Genotype of Urothelial cancer: Stratified Treatment and Oncological outcomes (GUSTO): Phase II study

Research Question: Does the use of genomic stratified care indicate sufficiently improved treatment activity to warrant a phase III trial in invasive bladder cancer? Background: Bladder cancer is one of the commonest and most expensive human malignancies. Survival rates are not improving. Standard of care for muscle invasive bladder cancer (MIBC) is radical pelvic treatment (either cystectomy or radiotherapy) following neoadjuvant cisplatin based chemotherapy (NAC). NAC improves survival, but individual outcomes are mixed: 20-30% of cancers Completely Respond (pCR, defined as pT0) to NAC, whilst 40% are locally advanced at cystectomy. NAC may be harmful in chemoresistant tumours by delaying radical treatment. Multiple unselected immunotherapy trials are in progress and threaten to slow radical treatment further and escalate treatment. We propose a study to develop a gene expression subtype-selected approach to individualised care. Aim: Obtain information to guide the design of a phase III trial with respect to the feasibility of gene expression subtyping, the distribution of gene expression subtypes in the NHS population, the heterogeneity of intermediate endpoints (pCR) by subtype following standard of care treatment, and assess the activity of gene expression subtype-guided experimental treatments. Objectives: Stage 1: Assess the feasibility of gene expression subtype stratification in terms of the recruitment of patients and gene expression subtype assessment (time to allocation and success rate). Stage 2: Confirm feasibility of recruitment of patients, assess assumptions concerning the proportion of each gene expression subtype in recruited patients, assess the assumptions regarding the respective pCR rates in the MIBC control population and conduct a sample size re-estimation for stage 3. Stage 3: Assess the pCR rate in each gene expression subtype to explore treatment activity, evaluate acceptability of the trial design to patients, investigate toxicity and tolerability and explore survival outcomes to determine if a confirmatory phase III randomised controlled trial (RCT) is warranted. Methods: Multi-centre, prospective, open-label, multi-stage, individually randomised phase II trial. Eligible patients will be registered into the study and their TURBT samples will be assigned a gene expression subtype using the GUSTO classifier (consisting of the Decipher platform and the TCGA 2 classification system). Eligible patients will be randomised (1:1) to Standard Care (NAC and Radical Cystectomy) or Radical Cystectomy with Gene expression subtype-guided Care (Basal and Neuronal tumours receive NAC, Durvalumab and Tremelimumab; Luminal Infiltrated tumours receive Durvalumab and Tremelimumab; Luminal/Luminal Papillary tumours proceed directly to radical cystectomy. Patients will be followed up for a minimum of 12 months post-cystectomy. Timelines for Delivery: Following set up (12 months), we will recruit to Stage 1 over 6 months (aiming for 30 patients). If pre-defined progression criteria are met (recruitment rate, time to gene expression subtype allocation and gene expression subtyping success), we will progress to Stage 2 and continue to recruit for a further 18 months (aiming for 176 patients). If progression criteria are met (recruitment rate, gene expression subtyping distribution, pCR rates and confirmation of sample size assumptions) we will progress to stage 3 and continue to recruit for a further 12 months overall recruitment target 320 patients). We will have 6 months analyses and dissemination. Anticipated impact of dissemination: Initial impact will be to determine the feasibility of gene expression subtype-guided care and inform the design of a phase III RCT to evaluate effectiveness. We will also establish gene expression subtyping and test viability of personalised approaches for BC. Dissemination of this phase II trial will be through medical conferences, journals and social media. Dissemination to patients will be through advocacy networks, embedding Patient and Public Involvement (PPI) and printed/social media. If gene expression subtype-guided care is shown to be effective in a future phase III RCT it will improve survival rates, reduce the medical/financial burden of managing BC, could lead to chemotherapy and immunotherapy sparing approaches and earlier radical treatment in appropriate cancers.