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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 伊立替康是一种具有抗神经母细胞瘤活性的化疗药物。这种药物的临床前疗效可以通过延长给药程序和使用化疗药物替莫唑胺进行预处理来增强。最近完成的替莫唑胺和长期静脉注射伊立替康的I期试验表明，这种组合对患有难治性实体肿瘤的儿童患者具有很好的耐受性和活性，限量毒性是腹泻和感染。根据这一经验，我们现在提出修改意见，以进一步提高这一组合的有效性和可行性。由于较高剂量的延长伊立替康在临床前模型中产生更强的抗肿瘤活性，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新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价格昂贵，给药不便，我们将使用口服伊立替康，它可能具有独特的良好药代动力学效应。因此，这项试验的主要目的是评估口服伊立替康与固定剂量替莫唑胺和头孢克新联合使用对难治性高危神经母细胞瘤患者的最大耐受量。如果可以达到临床相关的药物暴露，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.