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

• Published in: BMC cancer 2021-11, Vol.21 (1), p.1238-1238, Article 1238
• Main Authors: Ursprung, Stephan, Mossop, Helen, Gallagher, Ferdia A, Sala, Evis, Skells, Richard, Sipple, Jamal A N, Mitchell, Thomas J, Chhabra, Anita, Fife, Kate, Matakidou, Athena, Young, Gemma, Walker, Amanda, Thomas, Martin G, Ortuzar, Mireia Crispin, Sullivan, Mark, Protheroe, Andrew, Oades, Grenville, Venugopal, Balaji, Warren, Anne Y, Stone, John, Eisen, Tim, Wason, James, Welsh, Sarah J, Stewart, Grant D
• Format: Article
• Language: English
• Subjects: Adverse events; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor agents; Bayes Theorem; Bayesian adaptive trial; Bayesian analysis; Bayesian statistical decision theory; Biomarkers; Biopsy; Birth control; Bone marrow; Cancer; Capillary Permeability - drug effects; Carcinoma, Renal cell; Carcinoma, Renal Cell - blood supply; Carcinoma, Renal Cell - diagnostic imaging; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - pathology; Care and treatment; CD8 antigen; Cediranib [MeSH]; Clear cell renal cell carcinoma [MeSH]; Clinical trial protocol [MeSH]; Clinical trials; Computed tomography; Consent; DNA damage; Humans; Immune checkpoint inhibitors; Immunohistochemistry; Immunosuppressive agents; Immunotherapy; Kidney - pathology; Kidney cancer; Kidney Neoplasms - blood supply; Kidney Neoplasms - diagnostic imaging; Kidney Neoplasms - drug therapy; Kidney Neoplasms - pathology; Lymphocytes T; Lymphocytes, Tumor-Infiltrating; Magnetic Resonance Imaging; Medical Futility; Metastasis; Methods; Monoclonal antibodies; Mutation; Nephrectomy; Non-Randomized Controlled Trials as Topic; Objectives; Olaparib [MeSH]; Oncology, Experimental; Ovarian cancer; Patients; Permeability; Phase II clinical trial [MeSH]; Phthalazines - therapeutic use; Piperazines - therapeutic use; Proof of Concept Study; Quinazolines - therapeutic use; Renal cell carcinoma; Study Protocol; Surgery; Targeted cancer therapy; Treatment Outcome; Tumor Burden; Tumors; Vascular endothelial growth factor
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-021-08965-4

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 7 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). 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 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. 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. ClinicalTr