NANT 2003-01: A PHASE I STUDY OF ORAL IRINOTECAN, TEMOZOLOMIDE, AND CEFIXIME

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。伊立替康是一种具有抗神经母细胞瘤活性的化疗药物。该药物的临床前疗效可以通过延长给药时间和用化疗药物替莫唑胺进行预处理来提高。最近完成的替莫唑胺和伊立替康长期静脉注射的I期试验显示，这种组合在患有难治性实体瘤的儿科患者中具有良好的耐受性和活性，其剂量限制性毒性是腹泻和感染。在此经验的基础上，我们现在提出修改建议，以进一步提高这种组合的有效性和可行性。因为在临床前模型中，高剂量的延长伊立替康能产生更大的抗肿瘤活性，我们计划通过将治疗间隔从28天压缩到21天来增加剂量强度。此外，我们假设，当使用口服抗生素头孢克肟以减少治疗相关性腹泻时，更高剂量的伊立替康是可以耐受的，这是长期使用伊立替康的剂量限制性毒性。最后，由于长期静脉注射伊立替康费用昂贵且不方便给药，我们将使用口服伊立替康，口服伊立替康可能具有独特的有利药代动力学效果。因此，本试验的主要目的是评估难治性高危神经母细胞瘤患者口服伊立替康与固定剂量替莫唑胺和头孢克肟联合使用时的最大耐受剂量。如果临床相关的药物暴露可以实现，这种全口服方案可能被证明对诱导和巩固治疗后的高危神经母细胞瘤的门诊治疗具有吸引力。

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. Irinotecan is a chemotherapeutic agent with demonstrated activity against neuroblastoma. Preclinical efficacy of this agent can be enhanced by using a protracted schedule of administration, and by pretreating with the chemotherapeutic agent temozolomide. A recently completed Phase I trial of temozolomide and protracted intravenous irinotecan showed this combination was well tolerated and active in pediatric patients with refractory solid tumors, with the dose-limiting toxicities being diarrhea and infection. Building on this experience, we now propose modifications to further increase the efficacy and feasibility of this combination. Because higher doses of protracted irinotecan result in greater antitumor activity in preclinical models, we plan to increase dose intensity by compressing the treatment interval from 28 to 21 days. In addition, we hypothesize that higher doses of irinotecan can be tolerated when using the oral antibiotic cefixime to reduce treatment-associated diarrhea, which is the dose-limiting toxicity of protracted irinotecan. Finally, because protracted intravenous irinotecan is costly and inconvenient to administer, we will use oral irinotecan, which may have uniquely favorable pharmacokinetic effects. Therefore, the primary purpose of this trial is to estimate the maximum tolerated dose of oral irinotecan when given in combination with fixed-dose temozolomide and cefixime to patients with refractory high-risk neuroblastoma. If clinically relevant drug exposures can be achieved, this all-oral regimen may prove attractive for outpatient treatment of high-risk neuroblastoma following induction and consolidation therapy.