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Allogeneic Hematopoietic Stem Cell Transplantation for 4/M Neuroblastoma

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ClinicalTrials.gov Identifier: NCT05303727
Recruitment Status : Not yet recruiting
First Posted : March 31, 2022
Last Update Posted : July 1, 2022
Sponsor:
Information provided by (Responsible Party):
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

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.


Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: Anti Thymocyte Globulin Drug: Fludarabine Drug: Cyclophosphamide injection Drug: Topotecan Drug: Melphalan Drug: Thiotepa Drug: Busulfan Drug: Cyclosporine Drug: Tacrolimus Drug: Mycophenolate Mofetil Drug: Methotrexate Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 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).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : August 2022
Estimated Primary Completion Date : August 2027
Estimated Study Completion Date : August 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
Experimental: 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).
Drug: Anti Thymocyte Globulin
2.5 mg/kg/day;2 doses on day -3 and day -2 for matched sibling donor transplantation;3 doses on day -4,-3 and day -2 for unrelated donor transplantation;4 doses on day -5,-4,-3 and day -2 for haploidentical donor transplantation
Other Name: ATG

Drug: Fludarabine
30 mg/m2/day for 5 days
Other Name: Fludara

Drug: Cyclophosphamide injection
60 mg/kg/day for 2 days in cord blood stem cell transplantation
Other Name: CTX

Drug: Topotecan
2mg/m2/day for 3 days in cord blood stem cell transplantation
Other Name: Topotecan Hydrochloride

Drug: Melphalan
70mg/m2/day,for peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation;2 doses on day -3 and day -2 when conditioning regimen containing thiotepa;3 doses on day -4,-3 and day -2 when conditioning regimen not containing thiotepa;
Other Name: Alkeran

Drug: Thiotepa
5 mg/kg/day for 2 days in peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation
Other Name: thiophosphoramide

Drug: Busulfan
0.8mg/kg/dose;8 doses in cord blood stem cell transplantation;12 doses in peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation when conditioning regimen containing thiotepa;16 doses in peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation when conditioning regimen not containing thiotepa;
Other Name: Busulfex

Drug: Cyclosporine
2.5~4 mg/kg/dose every 12 hours orally;1.5~2 mg /kg/dose every 12 hours intravenously; trough concentration maintained at 150~250ng/ml
Other Name: Sandimmune

Drug: Tacrolimus
0.02~0.03 mg/kg/day as continuous infusion or 12 hour divided doses
Other Name: Prograf

Drug: Mycophenolate Mofetil
15 mg/kg/dose every 12 hours
Other Name: Cellcept

Drug: Methotrexate
15 mg/m2/dose on d+1 and 10 mg/m2/dose on d+3,d+6 in peripheral stem cell transplantation
Other Name: amethopterin




Primary Outcome Measures :
  1. 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

  2. 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 Outcome Measures :
  1. incidence of conditioning toxicity [ Time Frame: 100 days post-HSCT ]
    Conditioning toxicity is graded according to the Common Terminology Criteria for Adverse Events(CTCAE Version 5.0)

  2. incidence of donor engraftment [ Time Frame: 100 days post-HSCT ]
    Donor engraftment represents donor cells replace at least 95% of recipient hematopoietic stem cells.

  3. early transplant-related mortality [ Time Frame: 100 days post-HSCT ]
    Death due to transplantation, excluding other causes such as disease progression or relapse.

  4. incidence of sinusoidal obstruction syndrome [ Time Frame: 3 years post-HSCT ]
    Sinusoidal obstruction syndrome is diagnosed according to classification from the European society for blood and marrow transplantation.

  5. incidence of transplant associated thrombotic microangiopathy(TA-TMA) [ Time Frame: 3 years post-HSCT ]
    TA-TMA is diagnosed according to the Jodele standard.

  6. incidence of acute graft versus host disease [ Time Frame: 100 days post-HSCT ]
    Acute graft versus host disease is diagnosed according to the modified Glucksberg grading standard.

  7. incidence of infection [ Time Frame: 3 years post-HSCT ]
    e.g. EBV/CMV viremia or related disease, bacteria/fungi /tuberculosis infection

  8. incidence of chronic graft versus host disease [ Time Frame: 3 years post-HSCT ]
    Chronic graft versus host disease is diagnosed according to the grading and scoring system recommended by the "Chinese Consensus on the Diagnosis and management of Chronic Graft-versus-Host Disease(2021)".



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

1. Evaluation criteria for disease before and after transplantation:

  1. Complete response (CR): all primary and metastatic lesions disappear, and neuron specific enolase (NSE), catecholamines and metabolites return to normal.
  2. Very good partial response (VGPR): the primary tumor volume is reduced by 90% to 99%, all measurable metastases disappear, and NSE, catecholamines and metabolites return to normal; radionuclide bone scanned lesions can be positive (because bone metastases have not healed), but if an metaiodobenzylguanidine (MIBG) scan is performed, all lesions are negative.
  3. Partial response (PR): The volume of all primary tumors and measurable metastases is reduced by more than 50%, the number of bone-positive lesions is reduced by more than 50%, and there is no more than one bone-positive site.
  4. Mixed response (MR): no new lesions, the volume of any one or more measurable lesions decreases more than 50%, and the volume of any other one or more lesions decreases less than 50%, and volume of any existing lesions increases less than 25%.
  5. No response (NR): There are no new lesions, and the volume of any existing lesions decreases less than 50% or increases less than 25%.
  6. Progressive disease (PD): new lesions appear, the volume of existing measurable lesions increases more than 25%, and the bone marrow changes from negative to positive.

2. 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:

  1. Age≤18 years old;
  2. 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;
  3. 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;
  4. 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;
  5. Whole brain and whole spinal cord radiotherapy have completed before HSCT in patients with central invasion at onset;
  6. The blood routine has generally returned to normal and there is no dysfunction of major organs such as the heart, liver, lung, and kidney;
  7. The guardian/patient accept the treatment of this research, sign the informed consent, and complete the follow-up.

3. Exclusion Criteria: meeting one of the following criterions:

  1. 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;
  2. With severe pulmonary insufficiency (severe obstructive and/or restrictive ventilation disorders), the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
  3. 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;
  4. 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;
  5. With severe active bleeding or severe active infection; the patient can not tolerate the conditioning regimen according to the investigators' evaluation;
  6. 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;
  7. The guardian/patient cannot understand or comply with the treatment plan;
  8. Other reasons for not being selected due to the investigator's evaluation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05303727


Contacts
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Contact: Ke Huang, MD +8602034070821 hke@mail.sysu.edu.cn
Contact: Su Liu, MD +8613512742517 liusu2009@163.com

Locations
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China, Guangdong
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
Guangzhou, Guangdong, China, 510120
Contact: Ke Huang, MD    +8602034070821    hke@mail.sysu.edu.cn   
Contact: Su Liu, MD    +8613512742517    liusu2009@163.com   
Principal Investigator: Yang Li, MD         
Principal Investigator: Jianpei Fang, MD         
Sponsors and Collaborators
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Investigators
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Study Director: Yang Li Sun Yat-sen Memorial Hospital,Sun Yat-sen University
Study Director: Jianpei Fang Sun Yat-sen Memorial Hospital,Sun Yat-sen University
Publications:

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Responsible Party: Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
ClinicalTrials.gov Identifier: NCT05303727    
Other Study ID Numbers: 2021-KY-126
First Posted: March 31, 2022    Key Record Dates
Last Update Posted: July 1, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University:
allogeneic stem cell transplantation
Additional relevant MeSH terms:
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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
Cyclosporine
Mycophenolic Acid
Cyclophosphamide
Melphalan
Busulfan
Thiotepa
Methotrexate
Fludarabine
Topotecan
Tacrolimus
Cyclosporins
Antilymphocyte Serum
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents