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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

Authors :
Grant D. Stewart
Tim Eisen
Gemma Young
Mark Sullivan
Richard Skells
Sarah J. Welsh
Anne Y. Warren
Amanda Walker
Helen Mossop
Ferdia A. Gallagher
Evis Sala
Balaji Venugopal
Grenville Oades
A. Chhabra
Andrew Protheroe
James Wason
Jamal A. N. Sipple
John Stone
Thomas J. Mitchell
Athena Matakidou
Kate Fife
Stephan Ursprung
Mireia Crispin Ortuzar
Martin G. Thomas
Stewart, Grant D [0000-0003-3188-9140]
Apollo - University of Cambridge Repository
Ursprung, Stephan [0000-0003-2476-178X]
Gallagher, Ferdia [0000-0003-4784-5230]
Sala, Evis [0000-0002-5518-9360]
Warren, Anne [0000-0002-1170-7867]
Eisen, Tim [0000-0001-9663-4873]
Welsh, Sarah [0000-0001-5690-2677]
Stewart, Grant [0000-0003-3188-9140]
Stewart, Grant D. [0000-0003-3188-9140]
Source :
BMC Cancer, Vol 21, Iss 1, Pp 1-11 (2021), BMC Cancer
Publication Year :
2021
Publisher :
Apollo - University of Cambridge Repository, 2021.

Abstract

Funder: AstraZeneca (GB)<br />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.

Details

ISSN :
14712407
Database :
OpenAIRE
Journal :
BMC Cancer, Vol 21, Iss 1, Pp 1-11 (2021), BMC Cancer
Accession number :
edsair.doi.dedup.....629392efc62a5735d8880553cf148d3e
Full Text :
https://doi.org/10.17863/cam.78332