Abstract 1157: Preclinical evaluation of PEG-[SN22]4 (PEEL-224), a multivalent polymeric camptothecin prodrug, in pediatric solid tumor patient-derived xenograft models

Abstract Background: PEEL-224 is a multivalent polymeric prodrug of the topoisomerase I inhibitor SN22 designed to sustain intratumoral exposure and reduce transporter-mediated efflux. Desmoplastic small round cell tumor (DSRCT) and osteosarcoma (OS) are high-risk sarcomas of children and adolescents/young adults where irinotecan+temozolomide (I/T) provides modest, short-lived benefit. Early-phase clinical evaluation of PEEL-224 is ongoing (NCT06709495, NCT06721689, NCT05329103). However, the comparative activity of PEEL-224±TMZ versus irinotecan-based therapy has not been defined in disease-relevant models, prompting evaluation in DSRCT and OS patient-derived xenografts (PDXs). Methods: PDX-bearing NSG mice were randomized to vehicle, irinotecan, I/T, PEEL-224, or PEEL-224+TMZ. Tumor growth was assessed using Vardi’s test for area-under-the-curve comparisons. Event-free survival (EFS) was defined as time to progression (≥100% relative tumor volume [RTV] increase from baseline) or euthanasia for tumor burden and analyzed by Kaplan-Meier with log-rank tests. Response criteria: PD = ≥100% RTV increase or euthanasia; SD = <100% increase and ≤50% reduction; PR = >50% reduction; CR = >95% reduction. Objective response rate (ORR) was the proportion achieving PR or CR. Treatment arms were expanded in an adaptive manner based on disease control to increase cohort size for key comparisons. Results: In DSRCT, tumor volume comparisons showed significantly greater control with PEEL-224 monotherapy vs irinotecan (p=0.04), while PEEL-224+TMZ and I/T showed similar control at this stage; cohort expansion is ongoing. EFS analysis showed PEEL-224 significantly prolonged EFS vs irinotecan (p=0.01) and PEEL-224+TMZ vs I/T (p=0.02). At end of therapy (Day 29), ORR was 0% (vehicle), 20% (irinotecan, 1/5 PR), 20% (I/T, 1/5 PR), 100% (PEEL-224, 5/5 PR), and 100% (PEEL-224+TMZ, 5/5 PR). At end of study (Day 113), irinotecan and I/T had 0% ORR, while PEEL-224 maintained 60% (3/5 PR, 2/5 SD) and PEEL-224+TMZ 100% (5/5 PR). Regimens were well tolerated. In OS, PEEL-224±TMZ produced disease stabilization and early regression, though statistical significance has not yet emerged (n=3/arm); expansion is ongoing. Conclusions: PEEL-224 demonstrated superior disease control as monotherapy and in combination over irinotecan-based therapy in DSRCT and early activity in OS. These preclinical data, alongside ongoing clinical evaluation, support advancement of PEEL-224 for high-risk pediatric and AYA sarcomas. Citation Format: Filemon S. Dela Cruz, Kristina C. Guillan, Samantha Brosius, Armaan H. Siddiquee, Glorife Ibanez Sanchez, Daoqi You, Kristen Victor, Paul Calder, Trent Fowler, Joshua D. Schiffman, Andrew L. Kung. Preclinical evaluation of PEG-[SN22]4 (PEEL-224), a multivalent polymeric camptothecin prodrug, in pediatric solid tumor patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1157.