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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个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 研究中心，而研究中心不一定是研究者所在的机构。 伊立替康是一种化疗药物，已证实对神经母细胞瘤具有活性。 这种药物的临床前疗效可以通过使用延长的给药时间表和用化疗药物替莫唑胺预处理来增强。 最近完成的替莫唑胺和长期静脉注射伊立替康的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，剂量限制性毒性为腹泻和感染。 基于这一经验，我们现在提出修改，以进一步提高这种组合的有效性和可行性。 由于在临床前模型中，更高剂量的长效伊立替康导致更大的抗肿瘤活性，我们计划通过将治疗间隔从28天压缩至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来减少治疗相关性腹泻时，可以耐受更高剂量的伊立替康，这是长期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成本高且给药不便，我们将使用口服伊立替康，其可能具有独特的有利药代动力学效应。 因此，本试验的主要目的是估计难治性高危神经母细胞瘤患者接受口服伊立替康联合固定剂量替莫唑胺和头孢克肟治疗时的最大耐受剂量。 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是有吸引力的门诊治疗高危神经母细胞瘤诱导和巩固治疗。

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.