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.

The survival rate of recurrent and refractory pediatric neuroblastoma is low and the prognosis is poor. Apatinib mesylate is a highly selective small-molecule vasoendothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor. Apatinib mesylate has been shown to be safe and effective in recurrent or refractory pediatric neuroblastoma in Sun Yat-sen University Cancer Center. Apatinib mesylate combined with IT regimen is expected to further improve the efficacy and survival rate of recurrent or refractory pediatric neuroblastoma.

Study Overview

• Status: Recruiting
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: Apatinib, Irinotecan, Temozolomide

Detailed Description

The enrolled patients diagnosed with recurrent or refractory pediatric 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 6 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 6 cycles. In the maintenance therapy phase, apatinib was administered orally as a single agent at the RP2D until disease progression or intolerable toxicity occurred.

• Study Type: Interventional
• Enrollment (Estimated): 125
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yizhuo Zhang; Phone Number: 020-87342460; Email: zhangyzh@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • Yizhuo Zhang
      • Contact: Yizhuo Zhang; Phone Number: 87342460; Email: zhangyzh@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: The first dose level; The first dose level of apatinib combined with fixed-dose 5-day courses of irinotecan (50 mg/m²/dose infused IV 90 min) plus temozolomide (100 mg/m²/dose infused IV 90 min) for up to six courses.	Drug: Apatinib, Irinotecan, Temozolomide; In 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 6 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 6 cycles. In the maintenance therapy phase, apatinib was administered orally as a single agent at the RP2D until disease progression or intolerable toxicity occurred.; Other Names: Irinotecan; temozolomide
Experimental: The second dose level; The second dose level of apatinib combined with fixed-dose 5-day courses of irinotecan (50 mg/m²/dose infused IV 90 min) plus temozolomide (100 mg/m²/dose infused IV 90 min) for up to six courses.	Drug: Apatinib, Irinotecan, Temozolomide; In 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 6 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 6 cycles. In the maintenance therapy phase, apatinib was administered orally as a single agent at the RP2D until disease progression or intolerable toxicity occurred.; Other Names: Irinotecan; temozolomide
Experimental: The third dose level; The third dose level of apatinib combined with fixed-dose 5-day courses of irinotecan (50 mg/m²/dose infused IV 90 min) plus temozolomide (100 mg/m²/dose infused IV 90 min) for up to six courses.	Drug: Apatinib, Irinotecan, Temozolomide; In 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 6 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 6 cycles. In the maintenance therapy phase, apatinib was administered orally as a single agent at the RP2D until disease progression or intolerable toxicity occurred.; Other Names: Irinotecan; temozolomide
Experimental: Phase 2: The RPIID group; Based on the Phase I stage of apatinib, the recommended phase II dose was administered in combination with the IT regimen every three weeks for up to six cycles, followed by maintenance therapy with apatinib until tumor progression recurrence or unacceptable toxicity.	Drug: Apatinib, Irinotecan, Temozolomide; In 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 6 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 6 cycles. In the maintenance therapy phase, apatinib was administered orally as a single agent at the RP2D until disease progression or intolerable toxicity occurred.; Other Names: Irinotecan; temozolomide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	In the phase I stage, the primary endpoint is RPIID. In the phase II stage, the primary outcome was the objective response rate of apatinib combined with IT in the treatment of recurrent or refractory pediatric neuroblastoma, including complete response (CR) and partial response (PR).	up to 6 courses of therapy, or about 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Progression-free survival of apatinib combined with IT regimen in the treatment of relapsed or refractory pediatric neuroblastoma;	up to 60 months
Overall survival	Overall survival of apatinib combined with IT regimen in the treatment of relapsed or refractory pediatric neuroblastoma	up to 60 months
Duration of remission	Duration of remission of apatinib combined with IT regimen in the treatment of relapsed or refractory pediatric neuroblastoma	up to 60 months
Disease control rate (DCR)	Disease control rate (DCR) of apatinib combined with IT regimen in the treatment of relapsed or refractory pediatric neuroblastoma	up to 6 courses of therapy, or about 36 months

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Principal Investigator: Yizhuo Zhang, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2021
• Primary Completion (Actual): February 4, 2026
• Study Completion (Estimated): February 4, 2026

Study Registration Dates

• First Submitted: August 22, 2021
• First Submitted That Met QC Criteria: August 24, 2021
• First Posted (Actual): August 30, 2021

Study Record Updates

• Last Update Posted (Actual): February 5, 2026
• Last Update Submitted That Met QC Criteria: February 4, 2026
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: apatinib; irinotecan; neuroblastoma; temozolomide
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neuroblastoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Camptothecin; Alkaloids; Dacarbazine; Triazenes; Imidazoles; Temozolomide; Irinotecan; apatinib
• Other Study ID Numbers: AIT-NB-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No