The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer

Objectives: To assess the safety of sub-urothelial injection of durvalumab and examine the impact on tissue and circulating immune cell populations. Patients and Methods: The patients were chemotherapy and immunotherapy naïve (bacille Calmette-Guérin allowed) with non-metastatic muscle-invasive bladder cancer or non-muscle-invasive bladder cancer planned for radical cystectomy (RC). The study was a Phase Ib 3 + 3 dose-escalation design with sub-urothelial injection of durvalumab at three pre-determined doses (25, 75, 150 mg) diluted in 25 mL normal saline, injected at 25 locations (25 × 1 mL injections), at least 2 weeks before RC. Results: A total of 11 patients were recruited (10 male, one female). No significant changes were reported on American Urological Association Symptom Score or O’Leary Interstitial Cystitis Scale. In all, 14 adverse events (AEs) were reported (10 Grade 1, three Grade 2, one Grade 3), none considered immune-related. No Grade 4 or 5 AEs were recorded. All the patients underwent RC. Tissue immune populations changed following durvalumab injection (P = 0.012), with a statistically significant increase in M2-macrophage (CD163) when comparing the 25–150 mg dose (P = 0.021). Basal/mixed cancers showed a larger CD163 increase than luminal cancers (P = 0.033). Conclusion: Sub-urothelial injection of durvalumab is feasible and safe without immune-related AEs and shows local immunological effects.