COG ANBL02P1: REGIMEN INCORPORATING TOPOTECAN FOR TREATMENT OF NEUROBLASTOMA

COG ANBL02P1：结合拓扑替康治疗神经母细胞瘤的方案

• 批准号: 7376886
• 负责人: SUSAN E COHN
• 金额: $ 2.07万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376886
• 关键词: COG; ANBL02P1; REGIMEN; INCORPORATING; TOPOTECAN

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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。这是一项初步研究，旨在评估含托泊替康的新型诱导方案在高危神经母细胞瘤儿童中的可行性。该诱导方案将采用基于当前A3973诱导方案（MSKCC N6）的6个周期的多药化疗序贯给药，维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，拓扑替康将与环磷酰胺联合使用，并将替代当前A3973诱导方案中给予的最初两个周期的长春新碱/环磷酰胺/多柔比星。 环磷酰胺/托泊替康的给药剂量将高于儿科I期和II期试验中达到的剂量。托泊替康的剂量递增得到了临床前鼠神经母细胞瘤异种移植模型的支持，该模型证明了托泊替康全身暴露量增加与抗肿瘤活性改善之间的相关性。相似剂量强度的拓扑替康和环磷酰胺方案的重复给药是可行的，预期血液学毒性增加。在A3973中使用的当前高风险神经母细胞瘤诱导治疗期间，剂量强化环磷酰胺/托泊替康联合给药观察到的血液学毒性在已知毒性范围内。非格司亭（G-CSF）将与每个周期的诱导化疗一起给药，以尽量减少血液学毒性。 方案治疗将包括化疗诱导期、外周血干细胞采集和肿瘤手术切除;清髓性化疗联合干细胞挽救的持续期、移植后体外放射治疗和顺式维甲酸生物改性剂治疗的维持期。将在第1周期和第2周期诱导的第1天获得托泊替康药代动力学，目的是个体化每例患者的托泊替康剂量以达到所需的托泊替康目标全身暴露（例如，单天托泊替康内酯AUC 50至70 ng/ml*hr）。外周血干细胞采集将在第2个周期诱导治疗后的造血恢复期间进行。在诱导治疗的第五个周期后，将进行手术切除任何可触及的残留肿瘤。如果患者有可用的免疫细胞学阴性干细胞产品，则在诱导完成时继续进行消融巩固治疗。巩固治疗将包括卡铂、依托泊苷和美法仑的清髓性方案，随后进行积极的局部照射，旨在尝试降低局部复发率，如目前在A3973上使用的那样。移植后将从干细胞输注当天开始给予G-CSF，直至中性粒细胞绝对计数（ANC）连续三天大于或等于2000/L。从干细胞移植后大约第66天开始，将给予6个周期的13-顺式维甲酸移植后维持治疗。