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

164 Background: 225 AcAc-FL-020 is a next-generation, prostate-specific membrane antigen (PSMA) alpha radioconjugate developed using the proprietary UniRDC linker-chelator technology designed to optimize biodistribution. 225 AcAc-FL-020 is intended for the treatment of patients with metastatic castration-resistant prostate cancer (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 Phase 1 clinical trial consists of 2 parts: a dose escalation phase (Part 1) and a dose expansion phase (Part 2). Patients eligible for enrollment must have: histologically confirmed mCRPC, evidence of disease progression, and ≥1 PSMA-positive lesion (uptake higher than liver) on PSMA positron-emission tomography/computed tomography imaging (PET/CT). 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. Part 1 will apply a Bayesian logistic regression model (BLRM) with overdose control to guide dose-escalation decisions. Dose cohorts of 1 to 3 patients (for Cohorts 1 and 2) and dose cohorts of 3 to 6 patients (for Cohorts 3 and beyond) will evaluate ascending dose levels from 1 to 10 MBq (intravenous; every 6 weeks; x 6 cycles) 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. Results: As of 23 September 2025, 7 eligible patients have received 225 AcAc-FL-020 (maximum dose per cycle: 4 MBq). No xerostomia, unexpected safety signals, or dose-limiting toxicities have been observed. One subject in Cohort 3 experienced an unrelated Grade 3 adverse event (AE) of exacerbation of asthma due to metapneumovirus infection; and 1 subject in Cohort 1 died due to disease progression. All other reported AEs were Grades 1 to 2. Updated clinical data will be presented at the conference. Conclusions: These initial findings support the feasibility and tolerability of 225 AcAc-FL-020 administration in heavily pretreated patients with mCRPC. The MTD has not yet been reached, and dose escalation continues. Further safety and efficacy data will be shared as enrollment progresses. Clinical trial information: NCT06492122 .