ProTACT: A first-in-human, phase 1 dose escalation and expansion study evaluating the safety, tolerability, and anti-tumor activity of 225 AcAc-FL-020, a PSMA-targeted radioconjugate, in patients with mCRPC.

TPS5141 Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is an emerging treatment modality for metastatic castration-resistant prostate cancer (mCRPC). However, many agents targeting PSMA have resulted in quality of life-limiting toxicities, such as xerostomia, due to expression of PSMA in salivary glands and other organs. 225 AcAc-FL-020 is a next-generation, PSMA alpha radioconjugate developed using the proprietary UniRDC linker-chelator technology designed to optimize biodistribution. It is intended for the treatment of patients with mCRPC and aims to enhance tumor uptake while sparing radiosensitive organs, such as salivary glands, thus potentially leading to an improved therapeutic window. Methods: ProTACT (FL-020-001) is a first-in-human, open-label, multicenter Phase 1 study investigating the safety, tolerability, and preliminary anti-tumor activity of 225 AcAc-FL-020 in patients with advanced PSMA-positive mCRPC. This study consists of 2 parts: dose escalation (Part 1) and dose expansion (Part 2). Patients eligible for enrollment must be aged ≥18 years and have: histologically confirmed mCRPC, evidence of disease progression, ≥1 PSMA-positive lesion (uptake higher than liver) on PSMA positron emission tomography/computed tomography imaging, an Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function. Prior treatment with androgen receptor signaling inhibitors or CYP17 inhibitors and ≥1 taxane-based chemotherapy is required, unless declined by the patient. Prior therapy with Lu-177 is allowed. Patients with extensive PSMA-negative disease are excluded. 225 AcAc-FL-020 will be administered intravenously at the assigned dose every 6 weeks for up to 6 cycles. Throughout the study, 10 eligible patients will receive 185 ± 20 MBq of 111 InIn-FL-020 for dosimetry evaluation ≥8 days prior to their first dose of 225 AcAc-FL-020. Part 1 will apply a Bayesian logistic regression model with overdose control to guide dose escalation decisions. Dose cohorts of 1–3 patients (for Cohorts 1 and 2) and 3–6 patients (for Cohorts 3 and beyond) will evaluate ascending dose levels from 1–10 MBq to determine the maximum tolerated dose and/or recommended Phase 2 dose (RP2D). Once the RP2D is established, 18 additional patients will be enrolled in Part 2 to further assess safety and explore early signals of efficacy. Primary endpoints include incidence of dose-limiting toxicities and type, frequency, and severity of adverse events/serious adverse events. Secondary endpoints include overall response rate, disease control rate, radiological progression-free survival, and pharmacokinetic parameters (eg, maximum plasma concentration). The study is active in Australia, the United States, Turkey, and China. Clinical trial information: NCT06492122 .