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. 2021 Nov 18;21(1):1238.
doi: 10.1186/s12885-021-08965-4.

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol

Stephan Ursprung  1 , Helen Mossop  2 , Ferdia A Gallagher  1   3 , Evis Sala  1   3 , Richard Skells  3   4 , Jamal A N Sipple  3 , Thomas J Mitchell  1   3   5 , Anita Chhabra  3 , Kate Fife  3 , Athena Matakidou  3 , Gemma Young  3 , Amanda Walker  3 , Martin G Thomas  3 , Mireia Crispin Ortuzar  1 , Mark Sullivan  6 , Andrew Protheroe  6 , Grenville Oades  7 , Balaji Venugopal  8 , Anne Y Warren  1   3 , John Stone  4 , Tim Eisen  1   3 , James Wason  3   9 , Sarah J Welsh  1   3 , Grant D Stewart  10   11
Affiliations

The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol

Stephan Ursprung et al. BMC Cancer. .

Abstract

Background: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE).

Methods: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by Ktrans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging.

Discussion: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda.

Trial registration: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 .

Keywords: Bayesian adaptive trial; Cediranib [MeSH]; Clear cell renal cell carcinoma [MeSH]; Clinical trial protocol [MeSH]; Durvalumab [MeSH]; Neoadjuvant therapy [MeSH]; Olaparib [MeSH]; Phase II clinical trial [MeSH]; Window-of-opportunity.

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Conflict of interest statement

This trial received funding from AstraZeneca, Cambridge, UK. G.D.S. declares educational grants from Pfizer, AstraZeneca, and Intuitive Surgical; consultancy fees from Pfizer, Merck, EUSA Pharma, and CMR Surgical; travel expenses from Pfizer; and speaker fees from Pfizer. S.J.W. has received travel support from Ipsen. E.S. declares being a co-founder and shareholder of Lucida Medical, consultancy fees from Amazon and speaker fees from GSK. S.U., M.G.T, R.S., G.Y. and J.A.N.S. declare no competing interests. T.E. was employed by and has stock in AstraZeneca, is employed by and has stock in Roche, has received research support from AstaZeneca, Bayer and Pfizer. K.F. has received advisory, consultancy or speaker fees from ESAI, Ipsen, Roche, Novartis, Merck, Pfizer, Eusa, BMS, conference support from Novartis, Ipsen and EUSA and institutional research funding from Roche, Merck, Exelixis. B.V. has received advisory, consultancy or speaker fees from Bristol Myers Squibb (BMS), Eisai, EUSA pharma, Ipsen, Merck Sorono, Merck Sharp & Dohme (MSD), Pfizer; conference support from Ipsen and Institutional research funding from Exelixis, Ipsen, MSD, Pfizer. A.P. has received advisory, consultancy or speaker fees from Eisai, BMS, Ipsen, MSD, Novartis, Roche, Astellas, Bayer, and Pfizer. Conference support from Pfizer, Ipsen, MSD, Roche, Astellas. Research funding from MSD. F.A.G. has research grants from GSK, research support from GE Healthcare and has consulted for AstraZeneca. M.C.O. has received research funding from Lilly. JS is an employee and stockholder in AstraZeneca, Cambridge, UK and a stockholder in GSK.

Figures

Fig. 1
Fig. 1
Bayesian adaptive trial design with interim analyses and decision boundaries for single-agent and combination-therapy arms. Green arrows denote efficacy, orange arrows denote futility
Fig. 2
Fig. 2
Timeline of interventions and assessments for the WIRE trial. *Optional, **Only in patients with cM1 disease. US: ultrasound
See this image and copyright information in PMC

References

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