SUBDUE-3: Sub-urothelial durvalumab-sirconium to investigate local and systemic distribution of durvalumab when injected in the sub-urothelium.

Abstract

TPS903 Background: Sub-urothelial injection of durvalumab presents a novel therapeutic approach for bladder cancer. SUBDUE-1, a first-in-human Phase Ib dose escalation study presented at ASCO 2022, demonstrated the safety and tolerability of sub-urothelial durvalumab in patients with bladder cancer scheduled for radical cystectomy, with no treatment-related adverse events and preliminary evidence of immunomodulation in the tumour microenvironment 1 . SUBDUE-3 will use radiolabelled 89 Zirconium-durvalumab ( 89 Zr-durvalumab) to define local and systemic biodistribution following sub-urothelial injection. Methods: SUBDUE-3 is an open-label, non-randomized Phase 0 trial sponsored by ANZUP (ANZUP 2402, ACTRN 12624001245583p). Ethics approval has been obtained for this study which is currently recruiting patients diagnosed with either high-risk non-muscle-invasive bladder cancer (HR-NMIBC) or muscle-invasive bladder cancer (MIBC), scheduled for radical cystectomy. 25mL of sub-urothelial 89 Zr-durvalumab will be injected in 1mL aliquots throughout the bladder using a 5Fr Bonee needle via 22Fr rigid cystoscope at a GA cystoscopy performed 2 weeks pre-cystectomy. After injection, PET imaging will be performed at several time points over 7 days. At each imaging time point, blood samples will be collected to evaluate the systemic bioavailability of 89 Zr-durvalumab using a gamma counter. Additionally, the urinary radiation dose will be measured during the first imaging session. Quality control measures will assess dissociation of 89 Zr from durvalumab. Dosimetric analyses will determine the distribution and radiation dose of 89 Zr-durvalumab both within the bladder and systemically, providing critical insights for future therapeutic strategies in bladder cancer treatment. Primary endpoint: visual and semi-quantitative assessment of 89 Zr-durvalumab distribution within the bladder wall and systemic organs (liver, kidney, lung, bone marrow) via PET imaging. Secondary endpoints: bladder and other organ tracer biodistribution; comparison of dosimetry data with cohorts receiving systemic 89 Zr-durvalumab; safety; feasibility. The trial has a one-year recruitment strategy aiming to recruit up to 3 patients and is expected to finish recruiting in 2025. References: 1. Hayne D. Et al. The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer. BJU Int. 2024 Aug;134(2):283-290. doi: 10.1111/bju.16325. Epub 2024 Mar 12. PMID: 38469652. Clinical trial information: ACTRN 12624001245583p.