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
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), th...
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2021
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oai:doaj.org-article:c51c1579691f49dabf5c4459307d83252021-11-21T12:30:37ZThe 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 protocol10.1186/s12885-021-08965-41471-2407https://doaj.org/article/c51c1579691f49dabf5c4459307d83252021-11-01T00:00:00Zhttps://doi.org/10.1186/s12885-021-08965-4https://doaj.org/toc/1471-2407Abstract 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 K trans 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 .Stephan UrsprungHelen MossopFerdia A. GallagherEvis SalaRichard SkellsJamal A. N. SippleThomas J. MitchellAnita ChhabraKate FifeAthena MatakidouGemma YoungAmanda WalkerMartin G. ThomasMireia Crispin OrtuzarMark SullivanAndrew ProtheroeGrenville OadesBalaji VenugopalAnne Y. WarrenJohn StoneTim EisenJames WasonSarah J. WelshGrant D. StewartBMCarticleClinical trial protocol [MeSH]Clear cell renal cell carcinoma [MeSH]Phase II clinical trial [MeSH]Bayesian adaptive trialOlaparib [MeSH]Cediranib [MeSH]Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBMC Cancer, Vol 21, Iss 1, Pp 1-11 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Clinical trial protocol [MeSH] Clear cell renal cell carcinoma [MeSH] Phase II clinical trial [MeSH] Bayesian adaptive trial Olaparib [MeSH] Cediranib [MeSH] Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
Clinical trial protocol [MeSH] Clear cell renal cell carcinoma [MeSH] Phase II clinical trial [MeSH] Bayesian adaptive trial Olaparib [MeSH] Cediranib [MeSH] Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Stephan Ursprung Helen Mossop Ferdia A. Gallagher Evis Sala Richard Skells Jamal A. N. Sipple Thomas J. Mitchell Anita Chhabra Kate Fife Athena Matakidou Gemma Young Amanda Walker Martin G. Thomas Mireia Crispin Ortuzar Mark Sullivan Andrew Protheroe Grenville Oades Balaji Venugopal Anne Y. Warren John Stone Tim Eisen James Wason Sarah J. Welsh Grant D. Stewart 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 |
| description |
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 K trans 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 . |
| format |
article |
| author |
Stephan Ursprung Helen Mossop Ferdia A. Gallagher Evis Sala Richard Skells Jamal A. N. Sipple Thomas J. Mitchell Anita Chhabra Kate Fife Athena Matakidou Gemma Young Amanda Walker Martin G. Thomas Mireia Crispin Ortuzar Mark Sullivan Andrew Protheroe Grenville Oades Balaji Venugopal Anne Y. Warren John Stone Tim Eisen James Wason Sarah J. Welsh Grant D. Stewart |
| author_facet |
Stephan Ursprung Helen Mossop Ferdia A. Gallagher Evis Sala Richard Skells Jamal A. N. Sipple Thomas J. Mitchell Anita Chhabra Kate Fife Athena Matakidou Gemma Young Amanda Walker Martin G. Thomas Mireia Crispin Ortuzar Mark Sullivan Andrew Protheroe Grenville Oades Balaji Venugopal Anne Y. Warren John Stone Tim Eisen James Wason Sarah J. Welsh Grant D. Stewart |
| author_sort |
Stephan Ursprung |
| title |
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 |
| title_short |
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 |
| title_full |
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 |
| title_fullStr |
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 |
| title_full_unstemmed |
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 |
| title_sort |
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 |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/c51c1579691f49dabf5c4459307d8325 |
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