INVEST: A phase Ib window of opportunity study of atezolizumab administered either intravesically or direct tumour injection in patients with bladder cancer prior to radical cystectomy.
Authors: Hussain Syed A. , Oughton Jamie B. , Smith Whelan Ruby , Green Angela , Hubbard Rachel , Kennish Steven , Senior Ethan , Kendall Jessica , McCready Dominic , Collinson Fiona J. , Griffin Jon , Catto James W.F. 
Published: January 2024

TPS710

Background: High-risk non-muscle invasive bladder cancer is a common and difficult to manage disease. The treatment of choice is radical cystectomy (RC), as BCG-unresponsive tumours have a poor prognosis. RC negatively impacts health related quality of life and therefore clinicians have explored alternative treatments. The FDA approved systemic pembrolizumab for BCG-refractory carcinoma in situ, but uptake is low, reflecting concerns around efficacy and safety for a non-invasive cancer. We hypothesize that 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 the tumour vasculature. INVEST is a phase Ib window of opportunity study aiming to investigate the safety and preliminary activity of both passive instillation and direct injection into the tumour/bladder wall of intravesical atezolizumab prior to RC. Methods: Eligible participants (ECOG performance status 0-2) are awaiting RC for urothelial cell carcinoma of the bladder (any stage). Those with muscle invasive cancer must be ineligible for or refuse cisplatin based neo-adjuvant chemotherapy. RC will not be delayed by study treatment. Each dose confirmation stage uses a conventional 3+3 design to establish safety based upon dose limiting toxicities. The recommended single dose will be determined first of either 600mg or 1200mg (n=3-12). This dose will then be evaluated further to determine the recommended multiple dose of either 600mg or 1200mg administered weekly for 3-6 weeks (n=3-12). A dose expansion stage will then treat 10 patients at the recommended multiple dose to further evaluate safety and toxicity. This schema will be followed independently for both the passive instillation and direct injection routes of intravesical atezolizumab administration. Efficacy signals will be explored via progression-free survival at two years and pathological complete response rate. INVEST will assess the pharmacokinetic profile of intravesical atezolizumab, anti-drug antibodies to atezolizumab. Samples are being prospectively collected for future translational research. Sampling (fresh, frozen, and FFPE blocks) of scar, tumour and background urothelium is being performed on cystectomy specimens. Tissue microarrays will be created from TURBT and cystectomy tissue. Translational samples include pre- and post-treatment blood cfDNA, PBMCs and serum and urine cfDNA. We will assess drug penetration into the bladder wall and the effects of treatment on circulating tumour cells, and local and systemic immune cell composition. Enrolment began in May 2023. This is a single-site UK-based study and we are not currently seeking additional recruiting centres. Clinical trial information: ISRCTN15842444 .