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dc.contributor.authorPratt, AG
dc.contributor.authorSiebert, S
dc.contributor.authorCole, M
dc.contributor.authorStocken, DD
dc.contributor.authorYap, C
dc.contributor.authorKelly, S
dc.contributor.authorShaikh, M
dc.contributor.authorCranston, A
dc.contributor.authorMorton, M
dc.contributor.authorWalker, J
dc.contributor.authorFrame, S
dc.contributor.authorNg, W-F
dc.contributor.authorBuckley, CD
dc.contributor.authorMcInnes, IB
dc.contributor.authorFiler, A
dc.contributor.authorIsaacs, JD
dc.date.accessioned2021-07-02T11:00:19Z
dc.date.available2021-07-02T11:00:19Z
dc.identifier.citationThe Lancet. Rheumatology, 2021, 3 (5), pp. e337 - e346
dc.identifier.issn2665-9913
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4665
dc.identifier.eissn2665-9913
dc.identifier.doi10.1016/s2665-9913(21)00061-8
dc.description.abstractBackground Current rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts-cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics.Methods Phase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR-European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (C max ) and area under the plasma concentration time curve 0-6 h (AUC 0-6 ) were measured. This study is registered with ISRCTN, ISRCTN36667085.Findings Between Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18-0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average C max and AUC 0-6 were two-times higher in participants developing dose-limiting toxicities.Interpretation The maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial.Funding UK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities.
dc.formatElectronic-eCollection
dc.format.extente337 - e346
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleTargeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial.
dc.typeJournal Article
dcterms.dateAccepted2021-03-09
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/s2665-9913(21)00061-8
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Lancet. Rheumatology
pubs.issue5
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.publication-statusPublished
pubs.volume3
pubs.embargo.termsNot known
icr.researchteamClinical Trials & Statistics Unit
icr.researchteamClinical Trials & Statistics Uniten_US
dc.contributor.icrauthorYap, Christinaen


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