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

Inclusion Criteria:

1. 5years ≤ age ≤18 years old, regardless of gender;;

2. ECOG performance status (PS) score: 0～1;

3. The expected survival time is more than 12 weeks;

4. Children with neuroblastoma confirmed by histopathology;

5. Patients who have progressed, recurrent or refractory disease after first-linetreatment (failure to obtain complete or partial remission after recent treatment);

6. With measurable lesions (according to the RECIST 1.1 standard, the CT scan of tumorlesions has a long diameter ≥10mm, and the CT scan of lymph node lesions has a shortdiameter ≥15mm. The measurable lesions have not been treated with radiotherapy orcryotherapy);

7. The patients must recover from the acute toxic effects of all previous anticancerchemotherapy fully;

8. Myelosuppressive chemotherapy: at least 21 days after the last myelosuppressivechemotherapy (If nitrosourea was used in the early stage, the interval time is 42days);

9. Experimental drugs or anti-cancer therapies other than chemotherapy: It is notallowed to use other experimental drugs within 28 days before the planned start ofuse, and it is necessary to fully recover from the clinically significant toxicityof the therapy;

10. Hematopoietic growth factors: at least 14 days after the last administration oflong-acting growth factors or 3 days after the last administration of short-actinggrowth factors;

12. Immunotherapy: At least 42 days after completing any type of immunotherapy (except steroids), such as immune checkpoint inhibitors and tumor vaccines;

14. X-ray therapy (XRT): at least 14 days after local palliative XRT (small-scalemouth); if it is another substantial bone marrow (BM) irradiation, includingpre-radio-iodinated metaiodobenformin (131I-MIBG) treatment, the interval timemust end at least 42 days;

15. Stem cell infusion without total body irradiation (TBI): there is no evidence ofactive graft-versus-host disease, at least 56 days after transplantation or stemcell infusion;

16. Laboratory inspections during the screening period should meet the followingconditions: The absolute value of neutrophils (ANC) ≥1.5×109/L (if the bone marrowis invaded, then ANC≥1.0×109/L) Platelet (PLT) ≥75×109/L (if bone marrow invades,then PLT ≥50×109/L) Bilirubin ≤1.5 times ULN Creatinine ≤ 1.5 times ULN (calculatedaccording to the standard Cockcroft-Gault formula) ALT/AST≤3 times ULN (if there isliver metastasis, it can be relaxed to 5 times ULN);

17. During the study period, patients should be able to comply with outpatienttreatment, laboratory monitoring, and necessary clinical visits;

18. Parents/guardians of a child or young patients have the ability to understand,agree, and sign the research informed consent form (ICF) and applicable childconsent form before initiating any program related procedures; Subjects can expressconsent (where applicable) with the consent of the parent/guardian.

Exclusion Criteria:

1. Symptomatic brain metastases (patients with brain metastases who have completedtreatment 21 days before enrollment and have stable symptoms can be enrolled, butthey need to be evaluated by cranial MRI, CT, or venography to confirm that theyhave no symptoms of cerebral hemorrhage);

2. Imaging (CT or MRI) shows that the tumor focus is ≤ 5 mm from large blood vessels,or there is a tumor that invades local large blood vessels;

3. Patients with hypertension who are using two or more antihypertensive drugs incombination therapy;

4. Patients who suffer from the following cardiovascular diseases: Myocardial ischemiaor myocardial infarction above grade II, poorly controlled arrhythmia (including QTcinterval ≥450 ms for males and ≥470 ms for females); according to NYHA standards,grade III to IV cardiac insufficiency, or the heart color Doppler ultrasoundexamination showed that the left ventricular ejection fraction (LVEF) <50%;

5. Patients with a history of interstitial pulmonary disease or who also suffer fromthe interstitial pulmonary disease;

6. Abnormal coagulation function (INR>1.5 or prothrombin time (PT)>ULN+4 seconds orAPTT>1.5 ULN), have a bleeding tendency or are receiving thrombolytic oranticoagulant therapy;

7. The daily volume of hemoptysis reached two teaspoons or more before enrollment;

8. Patients who have had clinically significant bleeding symptoms or a clear bleedingtendency within 3 months before enrollment, such as gastrointestinal bleeding,hemorrhagic hemorrhoids, hemorrhagic gastric ulcer, fecal occult blood++ and aboveat baseline, or vascular

9. Arterial/venous thrombosis events that occurred in the 12 months before enrollment,such as cerebrovascular accidents (including temporary ischemic attacks, cerebralhemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;

10. Known existing hereditary or acquired bleeding and thrombotic tendency (such ashemophilia, blood coagulation dysfunction, thrombocytopenia, hypersplenism, etc.);

11. Long-term unhealed wounds or fractures (pathological fractures caused by tumors arenot counted);

12. Patients who received major surgery or suffered severe traumatic injury, fracture,or ulcer within 4 weeks of enrollment;

13. some factors significantly affect the absorption of oral drugs, such as inability toswallow, chronic diarrhea, and intestinal obstruction;

14. Abdominal fistula, gastrointestinal perforation, or abdominal abscess occurredwithin 6 months before enrollment;

15. Urine routine test showed urine protein ≥ ++, and confirmed 24-hour urine protein ≥ 1.0 g; Notes: Asymptomatic serous effusions can be included in the group, andsymptomatic serous effusions have been actively treated symptomatically (anti-cancerdrugs cannot be used for the treatment of serious effusions), and patients who arejudged by the investigator can be included in the group，allow to join the group.

16. Active infections require antimicrobial treatment (for example, antibacterial drugsand antiviral drugs are required, excluding chronic hepatitis B anti-hepatitis Btreatment, antifungal drug treatment);

17. Those who have a history of psychotropic drug abuse and cannot be quit or havemental disorders;

18. Participated in other anti-tumor drug clinical trials within 4 weeks before joiningthe group;

19. Previously or concurrently suffering from other uncured malignant tumors, except forcured skin basal cell carcinoma, cervical carcinoma in situ, and superficial bladdercancer;

20. Within 7 days before the first administration, patients used drugs or foods known tobe potent inhibitors of CYP3A4, including but not limited to: atazanavir,clarithromycin, indinavir, itraconazole, ketocon Azole, nefazodone, nelfinafil,ritonavir, saquinavir, telithromycin, acetoeandomycin, voriconazole, etc.;

21. Within 12 days before the first administration, use drugs known to be stronginducers of CYP3A4, including but not limited to: carbamazepine, phenobarbital,phenytoin, rifabutin, and rifapar;

22. Pregnant or breast-feeding women; fertility patients who are unwilling or unable totake effective contraceptive measures;

23. The investigator judges other situations that may affect the conduct of clinicalresearch and the judgment of research results.

24. When the virological test during the screening period shows that any of thefollowing is met:HBsAg is positive and HBV DNA exceeds the upper limit of normalAnti-HCV positive and HCV RNA positive HIV positive.