Award Title: Genotype of Urothelial cancer: Stratified Treatment and Oncological outcomes (GUSTO): Phase II study
Funder: Medical Research Council

Abstract: We want to improve the outcomes from Bladder Cancer. We think this can be achieved by using the genetic information within each cancer to tailor treatments to individual patients. However, before testing our approach, we have to understand if this is possible within the NHS and if our choices appear to work._x000D_
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Bladder cancer is a common disease and one of the most expensive cancers for the NHS. The treatments for aggressive bladder cancer include surgery to remove the bladder, radiotherapy to the pelvis, chemotherapy and immunotherapy. These treatments combine local approaches to the bladder with whole body treatments to stop the cancer spreading. _x000D_
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Combined treatments have the best cure rates, but have most complications, are expensive and affect a person’s well-being for many months. Regardless, our current approach is to treat all individual patients as though they have the same type of bladder cancer, with everyone receiving the same treatment schedules._x000D_
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However, treating all bladder cancers in the same way may not be best for individual patients. For example, some cancers respond exceptionally well to chemotherapy and so may not need surgery. Other cancers may respond better to immunotherapy and so need this treatment alone or as a boost to chemotherapy. Finally, some cancers do not respond to either chemotherapy or immunotherapy and so need immediate surgery. Recent advances have suggested the genetic information within a bladder cancer may identify which treatment is best for an individual patient. This approach has not yet been tested in a clinical trial. We think it is time to test the ability of genetic profiling to direct a patient care. We want to understand if tailored treatments are better than the current standard of care. These tailored treatments include surgery, immunotherapy or chemotherapy alone and in combination._x000D_
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We will recruit patients from our clinics and test whether we can profile their cancers quickly (so that their treatment is not delayed) and whether their cancers appear to respond to a tailored approach. We will randomise patients to our new pathway or standard care. We will look to see how many respond to chemotherapy and/or immunotherapy, and whether immediate surgery is better than standard care._x000D_
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In this study we will assess the practicalities of our proposed pathway, our underlying assumptions and prepare for a large trial that fully tests our choices. The larger trial needs key information to help its planning and proof that our hypotheses appear to work. If successful, our approach would improve survival rates for bladder cancer, reduce the cost of treating these patients and reduce the number of potentially toxic treatments individuals would need.

Lay Abstract: Research Question: Does the use of genomic stratified care indicate sufficiently improved treatment activity to warrant a phase III trial in invasive bladder cancer? _x000D_
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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._x000D_
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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._x000D_
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Objectives:_x000D_
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). _x000D_
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._x000D_
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. _x000D_
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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._x000D_
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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._x000D_
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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.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;5.4 SURGERY;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health Categories: CANCER AND NEOPLASMS