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Lookup NU author(s): Dr Arthur PrattORCiD, Dr Stefan Siebert, Mike Cole, Dr Deborah Stocken, Amy Cranston, Dr Miranda PattersonORCiD, Jenn Walker, Professor Fai NgORCiD, Professor Iain McInnes, Professor John IsaacsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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 (Cmax) and area under the plasma concentration time curve 0-6 h (AUC0-6) 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 Cmax and AUC0-6 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.
Author(s): Pratt AG, Siebert S, Cole M, Stocken DD, Yap C, Kelly S, Shaikh M, Cranston S, Morton M, Walker J, Frame S, Ng WF, Buckley CD, McInnes IB, Filer A, Isaacs JD
Publication type: Article
Publication status: Published
Journal: The Lancet Rheumatology
Year: 2021
Volume: 3
Issue: 5
Pages: e337-e346
Print publication date: 01/05/2021
Online publication date: 07/03/2021
Acceptance date: 02/04/2021
Date deposited: 09/11/2023
ISSN (electronic): 2665-9913
Publisher: The Lancet Publishing Group
URL: https://doi.org/10.1016/S2665-9913(21)00061-8
DOI: 10.1016/S2665-9913(21)00061-8
Data Access Statement: Due to commercial sensitivity, the data beyond those presented in the manuscript and appendix are not immediately available for sharing. Should this status change, requests will be considered by the research team, including Newcastle Clinical Trials Unit and the Chief Investigator, in the context of the research question proposed, as well as ethical considerations such as patient anonymity and informed consent. The patient information sheet and informed consent documentation are available on request from the corresponding author. The clinical trial protocol has been published previously.10 [ Siebert S / Pratt AG / Stocken DD et al. Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: an early phase trial. Medicine. 2020; 99e20458]
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