Apatinib Mesylate Combined With IT Regimen for the Treatment of Recurrent or Refractory Neuroblastoma: A Single-arm, Phase I/II，Multi-center, Clinical Study.

The enrolled patients diagnosed with recurrent or refractory neuroblastoma received apatinib combined with IT regimen chemotherapy, including phase I and phase II stage. During the Phase I stage, apatinib was administered using a 3+3 dose escalation design with three dose cohorts. The IT regimen was maintained at fixed doses, with patients receiving up to 8 cycles of chemotherapy. The recommended Phase II dose (RP2D) was determined from the Phase I dose-escalation phase.

In the Phase II stage, the study included an apatinib combination therapy phase and an apatinib maintenance therapy phase. During the combination therapy phase, apatinib was administered at the RP2D in combination with the IT regimen (at fixed doses) for up to 8 cycles. In the maintenance therapy phase, apatinib was administered orally as a single agent at the RP2D until disease progression or intolerable toxicity occurred.

Inclusion criteria

• Age ≥2 years (for patients enrolled in Phase 1, age <18 years); no gender restriction.
• Karnofsky Performance Status (KPS) score ≥50 for patients aged ≥16 years, or Lansky Performance Status (LPS) score ≥50 for patients aged <16 years (see Appendix 1).
• Estimated life expectancy of at least 12 weeks.
• Histologically confirmed diagnosis of neuroblastoma meeting clinical diagnostic criteria.
• Disease progression, recurrence, or treatment resistance (failure to achieve CR or PR following the most recent therapy) after first-line treatment.
• Measurable or evaluable disease (per INRC criteria; see Appendix 3; target lesions must not have received prior local treatment such as radiotherapy or cryotherapy).
• Complete recovery from all acute toxic effects of prior anticancer chemotherapy.
• Myelosuppressive chemotherapy: at least 21 days since the last myelosuppressive chemotherapy regimen (or 42 days if nitrosoureas were administered).
• Investigational agents or anticancer therapies other than chemotherapy: must not have been administered within 28 days prior to the planned initiation of the AIT regimen. Complete recovery from any clinically significant toxicity associated with such therapy must be confirmed.
• Hematopoietic growth factors: at least 14 days since the last administration of long-acting growth factors, or at least 3 days since the last administration of short-acting growth factors.
• Immunotherapy: at least 42 days since completion of any type of immunotherapy (excluding corticosteroids), such as immune checkpoint inhibitors or tumor vaccines.
• Radiotherapy (XRT): at least 14 days since localized palliative XRT (small-field irradiation); for other substantial bone marrow irradiation, including prior ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) therapy, a minimum interval of 42 days is required.
• Stem cell infusion without total body irradiation: no evidence of active graft-versus-host disease, and at least 56 days since transplantation or stem cell infusion.
• Laboratory tests during the screening period must meet the following criteria:

(1)Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L (≥1.0 × 10⁹/L if bone marrow involvement is present) (2)Platelet count (PLT) ≥75 × 10⁹/L (≥50 × 10⁹/L if bone marrow involvement is present) (3)Total bilirubin ≤1.5 × upper limit of normal (ULN) (4)Serum creatinine ≤1.5 × ULN (5)Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤3 × ULN (may be ≤5 × ULN in the presence of liver metastases) 15.Ability to comply with outpatient treatment, laboratory monitoring, and required clinical visits during study participation.

16.Parents/legal guardians of pediatric or adolescent subjects must be capable of understanding, agreeing to, and signing the informed consent form (ICF) and applicable pediatric assent forms prior to the initiation of any protocol-related procedures. With parental/guardian consent, subjects must be capable of expressing assent (where applicable).

Exclusion criteria

Patients meeting any of the following criteria are ineligible for inclusion in this study:

• Symptomatic brain metastases (patients with brain metastases who have completed treatment within 21 days prior to enrolment and have stable symptoms may be enrolled, provided that cranial magnetic resonance imaging [MRI], computed tomography [CT], or venography confirms the absence of cerebral haemorrhage).
• Imaging (CT or MRI) demonstrating that the tumour lesion is located ≤5 mm from a major blood vessel, or that the tumour invades a local major blood vessel.
• Hypertension currently requiring treatment with two or more antihypertensive medications.
• Prior or concurrent clinically significant cardiovascular disease, including congenital heart disease, pericardial disease, history of heart failure, myocardial infarction, coronary artery disease, valvular heart disease, cardiomyopathy, or arrhythmias (including persistent atrial fibrillation, complete left bundle branch block, or frequent premature ventricular contractions); corrected QT interval (QTc) >480 ms; New York Heart Association (NYHA) Class III-IV cardiac dysfunction for patients aged >3 years or corresponding criteria for infantile cardiac function for patients aged ≤3 years (see Appendix 2); or echocardiography demonstrating left ventricular ejection fraction (LVEF) <50%.
• History of or concurrent interstitial lung disease.
• Abnormal coagulation function (international normalised ratio [INR] >1.5, prothrombin time [PT] >ULN + 4 seconds, or activated partial thromboplastin time [APTT] >1.5 × ULN), bleeding tendency, or ongoing thrombolytic or anticoagulant therapy.
• Haemoptysis of ≥2 teaspoons daily prior to enrolment.
• Clinically significant bleeding symptoms or clear bleeding tendency within the preceding 3 months, such as gastrointestinal bleeding, haemorrhagic haemorrhoids, haemorrhagic gastric ulcer, baseline faecal occult blood ≥++, or vasculitis.
• Arterial or venous thromboembolic events within 12 months prior to enrolment, including cerebrovascular accident (transient ischaemic attack, cerebral haemorrhage, or cerebral infarction), deep vein thrombosis, or pulmonary embolism.
• Known hereditary or acquired bleeding or thrombotic tendency (e.g., haemophilia, coagulation disorders, thrombocytopenia, or hypersplenism).
• Chronic non-healing wounds or fractures (excluding pathological fractures caused by tumours).
• Major surgical procedure, severe traumatic injury, fracture, or ulcer within 4 weeks prior to enrolment.
• Factors that significantly affect absorption of oral medications, such as inability to swallow, chronic diarrhoea, or intestinal obstruction.
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to enrolment.
• Urinalysis showing urinary protein ≥++, with confirmed 24-hour urinary protein excretion ≥1.0 g.
• Symptomatic serous effusion requiring intervention (including pleural effusion, ascites, and pericardial effusion). Note: Patients with asymptomatic serous effusion may be enrolled. Patients with symptomatic serous effusion who have received active symptomatic management (anticancer drugs are not permitted for the treatment of serous effusion) and are deemed eligible by the investigator may be enrolled.
• Active infection requiring antimicrobial therapy (e.g., antibacterial or antiviral agents, excluding anti-hepatitis B virus [HBV] therapy for chronic hepatitis B or antifungal therapy).
• History of psychotropic substance abuse with inability to abstain, or presence of a psychiatric disorder.
• Participation in another clinical trial involving antitumour agents within 4 weeks prior to enrolment.
• Prior or concurrent untreated malignancy, excluding cured basal cell carcinoma of the skin, cervical carcinoma in situ, or superficial bladder cancer.
• Use of medications or foods known to be potent cytochrome P450 3A4 (CYP3A4) inhibitors within 7 days prior to the first dose, including but not limited to: atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole.
• Use of medications known to be potent CYP3A4 inducers within 12 days prior to the first dose, including but not limited to: carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampicin.
• Any other condition that, in the investigator's judgement, may affect the conduct of the clinical study or interpretation of results.
• Virological tests during the screening period meeting any of the following criteria:

(1)Hepatitis B surface antigen (HBsAg)-positive with HBV DNA levels exceeding the ULN (2)Anti-hepatitis C virus (HCV) antibody-positive and HCV ribonucleic acid (RNA)-positive Human immunodeficiency virus (HIV)-positive