Window-of-opportunity clinical trial platform for evaluation of novel treatment strategies in renal cell cancer (WIRE).

TPS406 Background: Renal cell cancer (RCC) is the 7th commonest cancer in the UK. The WIRE trial ‘exploits’ a window-of-opportunity between clear cell RCC diagnosis and nephrectomy to use vascular endothelial growth factor tyrosine kinase inhibitors, PARP inhibitors, and immune checkpoint inhibitor therapies in isolation and in combination. WIRE aims to provide biological proof-of-mechanism of these therapies, and build on encouraging pre-clinical evidence of DNA damage response inhibition to be an effective future therapeutic strategy in RCC. Methods: WIRE is a phase II, multi-IMP, multi-arm, non-randomised clinical trial featuring a Bayesian adaptive design with five treatment arms, and three recruitment stages per arm. The treatment groups: cediranib, cediranib and olaparib, olaparib, durvalumab, and durvalumab and olaparib form the initial set of therapy options with the opportunity for additional treatments to be deployed on this platform-trial in future. The primary endpoint for the first three arms is tumour capillary permeability, measured using multiparametric MRI, defined as a 30% reduction in Ktrans compared to pre-treatment. Whereas in the remaining two arms the primary endpoint is changed to intra-tumoural CD8 positive T cells, defined as an increase of 30% cell count compared to pre-treatment. Up to 76 evaluable participants will be recruited. Monotherapy arms will recruit a maximum of 12 participants each, whereas a maximum of 20 participants will be recruited into each dual-therapy arm. Participants are assigned to the current recruiting arm for treatment lasting between 14 and 28 days before proceeding with standard-of-care nephrectomy. Participants will undergo a biopsy and imaging before and after treatment for primary endpoint analysis, alongside blood and urine collections for translational endpoints. A final two follow-up visits are scheduled before concluding the trial pathway. Rapid interim analysis will follow at the end of a recruitment stage to determine whether to cease recruitment to the current treatment arm due to biological response, or due to futility – defined as lacking in promising evidence for proof of mechanism. Alternatively, if more data is required, recruitment will continue within the same treatment arm until the next interim analysis, where endpoints are re-examined. This highly-efficient design accelerates the exploration of multiple therapies with a strong emphasis on determining early proof-of-mechanism. Promising therapies can then be taken forward to later phase trials in RCC with greater confidence. Clinical trial information: NCT03741426.