Abstract
Abstract Background: Pediatric solid tumors are rare and the use of well characterized preclinical models can be a helpful tool to prioritize novel drug combinations and formulations which are challenging to test in a limited patient population. Irinotecan (IRN) has shown efficacy in diverse pediatric cancers where children are often treated on an extended low-dose schedule rather than a single large dose commonly used in adults. The use of nano-liposomal irinotecan (nal-IRI) is a promising strategy as 95% of the drug remains encapsulated during systemic exposure while maintaining prolonged exposure in the tumor. Adult clinical trials have shown reduced side effects without compromising efficacy but nal-IRI has had limited use thus far in pediatric cancers. Methods: Orthotopic xenograft models of Ewing sarcoma (EWS, 4 models) and rhabdomyosarcoma (RMS, 2 models) were generated by injecting luciferase labeled cells into the femur and hind-leg muscle of nude mice respectively. Pharmacokinetic (PK) studies on normal and tumor-bearing mice were performed for both nal-IRI and standard IRN to determine matched human AUC-guided dosing and schedule of chemotherapy agents. Mice were randomized to single agent and relevant combinations of nal-IRI with PARP inhibitors and temozolomide (EWS) and with vincristine and temozolomide (RMS) and compared to the same regimens using standard IRN. Therapy was given on a clinically relevant schedule with each course consisting of 21 days and tumor response was measured weekly using bioluminescence. Results: PK studies showed that plasma levels of the active metabolite of IRN (SN-38) drop quickly for both standard IRN and nal-IRI single dosed mice while the levels of SN-38 were maintained in the tumor for several days using the nal-IRI formulation. In all 6 models tested, nal-IRI combinations were as or more effective when compared to regimens using standard IRN. No significant toxicity was seen in mice treated with nal-IRI combinations. Conclusions: The substitution of nal-IRI for standard IRN remains a promising strategy in pediatrics with the potential to reduce side effects as well as hospital visits due to the dosing schedule with nal-IRI given once per cycle where standard IRN is often given for 5 or 10 days in children. Our preclinical PK data confirmed the liposomal formulation resulted in sustained SN-38 levels in the tumor and efficacy was maintained or improved in pediatric cancer models. The combination of nal-IRI with temozolomide and talazoparib is now being tested in a multi-center randomized phase I/II trial for children with relapsed solid tumors and this data supports consideration for use in other pediatric cancer trials both in the upfront and relapse setting. Citation Format: Elizabeth Stewart, Kaley Blankenship, Burgess Freeman, Sara Federico, Michael Dyer. Preclinical evaluation of nano-liposomal irinotecan in pediatric solid tumor patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6716.
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