Phase Ib/IIa dose escalation and expansion study of [ <sup>212</sup> Pb]Pb-ADVC001 in metastatic castration-resistant prostate cancer: TheraPb–phase I/II study.
Authors: Aaron Richard Hansen, David A. Pattison, Stanley Ngai, Anna Karmann, Amanda J. Walker, Louise Campbell, Jasmine Brady, Loren Katchel, Ingrid Holmes, Stephen E. Rose, Meghan C. Baronet, Thomas Kryza, Alyssa Vito, William Tieu, Kevin Kuan, Matthew R. Griffiths, Eoin O’Mahoney, Melissa Latter, Chun Loo Loo Gan, David Wyld
Journal: Journal of Clinical Oncology (2025)

TPS275 Background: Prostate cancer (PC) is the second most common cancer and second leading cause of cancer-related death in men. A recent Lancet Commissionarticle predicts a rise in PC cases from 1.4 million in 2020 to 2.9 million by 2040. Despite ten new therapies being available for metastatic PC in the recent decade, the survival advantage from most agents in the setting of metastatic castration-resistant prostate cancer (mCRPC) is measured in months largely due to cross-resistance, and the 5-year survival is approximately 32%. The radioligand therapy 177 Lu-PSMA-617, which uses a beta-emitting isotope linked to a PSMA-targeting small molecule, has shown a median survival advantage in mCRPC of four months, underpinning the critical need for more effective treatments. Excitement has shifted towards the use of alpha-emitting isotopes that deliver a more lethal payload. Unlike beta particles, alpha particles have a short range of tissue penetration (&lt; 0.1 mm) and high linear energy transfer that induces double-stranded DNA breaks and high levels of cytotoxicity to target expressing cancer cells irrespective of cell cycle or oxygenation state. Herein we describe the ongoing clinical trial of [ 212 Pb]Pb-ADVC001 – a novel PSMA-targeted radioligand labelled with the potent alpha-emitting isotope 212 Pb. Methods: This is a prospective, open-label, non-randomized, dose-escalation, dose optimization and expansion study. The study aims to determine the safety and tolerability of escalating doses of [ 212 Pb]Pb-ADVC001 administered every 6, 4 or 2 weeks during the dose-finding phase (Phase 1b) in participants with PSMA-positive mCRPC who have had exposure to at least one androgen receptor pathway inhibitor (ARPi) and taxane-based chemotherapy at any time in the course of their disease. The dose escalation phase will follow an i3+3 design, with each cohort able to backfill up to 20 participants for further characterization of the safety, tolerability and preliminary efficacy of dose and schedules. The expansion phase (Phase 2a) aims to assess the efficacy, safety and tolerability of [ 212 Pb]Pb-ADVC001 at the recommended Phase 2 dose in three groups of participants with PSMA-positive mCRPC. Group 1: Participants who have had exposure to at least one ARPi and have not received a taxane for the treatment of mCRPC. Group 2: Participants who have had exposure to at least one ARPi and received taxane-based chemotherapy for the treatment of mCRPC. Group 3: Participants who have had exposure to 177 Lu-PSMA. If data from Phase 1b demonstrates multiple dosing regimens are reasonably equivalent in terms of safety, tolerability and anti-tumor activity, the Phase 2a expansion study may include adaptive randomization to identify an optimized dose and schedule. The trial is currently enrolling at two clinical sites in Australia. Clinical trial information: NCT05720130 .