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

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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.