Abstract B001: Phase 1/2 trial to evaluate the safety and efficacy of PEEL-224 in combination with vincristine and temozolomide in adolescents and young adults with relapsed or refractory sarcomas

Abstract BACKGROUND: Sarcomas affecting adolescents and young adults, including Ewing sarcoma (EWS), desmoplastic small round cell tumor (DSRCT), rhabdomyosarcoma (RMS) and osteosarcoma (OS), cause significant disease and treatment related morbidity and mortality. Conventional topoisomerase 1 (TOP1) inhibitors like irinotecan are active agents in each of these diseases but have numerous shortcomings including poor bioavailability, susceptibility to resistance and often intractable diarrhea. PEEL-224 is a tetravalent, pegylated, pro-drug of SN22, a pharmacologically enhanced TOP1 inhibitor. PEEL-224 is water-soluble, does not require hepatic activation, and has a prolonged half-life, allowing for increased drug delivery to tumor and once weekly dosing. SN22 does not undergo glucuronidation and ABC transporter-mediated cellular export, thereby reducing acquired resistance. The lack of glucuronidation and anticholinergic activity reduces GI toxicity. Pre-clinical data in EWS, DSRCT and RMS mouse models demonstrate significantly improved efficacy over irinotecan. METHODS: This prospective, open-label, single-arm, non-randomized, phase 1/2 clinical trial is the first to assess PEEL-224 in combination with other agents. Sites will be Dana-Farber Cancer Institute, Children’s Hospital of Philadelphia, UCSF, and MD Anderson Cancer Center. Patients 12-49 years of age with relapsed or refractory sarcomas receive PEEL-224 (days 1,8) in 21-day cycles in combination with vincristine (days 1,8) and oral temozolomide [days 1-5; V(P)T]. The phase 1 dose escalation portion of the trial is designed to determine the recommended phase 2 dose of PEEL-224 given in combination with vincristine and temozolomide. During phase 2, there are two dedicated cohorts for patients with relapsed or refractory EWS and DSRCT designed to determine the objective response rate to V(P)T. In each cohort, patients will be required to have measurable disease by RECIST v1.1. A third expansion cohort for patients with “other” sarcomas will estimate progression-free survival in patients treated with V(P)T. Phase 1 includes limited pharmacokinetic profiling of PEEL-224 and free SN22 since PEEL-224 has not been given on a three-week schedule previously. Phase 1 and 2 include tumor sequencing and ctDNA analysis to assess ctDNA burden over time as well as genomic markers of sensitivity and resistance. The trial is now open and enrolling (NCT06709495). Citation Format: David S. Shulman, Alexandra Sala, Ketki Bhushan, Emily Blair, Jeanine M. McManus, Kerri L. Cavanaugh, Julia H. Garland, Rebecca Divirgilio, Sarah Sexton, Julie P. Field, Sarah Garcia, Susan Carrozza, Melissa B. Hohos, Mary M. Murphy, Michael J. Wagner, Jacquelyn Crane, Amit Sabnis, Jennifer Michlitsch, Theodore Laetsch, J Andrew. Livingston, Jonathan B. Gill, Nan Chen, Kelly Klega, Catherine Clinton, Brian D. Crompton, Frank M. Balis, Wendy B. London, Steven G. DuBois. Phase 1/2 trial to evaluate the safety and efficacy of PEEL-224 in combination with vincristine and temozolomide in adolescents and young adults with relapsed or refractory sarcomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B001.