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-line
treatment (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 tumor
lesions has a long diameter ≥10mm, and the CT scan of lymph node lesions has a short
diameter ≥15mm. The measurable lesions have not been treated with radiotherapy or
cryotherapy);
7. The patients must recover from the acute toxic effects of all previous anticancer
chemotherapy fully;
8. Myelosuppressive chemotherapy: at least 21 days after the last myelosuppressive
chemotherapy (If nitrosourea was used in the early stage, the interval time is 42
days);
9. Experimental drugs or anti-cancer therapies other than chemotherapy: It is not allowed
to use other experimental drugs within 28 days before the planned start of use, and it
is necessary to fully recover from the clinically significant toxicity of the therapy;
10. Hematopoietic growth factors: at least 14 days after the last administration of
long-acting growth factors or 3 days after the last administration of short-acting
growth factors;
11. 11. Immunotherapy: At least 42 days after completing any type of immunotherapy (except
steroids), such as immune checkpoint inhibitors and tumor vaccines;
12. 12. X-ray therapy (XRT): at least 14 days after local palliative XRT (small-scale
mouth); if it is another substantial bone marrow (BM) irradiation, including
pre-radio-iodinated metaiodobenformin (131I-MIBG) treatment, the interval time must
end at least 42 days;
13. Stem cell infusion without total body irradiation (TBI): there is no evidence of
active graft-versus-host disease, at least 56 days after transplantation or stem cell
infusion;
14. Laboratory inspections during the screening period should meet the following
conditions: The absolute value of neutrophils (ANC) ≥1.5×109/L (if the bone marrow is
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 (calculated
according to the standard Cockcroft-Gault formula) ALT/AST≤3 times ULN (if there is
liver metastasis, it can be relaxed to 5 times ULN);
15. During the study period, patients should be able to comply with outpatient treatment,
laboratory monitoring, and necessary clinical visits;
16. Parents/guardians of a child or young patients have the ability to understand, agree,
and sign the research informed consent form (ICF) and applicable child consent form
before initiating any program related procedures; Subjects can express consent (where
applicable) with the consent of the parent/guardian.
Exclusion Criteria:
1. Symptomatic brain metastases (patients with brain metastases who have completed
treatment 21 days before enrollment and have stable symptoms can be enrolled, but they
need to be evaluated by cranial MRI, CT, or venography to confirm that they have 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 in
combination therapy;
4. Patients who suffer from the following cardiovascular diseases: Myocardial ischemia or
myocardial infarction above grade II, poorly controlled arrhythmia (including QTc
interval ≥450 ms for males and ≥470 ms for females); according to NYHA standards,
grade III to IV cardiac insufficiency, or the heart color Doppler ultrasound
examination showed that the left ventricular ejection fraction (LVEF) <50%;
5. Patients with a history of interstitial pulmonary disease or who also suffer from the
interstitial pulmonary disease;
6. Abnormal coagulation function (INR>1.5 or prothrombin time (PT)>ULN+4 seconds or
APTT>1.5 ULN), have a bleeding tendency or are receiving thrombolytic or anticoagulant
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 bleeding
tendency within 3 months before enrollment, such as gastrointestinal bleeding,
hemorrhagic hemorrhoids, hemorrhagic gastric ulcer, fecal occult blood++ and above at
baseline, or vascular. 9. Arterial/venous thrombosis events that occurred in the 12 months before enrollment,
such as cerebrovascular accidents (including temporary ischemic attacks, cerebral
hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
10. Known existing hereditary or acquired bleeding and thrombotic tendency (such as
hemophilia, blood coagulation dysfunction, thrombocytopenia, hypersplenism, etc.);
11. Long-term unhealed wounds or fractures (pathological fractures caused by tumors are
not 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 to
swallow, chronic diarrhea, and intestinal obstruction;
14. Abdominal fistula, gastrointestinal perforation, or abdominal abscess occurred within
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, and
symptomatic serous effusions have been actively treated symptomatically (anti-cancer
drugs cannot be used for the treatment of serious effusions), and patients who are
judged by the investigator can be included in the group，allow to join the group.
16. Active infections require antimicrobial treatment (for example, antibacterial drugs
and antiviral drugs are required, excluding chronic hepatitis B anti-hepatitis B
treatment, antifungal drug treatment);
17. Those who have a history of psychotropic drug abuse and cannot be quit or have mental
disorders;
18. Participated in other anti-tumor drug clinical trials within 4 weeks before joining
the group;
19. Previously or concurrently suffering from other uncured malignant tumors, except for
cured skin basal cell carcinoma, cervical carcinoma in situ, and superficial bladder
cancer;
20. Within 7 days before the first administration, patients used drugs or foods known to
be 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 strong inducers
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 to
take effective contraceptive measures;
23. The investigator judges other situations that may affect the conduct of clinical
research and the judgment of research results.
24. When the virological test during the screening period shows that any of the following
is met:HBsAg is positive and HBV DNA exceeds the upper limit of normal Anti-HCV
positive and HCV RNA positive HIV positive.
