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

Autor: 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
Přispěvatelé: 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]
Rok vydání: 2021
Předmět:
Oncology
Cancer Research
Durvalumab
Non-Randomized Controlled Trials as Topic
medicine.medical_treatment
Biopsy
Kidney
Clear cell renal cell carcinoma [MeSH]
Nephrectomy
Piperazines
chemistry.chemical_compound
Study Protocol
Clinical trial protocol [MeSH]
Phase II clinical trial [MeSH]
Renal cell carcinoma
Antineoplastic Combined Chemotherapy Protocols
Clinical endpoint
Medicine
Durvalumab [MeSH]
RC254-282
Antibodies
Monoclonal
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Bayesian adaptive trial
Magnetic Resonance Imaging
Kidney Neoplasms
Tumor Burden
Treatment Outcome
Medical Futility
medicine.drug
medicine.medical_specialty
Olaparib [MeSH]
Antineoplastic Agents
Neoadjuvant therapy [MeSH]
Proof of Concept Study
Olaparib
Cediranib
Capillary Permeability
Lymphocytes
Tumor-Infiltrating
Internal medicine
Genetics
Humans
Adverse effect
Carcinoma
Renal Cell
Window-of-opportunity
business.industry
Bayes Theorem
Cediranib [MeSH]
medicine.disease
Clinical trial
chemistry
Quinazolines
Phthalazines
business
Zdroj: BMC Cancer, Vol 21, Iss 1, Pp 1-11 (2021)
BMC Cancer
ISSN: 1471-2407
DOI: 10.17863/cam.78332
Popis: Funder: AstraZeneca (GB)
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.
Databáze: OpenAIRE
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