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
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