Evaluation of the safety and efficacy of TRC003 in metastatic triple-negative breast cancer: A prospective, open-label, multicenter, single-arm exploratory clinical trial.

TPS1161 Background: TRC003 (also named 225 Ac-TR2205) is a novel molecule of targeted alpha therapy (TAT) designed to deliver alpha-particle radiation to cancer cells expressing prostate-specific membrane antigen (PSMA). Compared to beta-particles, alpha-particles have a shorter path length and higher linear energy transfer, resulting in more frequent double-strand DNA breaks and potentially superior antitumor efficacy. In an ongoing pilot study, TRC003 has demonstrated a favorable safety profile and promising activity in patients with prostate cancer. Notably, PSMA expression has been reported in up to 60% of breast cancer neovasculature, with the highest rates observed in triple-negative breast cancer (TNBC). A head-to-head study found valuable insights into the expression of PSMA in TNBC and underscore the potential clinical significance of PSMA PET/CT in enhancing both diagnostic and therapeutic approaches for TNBC. This study aims to investigate the preliminary safety and efficacy of 225 Ac-TRC003 in patients with metastatic TNBC (mTNBC). Methods: This is a prospective, open-label, multicenter, single-arm study in accordance with ICH GCP guidelines at two centers. The primary objective is to evaluate the safety and tolerability of TRC003. Secondary endpoints include Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), Time to Progression (TTP), progression-free survival (PFS) and overall survival (OS). Key eligibility criteria include: 1) age ≥18 years; 2) histologically confirmed mTNBC with documented progression after ≥2 prior lines of systemic therapy (including at least 1 line for metastatic disease); 3) presence of PSMA-positive lesions on imaging, without FDG-positive & PSMA-negative target lesions; 4) at least one measurable lesion per Response Evaluation Criteria in Solid Tumors version (RECIST) 1.1; 5) Eastern Cooperative Oncology Group performance status of ≤ 1; and 6) adequate bone marrow, renal, and hepatic function. Fifteen eligible participants will be enrolled to receive 7.40 MBq (200 μCi) (±10%) of TRC003 by intravenous infusion every 8 weeks (±1 week), for up to 8 cycles if clinical benefit is observed. Treatment will continue until disease progression, unacceptable toxicity, or consent withdrawal, meeting any study withdrawal criterion, whichever occurs first. Tumor assessments (contrast-enhanced CT/MRI and bone scan) will be performed every 8 weeks until disease progression is confirmed per RECIST 1.1. Clinical trial information: MR-37-25-039070.