Clinical Trials/NCT05303727

NCT05303727

Not yet recruiting

Phase 2

Clinical Research of Allogeneic Hematopoietic Stem Cell Transplantation for Treatment of Children With Stage 4/M Neuroblastoma: A Prospective, Single-arm, Phase II, Multi-center Trial

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University1 site in 1 country64 target enrollmentAugust 2022

Overview

Phase: Phase 2
Intervention: Anti Thymocyte Globulin
Conditions: Neuroblastoma
Sponsor: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Enrollment: 64
Locations: 1
Primary Endpoint: overall survival(OS) at 3 year
Status: Not yet recruiting
Last Updated: 3 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

Neuroblastoma (NB) is the most common extracranial solid tumor of embryonal origin in children. According to the International Neuroblastoma Risk Group (INRG) staging criteria and the International Neuroblastoma Staging System (INSS) ，NB preoperative staging is divided into L1, L2, M and Ms stages, the postoperative staging is divided into 1 to 4 stages and 4s stage. Among them, 4/M stage is of the highest degree of malignancy and the worst prognosis. Despite the aggressive combination therapy, the 5-year survival rate (OS) is still less than 15%, and the 2-year relapse rate is 80%. Currently, no effective treatment is accessible for refractory/relapsed stage 4/M NB after completing conventional therapy.

In hematopoietic stem cell transplantation (HSCT) , conditioning regimen with high-dose radiotherapy and chemotherapy is implemented to eradicate tumor cells and abnormal clonal cells in the patient, block the pathogenesis, and restore the patient's hematopoietic and immune systems by transplanting normal hematopoietic stem cells. According to the source of hematopoietic stem cells, HSCT can be divided into two types: autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). It has been confirmed that benefiting from the graft versus tumor(GVT) effect, allo-HSCT can clear residual lesions in refractory/relapsed NB patients post-auto-HSCT，and prolong the survival time of patients. Our center has explored the conditioning regimen, treatment of residual tumor lesions before transplantation, and strategies to reduce transplantation-related death (TRM) and enhance the GVT effect. However, the sample size is small, and multicenter and larger sample size research are needed. This study will further observe the clinical efficacy and safety of allo-HSCT in the treatment of 4/M stage NB, and provide a new treatment method and option for 4/M stage NB.

Detailed Description

Purposes: To evaluate the efficacy and safety of allo-HSCT in children with stage 4/M high-risk NB through a multi-center prospective single-arm clinical research grouped according to different types of donors, graft sources, and stratified conditioning regimen. Primary objectives: To evaluate the efficacy (3-year OS, EFS) of allo-HSCT in the treatment of children with stage 4/M NB through a multicenter prospective single-arm clinical study. Secondary objectives: 1. To evaluate the safety of allo-HSCT in the treatment of children with stage 4/M NB \[toxicity of conditioning regimen, engraftment rate, early transplantation-related mortality (\<100d TRM), transplantation-related complications (VOD, thrombotic microangiopathy(TMA), acute/chronic graft-versus-host disease (GVHD), Epstein-Barr virus(EBV)/cytomegalovirus(CMV) viremia and EBV/CMV related diseases or other pathogenic infections, etc.\]; 2. Improvement and optimization of allo-HSCT conditioning regimen. Outline: This is a multicenter study. Conditioning regimen: There are 3 protocols according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+cyclophosphamide (CTX)+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used). Transplantation: Patients undergo cord blood stem cell or bone marrow or granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood stem cell transplantation on day 0. GVHD prophylaxis: Cyclosporine or tacrolimus combined with methotrexate is used for related matched transplantation, cyclosporine combined with mycophenolate mofetil for umbilical cord blood transplantation, and cyclosporine combined with mycophenolate mofetil and methotrexate for haploidentical transplantation to prevent GVHD. After completion of transplantation, patients are followed periodically at least 3 years.

Registry

clinicaltrials.gov

Start Date

August 2022

End Date

August 2027

Last Updated

3 years ago

Study Type

Interventional

Study Design

Single Group

Sex

All

Investigators

Sponsor

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•one of the following criteria (2), (3) or (4) must be met and all other criterions must be met at the same time:
•Age≤18 years old;
•After at least 7 courses of induction chemotherapy (surgical resection of the primary tumor or metastatic disease has been completed during the period), evaluation of disease is CR, tumor markers (blood NSE and urine VMA) and minimal residual disease by flow cytometry of bone marrow and peripheral blood are negative; the primary tumor has completed radiotherapy before HSCT;
•For patients with PR or VGPR, tumor markers (blood NSE and urine VMA) and minimal residual disease by flow cytometry of bone marrow and peripheral blood are negative; the primary tumor and metastatic lesions have completed radiotherapy before HSCT;
•Relapsed patients achieve CR/VGPR/PR after re-induction or salvage chemotherapy, tumor markers (blood NSE and urine VMA) and minimal residual disease by flow cytometry of bone marrow and peripheral blood are negative; the primary tumor and metastatic lesions have completed radiotherapy before HSCT;
•Whole brain and whole spinal cord radiotherapy have completed before HSCT in patients with central invasion at onset;
•The blood routine has generally returned to normal and there is no dysfunction of major organs such as the heart, liver, lung, and kidney;
•The guardian/patient accept the treatment of this research, sign the informed consent, and complete the follow-up.

Exclusion Criteria

•meeting one of the following criterions:
•With severe cardiac insufficiency, cardiac ejection fraction (EF) is less than 50%; or severe cardiac disease, the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
•With severe pulmonary insufficiency (severe obstructive and/or restrictive ventilation disorders), the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
•With severe liver function impairment, ALT\>5 times upper limit of normal, or total bilirubin\>3 times upper limit of normal; the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
•With severe renal insufficiency, creatinine\>2 times upper limit of normal; or corrected creatinine clearance rate Ccr\<50ml/min; the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
•With severe active bleeding or severe active infection; the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
•Allergic reactions or serious adverse reactions occurred in the previous use of conditioning regimen-related drugs, the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
•The guardian/patient cannot understand or comply with the treatment plan;
•Other reasons for not being selected due to the investigator's evaluation.

Arms & Interventions

Conditioning regimen for different sources of donors

There are 3 groups according to different sources of donor: (1) Cord blood HSCT: Flu+Bu+CTX+Topotecan (without ATG); (2) Peripheral blood HSCT or haploid bone marrow combined with peripheral stem cell transplantation: Flu+Bu+Melphalan+Antithymocyte globulin (ATG)+ Thiotepa (TT) or (3) Flu+Bu+Melphalan+ATG (applicable to peripheral stem cells or haploid bone marrow combined with peripheral stem cell transplantation for which TT cannot be used).

Intervention: Anti Thymocyte Globulin

Conditioning regimen for different sources of donors

Intervention: Fludarabine

Conditioning regimen for different sources of donors

Intervention: Cyclophosphamide injection

Conditioning regimen for different sources of donors

Intervention: Topotecan

Conditioning regimen for different sources of donors

Intervention: Melphalan

Conditioning regimen for different sources of donors

Intervention: Thiotepa

Conditioning regimen for different sources of donors

Intervention: Busulfan

Conditioning regimen for different sources of donors

Intervention: Cyclosporine

Conditioning regimen for different sources of donors

Intervention: Tacrolimus

Conditioning regimen for different sources of donors

Intervention: Mycophenolate Mofetil

Conditioning regimen for different sources of donors

Intervention: Methotrexate

Outcomes

Primary Outcomes

overall survival(OS) at 3 year

Time Frame: 3 years post-HSCT

From the date of day 0 of transplantation until the date of death from any cause

event free survival(EFS) at 3 year

Time Frame: 3 years post-HSCT

Survival time from day 0 of transplantation to the occurrence of the first adverse event. Disease or treatment-related adverse events, such as tumor recurrence, implant failure, and death, are counted in this study; accidental deaths that assessed unrelated to the above factors are not included

Secondary Outcomes

incidence of transplant associated thrombotic microangiopathy(TA-TMA)(3 years post-HSCT)
incidence of donor engraftment(100 days post-HSCT)
early transplant-related mortality(100 days post-HSCT)
incidence of infection(3 years post-HSCT)
incidence of conditioning toxicity(100 days post-HSCT)
incidence of sinusoidal obstruction syndrome(3 years post-HSCT)
incidence of acute graft versus host disease(100 days post-HSCT)
incidence of chronic graft versus host disease(3 years post-HSCT)