In the clinic
‘WIRE’ stands for WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer, a clinical trial that makes opportunistic investigational use of the existing 4-week surgical window-of-opportunity between the decision to operate on surgically resectable renal cell cancer (RCC) and surgery itself.
By utilising a period when patients would otherwise remain untreated, WIRE enables investigation into the therapeutic effects and safety of individual or synergistic combinations of systemic anti-cancer agents without any delay in potentially curative nephrectomy. Its primary aim is to evaluate changes in multiple molecular, genetic and imaging-based factors in relation to the tumour and host response to the drugs being tested, as well as to develop new models of RCC for better pre-clinical testing of promising Investigational Medicinal Products (IMPs) in the future. The results will guide and facilitate greater understanding of the optimal combinations of anti-cancer drugs to prioritise for later phrase clinical trials, as well as potential development of predictive biomarkers or methods of tracking response.
Designed as a Phase 2, multi-arm, multicentre, non-randomised, proof-of-mechanism platform trial using a Bayesian adaptive design, WIRE’s primary aim is to investigate the activity of three initial IMPs: cediranib (a growth factor blocker), olaparib (a PARP inhibitor), and durvalumab (an immunotherapy drug). By testing IMPs both as individual and combination therapies, the relative contribution of each individual agent to any successful combinations can be determined. Thanks to its platform study design, WIRE also has the future capacity to expand and incorporate new drug monotherapy and combination arms beyond these initial three, incorporating clinical data from the initial trial arms to guide and inform new iterations for maximal biological outcomes and clinical benefit.
In the first instance, WIRE aims to recruit up to 76 evaluable participants with surgically resectable renal cell cancer (Stage M0/M1) from specialist clinics at participating sites. Following a maximum 28 day screening period, participants will be sequentially allocated to one of five trial arms:
Up to 12 participants will be registered for each of the single treatment arms and up to 20 participants for the combination treatment arm(s), as per the Bayesian adaptive design. Treatment will involve a minimum of 14 days oral IMP treatment or a single IV infusion dose of durvalumab - alone or in combination, as per each trial arm - in the window-of-opportunity period prior to surgery, after which surgery will be performed as per standard care.
The expression of biomarkers of RCC response will be evaluated in biosamples donated before, during and after study drug therapy to define proof of mechanism. Tissue, blood and urine will be collected at baseline, during the treatment period (blood and urine), at the pre-surgery imaging visit (blood and urine), at surgery (tissue), and at 3 months post-surgery (blood and urine). Evaluations will be made at statistically specified intervals to assess either biological proof-of-mechanism or futility for that particular trial arm, determining whether recruitment is continued or halted. This adaptive trial design allows rapid assessment of IMPs by recruiting a cohort of participants from one treatment arm to the next and concluding recruitment as soon as convincing biological effects are determined at the end of each interim analysis. By maximising biological outcomes with sequential testing of each arm, each treatment regime can be stopped early for success or failure.
WIRE’s primary endpoint is to assess proof-of-mechanism, utilising novel techniques to gain a better fundamental understanding of the effect of the study drug regimens on these measures. Biological evidence of treatment effect will be assessed by imaging (i.e. vascular permeability by a reduction in ktrans assessed by DCE MRI) or molecular analysis (e.g. activation of the immune system as measured by an increase in CD8 positive T-cells). Secondary endpoints include safety, change in primary tumour size (assessed by mpMRI including DCE-MRI), overall tumour response (RECIST V1.1 assessment), changes in pre and post treatment tumour capillary permeability measured using mpMRI, and change in pre- and post- treatment intra-tumoural CD8 positive T cells. It is hoped that rapid assessment of IMP(s) treatment effects in this setting will enable promotion of the best combinations to later phase clinical trials in ccRCC.
Led by Professor Grant Stewart as Chief Investigator, WIRE is managed by the Cambridge Clinical Trials Unit and sponsored by Cambridge University Hospitals NHS Foundation Trust (CUH) and University of Cambridge (UoC). The trial is part funded by the Cancer Research UK Cambridge Centre and AstraZeneca.
WIRE is supported by The Mark Foundation Institute for Integrated Cancer Medicine (MFICM). MFICM is hosted at the University of Cambridge, with funding from The Mark Foundation for Cancer Research (NY, USA) and the Cancer Research UK Cambridge Centre [C9685/A25177] (UK).