Targeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial
Arthur G. Pratt, Stefan Siebert, Michael Cole, Deborah Stocken, Christina Yap, Stephen Kelly, Muddassir Shaikh, Amy Cranston, Miranda Morton, Jenn Walker, Sheelagh Frame, Wan‐Fai Ng, Christopher D. Buckley, Iain B. McInnes, Andrew Filer, John D. Isaacs
Abstract
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: ) were measured. This study is registered with ISRCTN, ISRCTN36667085. FINDINGS: 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.