Apatinib Mesylate Combined With IT Regimen for the Treatment of Recurrent or Refractory Pediatric Neuroblastoma

• ClinicalTrials.gov Identifier: NCT05027386
• Recruitment Status: Not yet recruiting
• First Posted: August 30, 2021
• Last Update Posted: August 31, 2021
• Sponsor: Sun Yat-sen University
• Information provided by (Responsible Party): Yizhuo Zhang, Sun Yat-sen University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Neuroblastoma	Drug: Apatinib, Irinotecan, Temozolomide	Phase 2

Detailed Description:

The enrolled patients diagnosed with recurrent or refractory pediatric neuroblastoma received apatinib combined with IT regimen chemotherapy, the treatment including combination therapy phase and monotherapy maintenance phase.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 62 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Apatinib Mesylate Combined With IT Regimen for the Treatment of Recurrent or Refractory Pediatric Neuroblastoma: Multi-center, Single-arm, Phase II Clinical Study.
• Estimated Study Start Date: August 26, 2021
• Estimated Primary Completion Date: August 26, 2023
• Estimated Study Completion Date: August 30, 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Apatinib Mesylate combined with IT Regimen; The enrolled patients diagnosed with recurrent or refractory pediatric neuroblastoma received apatinib combined with IT regimen chemotherapy, the treatment including combination therapy phase and monotherapy maintenance phase. Combination therapy phase: Apatinib (orally once daily continuously in a 21-day cycle) was combined with IT regimen (repeated every 3 weeks) for up to 6 courses of treatment. Apatinib: <25Kg：0.25g，po，qd； 25Kg≤wight<40Kg：0.425g，po，qd； 40Kg≤wight<50Kg：0.5g，po，qd. IT regimen: Temozolomde：150mg/m2，iv 90min，d1-5，（1h before irinotecan）； Irinotecan: 50mg/m2，iv 90min，d1-5. Monotherapy maintenance phase: Apatinib is administered as a monotherapy until tumor progression, patient withdrawal, or toxicity becomes intolerable.

Drug: Apatinib, Irinotecan, Temozolomide; The enrolled patients diagnosed with recurrent or refractory pediatric neuroblastoma received apatinib combined with IT regimen chemotherapy, the treatment including combination therapy phase and monotherapy maintenance phase.; Other Names: Irinotecan; temozolomide

Outcome Measures

Primary Outcome Measures :

1. Objective response rate [ Time Frame: up to 6 courses of therapy, or about 6 months ]
   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).

Secondary Outcome Measures :

1. Progression-free survival [ Time Frame: up to 60 months ]
   Progression-free survival of apatinib combined with IT regimen in the treatment of relapsed or refractory pediatric neuroblastoma;
2. Overall survival [ Time Frame: up to 60 months ]
   Overall survival of apatinib combined with IT regimen in the treatment of relapsed or refractory pediatric neuroblastoma
3. Duration of remission [ Time Frame: up to 60 months ]
   Duration of remission of apatinib combined with IT regimen in the treatment of relapsed or refractory pediatric neuroblastoma
4. Disease control rate (DCR) [ Time Frame: up to 6 courses of therapy, or about 36 months ]
   Disease control rate (DCR) of apatinib combined with IT regimen in the treatment of relapsed or refractory pediatric neuroblastoma

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Yizhuo Zhang; 020-87342460; zhangyzh@sysucc.org.cn

Sponsors and Collaborators

Sun Yat-sen University

Investigators

• Principal Investigator: Yizhuo Zhang; Sun Yat-sen University

More Information

• Responsible Party: Yizhuo Zhang, Director of department of pediatric cancer,Principal Investigator,Clinical Professor,, Sun Yat-sen University
• ClinicalTrials.gov Identifier: NCT05027386
• Other Study ID Numbers: APTN-01
• First Posted: August 30, 2021
• Last Update Posted: August 31, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Yizhuo Zhang, Sun Yat-sen University:

apatinib; irinotecan; temozolomide; neuroblastoma

Additional relevant MeSH terms:

Neuroblastoma; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Irinotecan; Temozolomide; Apatinib; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors