Allogeneic Hematopoietic Stem Cell Transplantation for 4/M Neuroblastoma

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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
• Препарат Fludarabine
  30 mg/m2/day for 5 days
• Препарат Cyclophosphamide injection
  60 mg/kg/day for 2 days in cord blood stem cell transplantation
• Препарат Topotecan
  2mg/m2/day for 3 days in cord blood stem cell transplantation
• Препарат 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；
• Препарат Thiotepa
  5 mg/kg/day for 2 days in peripheral stem cell transplantation or haploidentical bone marrow combined with peripheral stem cell transplantation
• Препарат 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；
• Препарат 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
• Препарат Tacrolimus
  0.02\~0.03 mg/kg/day as continuous infusion or 12 hour divided doses
• Препарат Mycophenolate Mofetil
  15 mg/kg/dose every 12 hours

Первичные конечные точки

• overall survival(OS) at 3 year [Срок оценки: 3 years post-HSCT]
• event free survival(EFS) at 3 year [Срок оценки: 3 years post-HSCT]

Вторичные конечные точки (8)

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

Критерии участия

1\. Evaluation criteria for disease before and after transplantation:

• Complete response (CR): all primary and metastatic lesions disappear, and neuron specific enolase (NSE), catecholamines and metabolites return to normal.
• 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.
• 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.
• 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%.
• No response (NR): There are no new lesions, and the volume of any existing lesions decreases less than 50% or increases less than 25%.
• 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:

• 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.

3\. 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Sun Yat-sen Memorial Hospital, Sun Yat-sen University — Гуанчжоу

Публикации

• Pastor ER, Mousa SA. Current management of neuroblastoma and future direction. Crit Rev Oncol Hematol. 2019 Jun;138:38-43. doi: 10.1016/j.critrevonc.2019.03.013. Epub 2019 Apr 1. PMID 31092383
• Basta NO, Halliday GC, Makin G, Birch J, Feltbower R, Bown N, Elliott M, Moreno L, Barone G, Pearson AD, James PW, Tweddle DA, McNally RJ. Factors associated with recurrence and survival length following relapse in patients with neuroblastoma. Br J Cancer. 2016 Oct 25;115(9):1048-1057. doi: 10.1038/bjc.2016.302. Epub 2016 Oct 4. PMID 27701387
• Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, Kaneko M, London WB, Matthay KK, Nuchtern JG, von Schweinitz D, Simon T, Cohn SL, Pearson AD; INRG Task Force. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol. 2009 Jan 10;27(2):298-303. doi: 10.1200/JCO.2008.16.6876. Epub 2008 Dec 1. PMID 19047290
• Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, Evans AE, Favrot M, Hedborg F, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993 Aug;11(8):1466-77. doi: 10.1200/JCO.1993.11.8.1466. PMID 8336186
• Smith V, Foster J. High-Risk Neuroblastoma Treatment Review. Children (Basel). 2018 Aug 28;5(9):114. doi: 10.3390/children5090114. PMID 30154341
• London WB, Bagatell R, Weigel BJ, Fox E, Guo D, Van Ryn C, Naranjo A, Park JR. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials. Cancer. 2017 Dec 15;123(24):4914-4923. doi: 10.1002/cncr.30934. Epub 2017 Sep 8. PMID 28885700
• Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, Gerbing RB, London WB, Villablanca JG. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol. 2009 Mar 1;27(7):1007-13. doi: 10.1200/JCO.2007.13.8925. Epub 2009 Jan 26. PMID 19171716
• Ladenstein R, Potschger U, Pearson ADJ, Brock P, Luksch R, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, de Lacerda AF, Beck-Popovic M, Bician P, Garami M, Trahair T, Canete A, Ambros PF, Holmes K, Gaze M, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D; SIOP Europe Neuroblastoma Group (SIOPEN). Busulfan and melphalan versus carboplat PMID 28259608

Идентификаторы

NCT: NCT05303727 · 2021-KY-126

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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