Targeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial.
| Autor: | Pratt AG; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Siebert S; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK., Cole M; Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK., Stocken DD; Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK., Yap C; Clinical Trial and Statistics Unit, The Institute of Cancer Research, London, UK., Kelly S; Department of Rheumatology, Barts Health NHS Trust, London, UK., Shaikh M; Department of Rheumatology, James Cook University Hospital, Middlesbrough, UK., Cranston A; Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK., Morton M; Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK., Walker J; Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK., Frame S; Cyclacel, Dundee, UK., Ng WF; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., Buckley CD; National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., McInnes IB; Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK., Filer A; National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK., Isaacs JD; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. |
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| Jazyk: | angličtina |
| Zdroj: | The Lancet. Rheumatology [Lancet Rheumatol] 2021 Mar 09; Vol. 3 (5), pp. e337-e346. Date of Electronic Publication: 2021 Mar 09 (Print Publication: 2021). |
| DOI: | 10.1016/S2665-9913(21)00061-8 |
| Abstrakt: | Background: 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 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 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. (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.) |
| Databáze: | MEDLINE |
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