Phase 1 dose escalation and expansion of AB001 in patients with metastatic castration resistant prostate cancer (mCRPC): The ARTISAN trial.

TPS289 Background: Treatment options for patients with mCRPC have been improved by radioligand therapies such as beta-emitting 177 Lu-PSMA-617. However, prostate cancer remains the fifth leading cause of cancer mortality, with the lives of more than 250,000 men shorted by mCRPC each year. New therapies with differentiated mechanisms of action that could extend survival while retaining quality of life are needed. Alpha-particle emitting radioisotopes offer significant advantages compared with beta-emitters. Alpha particles have higher atomic mass (4), charge (2+), and linear energy transfer. Furthermore, the short particle range (<100 µm) is expected to minimize damage to surrounding normal tissue. 212 Pb is attractive for alpha radiotherapeutics due to its short 10.6 hour half-life which fits well with the rapid tumor uptake achievable with PSMA-targeting small molecules. The ARTISAN trial is a Dose Escalation Expansion study of AB001, a 212 Pb-labelled, PSMA-targeted small molecule alpha-radiotherapeutic. Methods: This is a Phase 1, open-label, multicentre study in patients with advanced PSMA-positive mCRPC. Participants must have received previous treatment with at least one androgen receptor pathway inhibitor and at least one prior taxane. The study will evaluate the safety and tolerability of AB001 in two populations: participants with mCRPC who have not received prior treatment with 177 Lu-PSMA radioligand therapy and participants who have been treated with at least one dose 177 Lu-PSMA therapy. Dose Escalation will identify the recommended dose and schedule for each population for Dose Expansion. A Time-to-Event Bayesian Optimal Interval (TITE BOIN) design is employed to allow dosage optimization by both escalation of the 212 Pb radioactive dose (MBq) and assessment of optimal cycle duration. Dose Expansion will further evaluate safety, tolerability, and preliminary activity of AB001 in the two populations. Assessment of AB001 biodistribution and dosimetry estimation by 212 Pb SPECT imaging will be used in addition with radioactive and ligand PK evaluation to enable efficient dosage optimization of AB001 in this Phase 1 trial. Clinical trial information: NCT07214961 / EU CT 2024-516523-14.