Phase 1, multi-center clinical trial evaluating the safety, pharmacokinetics, pharmacodynamics and anti-cancer activity of PQ203, a first-in-class peptide drug conjugate targeting SORT1 in patients with advanced solid tumor malignancies (NCT07190469).

Abstract

TPS3171 Background: Antibody–drug conjugates (ADCs) have improved outcomes in several refractory cancers by enabling the targeted delivery of potent cytotoxins but their use is limited by suboptimal payload release, off-target and immune-related toxicities, poor tumor penetration and complex manufacturing. Peptide drug conjugates (PDCs) offer potential advantages over ADCs including smaller size, increased tumor penetration, more rapid systemic clearance and decreased immunogenicity. PQ203 is a first in class, AI-designed PDC comprised of a 17 amino acid peptide targeting sortilin (SORT1) conjugated to the cytotoxin monomethyl auristatin E (MMAE) via a para-amino-benzyl-valine-citrulline (PAB-VC) cleavable linker. SORT1, a receptor of the Vps10p family involved in protein trafficking, is overexpressed across multiple tumor types and associated with tumor invasiveness. Preclinical breast cancer models, including patient-derived xenografts, show that PQ203 can overcome resistance to commonly used TOP1-based ADCs. Methods: This first-in-human, multi-country Phase 1A/B dose-escalation, expansion and optimization clinical trial is designed to assess the safety, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of PQ203. Treatment consists of once weekly IV infusion × 4 weeks (Q1Wx4) and continues until the occurrence of disease progression or dose-limiting toxicity. In Part 1 of the study, up to 7 dose cohorts are anticipated (commencing at 0.02 mg/kg) in a backfill Bayesian optimization (BF-BOIN) dose escalation design with a target toxicity rate of 27.5%. Upon satisfaction of pre-defined safety criteria for particular dosing cohorts, up to 9 additional patients (pts.) in pre-defined settings of biologic and clinical interest may be enrolled to backfill expansion of that dose level. Upon identification of one or more recommended doses for expansion, up to 50 pts. across 1-3 tumor types of particular clinical interest, including pts. with triple negative breast cancer, will be enrolled in the expansion and dose optimization phases of the study. Alternative dosing schedule(s) with reduced frequency may additionally be explored based on emerging PK and safety data. At the time of submission, cohorts 1 and 2 were completed without DLTs and enrollment of Cohort 3 was initiated in January, 2026. Clinical trial information: NCT07190469 .