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.

Antibodies, Monoclonal / therapeutic use Antineoplastic Agents / therapeutic use Antineoplastic Combined Chemotherapy Protocols / therapeutic use Bayes Theorem Biopsy Capillary Permeability / drug effects Carcinoma, Renal Cell / blood supply Humans Kidney / pathology Kidney Neoplasms / blood supply Lymphocytes, Tumor-Infiltrating Magnetic Resonance Imaging Medical Futility Nephrectomy Non-Randomized Controlled Trials as Topic Phthalazines / therapeutic use Piperazines / therapeutic use Proof of Concept Study Quinazolines / therapeutic use Treatment Outcome Tumor Burden

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

Journal

BMC cancer

ISSN: 1471-2407

Titre abrégé: BMC Cancer

Pays: England

ID NLM: 100967800

Informations de publication

Date de publication:
18 Nov 2021

Historique:

received: 08 04 2021

accepted: 04 11 2021

entrez: 19 11 2021

pubmed: 20 11 2021

medline: 22 2 2022

Statut: epublish

Résumé

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

Sections du résumé

BACKGROUND BACKGROUND

METHODS 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

DISCUSSION CONCLUSIONS

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 BACKGROUND

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

Identifiants

DOI: 10.1186/s12885-021-08965-4 PMID: 34794412 PMC: PMC8600815

pubmed: 34794412

doi: 10.1186/s12885-021-08965-4

pii: 10.1186/s12885-021-08965-4

pmc: PMC8600815

doi:

Substances chimiques

Antibodies, Monoclonal 0

Antineoplastic Agents 0

Phthalazines 0

Piperazines 0

Quinazolines 0

durvalumab 28X28X9OKV

cediranib NQU9IPY4K9

olaparib WOH1JD9AR8

Banques de données

ClinicalTrials.gov

['NCT03741426']

Types de publication

Clinical Trial Protocol Clinical Trial, Phase II Journal Article Multicenter Study

Langues

eng

Sous-ensembles de citation

Pagination

1238

Subventions

Organisme : Medical Research Council

ID : MC_UU_00002/6

Pays : United Kingdom

Organisme : Medical Research Council

ID : MR/T024097/1

Pays : United Kingdom

Organisme : Cancer Research UK Cambridge Centre

ID : C9685/A25177

Organisme : NIHR Cambridge Biomedical Research Centre

ID : BRC-1215-20014

Informations de copyright

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