COG ANBL02P1: REGIMEN INCORPORATING TOPOTECAN FOR TREATMENT OF NEUROBLASTOMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这是一项初步研究，旨在评估一种含有拓扑替康的新型诱导方案在高风险神经母细胞瘤儿童中的可行性。该诱导方案将基于当前的A3973诱导方案（MSKCC N6），采用6个周期的多药化疗序贯给药，保持已知活性抗肿瘤药物的相似剂量强度和相似的治疗持续时间（18周）。基于已知的协同抗肿瘤活性，topotecan将与环磷酰胺联合使用，并将取代目前A3973诱导方案中初始两个周期的长春新碱/环磷酰胺/阿霉素。环磷酰胺/拓扑替康的剂量将高于儿科I期和II期试验的剂量。临床前小鼠神经母细胞瘤异种移植模型支持拓扑替康剂量增加，该模型显示全身暴露于拓扑替康增加与抗肿瘤活性增强之间存在相关性。相似剂量强度的拓扑替康和环磷酰胺方案的重复递送是可行的，但预期会增加血液毒性。目前在A3973中使用的高风险神经母细胞瘤诱导治疗中，观察到剂量强化环磷酰胺/拓扑替康联合治疗的血液学毒性在已知的毒性范围内。非格昔汀（G-CSF）将在诱导化疗的每个周期中使用，以尽量减少血液毒性。方案治疗将包括诱导期化疗、外周血干细胞采集和手术切除肿瘤；骨髓清除化疗与干细胞拯救的持续期，移植后外束放射治疗和顺式维甲酸生物修饰剂治疗的维持期。Topotecan药代动力学将在第1周期和第2周期诱导的第1天获得，目标是个体化每位患者的Topotecan剂量，以达到所需的Topotecan目标全身暴露量（例如，单日Topotecan内酯AUC 50至70 ng/ml*hr）。外周血干细胞采集将在诱导治疗第二周期后的造血恢复期间进行。手术切除任何可触及的残余肿瘤将在诱导治疗的第五个周期后进行。如果患者有免疫细胞阴性的干细胞产品，则在诱导完成后进行消融巩固治疗。巩固治疗将包括卡铂、依托泊苷和美法兰的清髓方案，随后进行积极的局部照射，旨在降低局部复发率，目前在A3973上使用。从干细胞输注之日起，移植后连续3天给予G-CSF，直至绝对中性粒细胞计数（ANC）大于或等于2000/¿L。移植后维持治疗将在干细胞移植后大约第66天开始，给予6个周期的13-顺式维甲酸

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a pilot study to assess the feasibility of a topotecan-containing novel Induction regimen in children with high risk neuroblastoma. This Induction regimen will utilize sequential administration of six cycles of multi-agent chemotherapy based upon the current A3973 Induction regimen (MSKCC N6), maintaining a similar dose intensity of known active anti-tumor agents and a similar duration of therapy (18 weeks). Based upon known synergistic anti-tumor activity, topotecan will be combined with cyclophosphamide and will replace the initial two cycles of vincristine/cyclophosphamide/doxorubicin administered in the current A3973 Induction regimen. Cyclophosphamide/topotecan will be delivered at doses above that achieved on pediatric Phase I and II trials. Dose escalation of topotecan is supported by pre-clinical murine neuroblastoma xenograft models that demonstrate a correlation between increased systemic exposure to topotecan and improved anti-tumor activity. Repetitive delivery of a topotecan and cyclophosphamide regimen of similar dose intensity has been feasible with expected increased hematologic toxicity. Observed hematologic toxicity of the dose intensive cyclophosphamide/topotecan combination was within the range of known toxicity during current high risk neuroblastoma Induction therapy utilized in A3973. Filgrastim (G-CSF) will be administered with each cycle of Induction chemotherapy to minimize hematologic toxicity. Protocol therapy will consist of Induction phase of chemotherapy, peripheral blood stem cell harvest and surgical resection of tumor; Continuation phase of myeloablative chemotherapy with stem cell rescue, and post-transplant external beam radiation therapy and Maintenance phase of biologic modifier therapy with cis-Retinoic acid. Topotecan pharmacokinetics will be obtained on Day 1 of cycle 1 and cycle 2 Induction with the goal of individualizing each patient's topotecan dosage to attain the desired topotecan target systemic exposure (e.g., single day topotecan lactone AUC 50 to 70 ng/ml*hr). Peripheral blood stem cell harvest will occur during hematopoietic recovery following the 2nd cycle of Induction therapy. Surgery to resect any accessible residual tumor will occur following the fifth cycle of Induction therapy. Patients proceed to ablative Consolidation therapy at completion of Induction if they have an immunocytologically negative stem cell product available. Consolidation therapy will consist of the myeloablative regimen of carboplatin, etoposide, and melphalan followed by aggressive local irradiation designed to attempt to decrease the local relapse rate as is currently utilized on A3973. G-CSF will be given post-transplant from the day of stem cell infusion until the absolute neutrophil count (ANC) is greater than or equal to 2000/¿L for three consecutive days. Post-transplant Maintenance therapy with six cycles of 13-cis-retinoic acid will be given starting at approximately Day 66 post stem cell transplan