Whelan, Ruby Smith

Background High‐risk non‐muscle‐invasive bladder cancer (HRNMIBC) has a variable prognosis, managed predominantly by local surgical resection and intravesical Bacillus Calmette–Guérin (BCG), or radical cystectomy (RC). Current treatments are poorly tolerated, have supply limitations and often fail to control the disease. Treatments overcoming these limitations are needed to improve HRNMIBC outcomes. Many novel agents have been approved in recent years (including systemic pembrolizumab, nogapendekin alfa inbakicept‐pmln, N‐803), but long‐term efficacy is unknown. Given advanced bladder cancer findings, we believe direct intravesical administration of atezolizumab may aid with managing HRNMIBC or muscle‐invasive bladder cancer in patients who are ineligible for cisplatin‐based neoadjuvant chemotherapy. Study design The INtraVESical immunoTherapy (INVEST) trial is a UK‐based, open‐label, non‐randomised, single‐centre, Phase Ib dose escalation, window of opportunity study exploring atezolizumab administration via intravesical routes (passive instillation and direct injection [sub‐urothelial]) in patients with bladder cancer with all stages undergoing RC. For both routes, an initial dose confirmation stage will determine toxicity and recommended atezolizumab dosage, followed by a dose expansion stage to further evaluate safety and toxicity at the recommended dose. Endpoints We aim to investigate safety (primary) and preliminary activity (secondary) of intravesical atezolizumab delivered by passive instillation and direct injection into the tumour/bladder wall in patients with bladder urothelial cell carcinoma prior to RC. Primary endpoints include dose limiting toxicities and adverse events. Secondary endpoints include progression‐free survival, pathological complete response rate and treatment compliance. Exploratory endpoints include pharmacokinetic profile (assessed by serum and urine concentrations at prespecified timepoints), spatial analysis of atezolizumab distribution within RC tissue by imaging mass spectrometry and overall survival. Patients and Methods Atezolizumab will be administered intravesically by either passive instillation or direct injection into the tumour/bladder wall. Cohorts will receive either 600 mg or 1200 mg doses administered as a single dose or as multiple doses (weekly for 3–6 weeks). Trial Registration International Standard Randomised Controlled Trial Number: ISRCTN15842444 , registered 2 December 2022.

773 Background: BCG-unresponsive High-risk non-muscle invasive bladder cancer (HRNMIBC) tumours have an ominous prognosis and require effective, tolerable treatments. Uptake remains low for FDA approved agents (including systemic pembrolizumab, nogapendekin alfa inbakicept-pmln or N-803) due to toxicity concerns. We hypothesize direct intravesical administration of a PDL1 inhibitor could be effective with less systemic toxicity. However, it is unknown whether antibodies delivered via this route can reach tumor vasculature. INVEST is a phase Ib window of opportunity study investigating the safety and preliminary activity of passive instillation and direct injection of intravesical atezolizumab into the tumour/bladder wall. Methods: Eligible participants (ECOG performance status 0-2) are awaiting radical cystectomy (RC) for any stage urothelial cell carcinoma. Participants with muscle invasive bladder cancer, must be ineligible for/ refuse cisplatin based neo-adjuvant chemotherapy. Atezolizumab (600mg or 1200mg) is administered via direct injection into the tumour/bladder or by instillation into the bladder. The 3+3 design is utilised in the dose confirmation stages where participants receive either Single or Multiple (between 3 and 6) dose(s) of treatment before RC. Efficacy signals are derived from pathological complete response at RC and progression-free survival at 2 years. Primary endpoint, Dose confirmation stage: The number of dose-limiting toxicities (DLTs) observed from first dose of trial treatment to RC. Results: Enrolment began in May 2023. 13 participants were recruited to the single dose cohorts: 11 male, and 2 female. Age (Range; 43-86); median 70y, 9 NMIBC, 4 MIBC. 7 for direct injection (4 at 600mg and 3 at 1200mg dose) and 6 for passive instillation (3 at 600mg and 3 at 1200mg). Due to technical issues (syringe size) the first direct injection participant did not receive the full 600mg and were replaced. 12 participants received trial treatment as planned. There were no DLTs; 5 participants experienced non-trial treatment related SAEs (4 infections, 2 ileus, 2 renal impairment; 7/8 events occurred post-RC and all SAEs resolved). All participants underwent planned RC within the protocol stipulated timeline. Median time from last treatment to RC was18 days. 5 of 13 participants had downstaging of tumour in cystectomy specimen. Following independent Safety Review Committee review, recruitment is now open for the dose confirmation phase (Multiple 1200mg dose) in both treatment routes. Conclusions: Single dose atezolizumab treatment at a dose of 600mg and 1200mg in passive instillation and direct injection cohorts was well tolerated. Early efficacy data is encouraging. Multiple weekly doses of 1200mg in each treatment route are now being investigated within the INVEST trial. Clinical trial information: ISRCTN15842444 .