PO.CL06.02 · 临床研究

多价聚合物喜树碱前药PEG-[SN22]₄（PEEL-224）在儿童实体瘤患者来源异种移植模型中的临床前评价

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

编号 1157 展板 10 时间 4/19 02:00–05:00 区域 Section 45 主讲 Filemon Dela Cruz, MD

分会场 Mechanistic Insights for Targeted Therapies in Pediatric Cancer

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作者与单位 Authors & Affiliations

Filemon S. Dela Cruz¹, Kristina C. Guillan¹, Samantha Brosius¹, Armaan H. Siddiquee¹, Glorife Ibanez Sanchez¹, Daoqi You¹, Kristen Victor¹, Paul Calder¹, Trent Fowler², Joshua D. Schiffman², Andrew L. Kung³

¹Memorial Sloan Kettering Cancer Center, New York, NY,²Peel Therapeutics, Salt Lake City, UT,³Chair, Division of Pediatric Hematology/Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

摘要 Abstract

中文摘要

背景： PEEL-224是拓扑异构酶I抑制剂SN22的多价聚合物前药，旨在维持瘤内暴露并减少转运体介导的外排。促结缔组织增生性小圆细胞肿瘤（DSRCT）和骨肉瘤（OS）是儿童及青少年/青年（AYA）的高危肉瘤，其中伊立替康+替莫唑胺（I/T）仅提供有限、短暂的获益。PEEL-224的早期临床评价正在进行中（NCT06709495、NCT06721689、NCT05329103）。然而，PEEL-224±TMZ相较于伊立替康为基础的治疗的比较活性，尚未在疾病相关模型中得到界定，因此促使在DSRCT和OS患者来源异种移植（PDX）模型中进行评价。方法：将荷PDX的NSG小鼠随机分配至载体、伊立替康、I/T、PEEL-224或PEEL-224+TMZ组。使用Vardi检验对曲线下面积进行比较以评估肿瘤生长。无事件生存期（EFS）定义为至疾病进展（相对肿瘤体积[RTV]较基线增加≥100%）或因肿瘤负荷而实施安乐死的时间，并采用Kaplan-Meier法及log-rank检验进行分析。反应标准：PD（疾病进展）＝RTV增加≥100%或安乐死；SD（疾病稳定）＝增加＜100%且缩小≤50%；PR（部分缓解）＝缩小＞50%；CR（完全缓解）＝缩小＞95%。客观缓解率（ORR）为达到PR或CR的比例。根据疾病控制情况，以适应性方式扩展各治疗组，以增加关键比较的队列规模。结果：在DSRCT中，肿瘤体积比较显示PEEL-224单药相较于伊立替康具有显著更佳的控制（p=0.04），而PEEL-224+TMZ与I/T在此阶段显示相似的控制；队列扩展正在进行中。EFS分析显示，PEEL-224相较于伊立替康显著延长了EFS（p=0.01），PEEL-224+TMZ相较于I/T亦然（p=0.02）。在治疗结束时（第29天），ORR分别为0%（载体）、20%（伊立替康，1/5 PR）、20%（I/T，1/5 PR）、100%（PEEL-224，5/5 PR）和100%（PEEL-224+TMZ，5/5 PR）。在研究结束时（第113天），伊立替康和I/T的ORR为0%，而PEEL-224维持在60%（3/5 PR，2/5 SD），PEEL-224+TMZ为100%（5/5 PR）。各方案的耐受性良好。在OS中，PEEL-224±TMZ产生了疾病稳定和早期消退，尽管统计学显著性尚未显现（n=3/组）；扩展正在进行中。结论： PEEL-224作为单药及联合治疗，在DSRCT中相较于伊立替康为基础的治疗表现出更优的疾病控制，并在OS中显示早期活性。这些临床前数据，连同正在进行的临床评价，支持推进PEEL-224用于高危儿童及AYA肉瘤。

查看英文原文 English 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.

利益披露 Disclosure

F. S. Dela Cruz, Eisai ). Y-mAbs Therapeutics ). K. C. Guillan, None.. S. Brosius, None.. A. H. Siddiquee, None.. G. Ibanez Sanchez, None.. D. You, None.. K. Victor, None.. P. Calder, None. T. Fowler, Peel Therapeutics Employment, Other, Equity. J. D. Schiffman, Peel Therapeutics Employment, Other, Equity. A. L. Kung, Karyopharm Therapeutics Other, Scientific Advisory Board. DarwinHealth Other, Scientific Advisory Board. Isabl Other Intellectual Property, Other, Co-Founder, Scientific Advisory Board, Equity. Labcorp Other, Royalty income.

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