(P 565) AN EARLY PHASE STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PRELIMINARY ANTITUMOR ACTIVITY OF PEEL-224 IN PATIENTS WITH ADVANCED SOLID TUMORS

Objective: PEEL-224 is an improved topoisomerase 1 (TOP1) inhibitor, derived from camptothecin, for the treatment of patients with relapsed or refractory advanced solid tumors. Due to the limitations of currently available camptothecin-derived therapies (i.e., toxicities and chemoresistance), the clinical utility of TOP1-inhibiting drugs has not been fully realized in sarcoma. PEEL-224 has been engineered to overcome efflux-mediated drug resistance, supported by compelling in vitro and in vivo data. Nonclinical in vivo studies of PEEL-224 demonstrate sustained complete responses for more than 6 months in the most aggressive solid tumors, including Ewing sarcoma and rhabdomyosarcoma (Figure 1). We describe here an early phase trial of PEEL-224 in patients with advanced solid tumors that have relapsed or are refractory to prior systemic therapy.

Methods: Study PEEL-224-001 is a first-in-human, dose escalation, repeat-dose, multi-center (7 sites), open-label study to evaluate safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of PEEL-224 in patients with advanced solid tumors. The primary objective is to determine the recommended phase 2 dose (RP2D) and to evaluate the overall safety and tolerability of PEEL-224. Secondary objectives include evaluation of the preliminary antitumor activity and characterization of the PK profile following PEEL-224 administration. Dose escalation is guided by the modified toxicity probability interval-2 (mTPI-2) design with a target toxicity rate of 25% and an acceptable dose limiting toxicity (DLT) interval of 20% to 30%. PEEL-224 is administered by intravenous infusion on Days 1, 8, and 15 of a 28-day cycle. The dose level increases between sequential cohorts of 3 or more patients according to mTPI-2 until a RP2D is determined. For each dose level, all patients must complete Cycle 1 before the decision to dose escalate the next cohort of patients is made. An additional arm of patients will be enrolled after dose escalation is completed to confirm the RP2D. Prior treatment with a TOP1 inhibitor is permitted and UGT genotyping is not required for enrollment since PEEL-224 is not metabolized via the glucuronidation pathway. Following this early-phase study, indications where PEEL224 has demonstrated clinically relevant activity and tolerability will be investigated in further studies. Other indications or treatment combinations will be explored where PEEL-224 may have promise. The study is registered with ClinicalTrials.gov as NCT05329103 and is currently accruing patients.

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