60 mL/min/1.73 m2 if serum creatinine is higher.
11. Adequate liver function: AST or ALT <=2.5 x upper limit of normal and total bilirubin <=1.5 x upper limit of normal; in the presence of hepatic metastases, AST or ALT <=5 x upper limit of normal and total bilirubin <=2.5 x upper limit of normal.
12. Cardiac shortening fraction >=29% on echocardiography.
13. Coagulation function with INR <=1.5 and APTT <=1.5 x upper limit of normal for age if not receiving anticoagulation; anticoagulation is permitted if INR or APTT is within the therapeutic range and the dose has been stable for at least 2 weeks before registration.
14. Oxygen saturation >94% without supplemental oxygen. Ability to comply with the visit schedule and other protocol requirements.

Exclusion Criteria:

1. Patients with CTCAE v5.0 Grade 3 or higher toxicities involving hearing impairment, hematologic disorders, hepatic, or renal diseases.
2. Patients with CTCAE v5.0 Grade 2 or higher neurotoxicity.
3. Major surgical procedure within 14 days prior to the first dose of the study drug.
4. Severe infection (requiring IV antibiotics, antifungals, or antivirals) within one week prior to treatment, or unexplained fever >38.5°C during screening or before the first dose.
5. Congenital or acquired immunodeficiency, or active infectious diseases such as HIV or active hepatitis (with transaminase levels not meeting inclusion criteria; HBV DNA ≥1000 IU/mL; HCV RNA ≥1000 IU/mL). Chronic HBV carriers with HBV DNA <2000 IU/mL may be enrolled if they receive concurrent antiviral therapy during the trial.
6. Any concomitant condition that, in the investigator's judgment, seriously jeopardizes patient safety, may confound the study results, or could impede the patient's completion of the study.