ACCEL: [Ac-225]-PSMA-62 phase Ia/Ib/II clinical trial to characterize efficacy, safety, tolerability, and dosimetry in oligometastatic hormone-sensitive and metastatic castration-resistant prostate cancer.

TPS282 Background: Actinium-225 (Ac-225)-based, prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a promising treatment modality for prostate cancer. First-generation PSMA-targeting ligands (e.g., PSMA-617 and PSMA-I&T) paired with Ac-225 have been associated with myelosuppression, renal toxicity, and xerostomia (1). LY4181530 (previously PNT2001) pairs Ac-225 with PSMA-62, a next-generation ligand, which was specifically designed to overcome these limitations. It employs an improved linker technology that increases cellular internalization, leading to improved biodistribution, tumor delivery of Ac-225, and efficacy in preclinical models (2). Methods: ACCEL (NCT06229366) is a multi-center, open-label, multiple-arm, Phase Ia/Ib/II study evaluating the safety, tolerability, and efficacy of [Ac-225]-PSMA-62 in patients with oligometastatic hormone-sensitive prostate cancer (OmHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Eligible patients with OmHSPC have metachronous disease, up to 5 PSMA-positive lesions, and have not initiated life-long ADT. Eligible patients with mCRPC have PSMA-positive lesions and have received prior androgen receptor pathway inhibitor, taxane chemotherapy (unless ineligible or declined), and up to 3 prior systemic therapy regimens in the mCRPC setting. Prior PSMA-targeted RLT, baseline Grade ≥1 xerostomia, and Grade ≥1 xerophthalmia are not permitted. In the Phase 1a, dose escalation decisions follow the Bayesian optimal interval (BOIN) design to separately determine the maximum tolerated dose of [Ac-225]-PSMA-62 for each patient population. In the Phase 1b, patients will be randomized to 2 or more arms to optimize dosing/schedule and inform the selection of the recommended Phase II dose of [Ac-225]-PSMA-62 for each patient population. The phase II aims to evaluate the efficacy of [Ac-225]-PSMA-62 compared to best standard of care in patients with mCRPC, with the primary endpoint being radiographic progression-free survival. The study is currently enrolling in Canada with plans to open in other countries. 1. Sathekge MM. et al. Lancet Oncol . 2024 Feb;25(2):175-183. 2. Vito A. et al. EP-039. Presented at EANM Oct 2022, Barcelona, Spain. Clinical trial information: NCT06229366 .