Rheumatoid arthritis Musculoskeletal Diseases Rheumatoid arthritis, unspecified
Conditions
Interventions
Part 1: Participants will receive either 200mg, 400mg, 600mg, 800mg or 1000mg seliciclib once daily for 4 consecutive days every week for 4 weekly cycles*. Results from part 1 will determine the Maxim
Sponsors
Newcastle Hospitals Foundation NHS Trust (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 11/08/2017: 1. Rheumatoid arthritis fulfilling the 1987 ACR or 2010 ACR/EULAR criteria 2. Age 18 years and over 3. At least 6 months’ disease duration 4. ACR Functional Class I-III 5. DAS28 =3.2 (for Part 1 only) 6. DAS28 =4.0, with clinical synovitis in at least three joints, at least one of which is a joint amenable to ultrasound-guided synovial biopsy (knee, elbow, ankle, wrist, MCP or PIP joint) (for part 2 only) 7. Currently taking anti-TNF as part of standard clinical care, and have received anti-TNF therapy for at least 3 months upon entry to the study 8. Anti-TNF may be administered as either monotherapy or with background conventional DMARDs. Permitted background DMARDs are methotrexate, sulphasalazine and hydroxychloroquine, either alone or in combination, at stable dose(s) for =4 weeks prior to baseline visit 9. Stable dose of non-steroidal anti-inflammatory drug (NSAID) or corticosteroid (prednisolone=7.5mg) for =4 weeks 10. No intramuscular glucocorticoid administration in the 4 week period prior to baseline visit 11. Willing and able to undergo MRI scanning on two occasions. (For Part 2 only) 12. Willing to undergo ultrasound guided synovial biopsy on two occasions (under local anaesthetic). (For part 2 only) Previous inclusion criteria: 1. Rheumatoid arthritis fulfilling the 1987 ACR or 2010 ACR/EULAR criteria 2. Age 18 years or above 3. At least 6 months? disease duration 4. ACR Functional Class IIII 5. DAS28 =4.0, with clinical synovitis in at least three joints, at least one of which is a joint amenable to ultrasound-guided synovial biopsy (knee, elbow, ankle, wrist, MCP or PIP joint). (For part 2 only). 6. Currently taking anti-TNF monotherapy as part of standard clinical care and have received anti-TNF therapy for at least 6 months upon entry to the study as per NICE guidelines. 7. Willing to undergo ultrasound guided synovial biopsy on two occasions (under local anaesthetic). (For part 2 only). 8. Stable dose of non-steroidal anti-inflammatory drug (NSAID) or corticosteroid (prednisolone=7.5mg) for =4 weeks. 9. No intramuscular glucocorticoid administration in the 6 week period prior to baseline visit. 10. Willing and able to undergo MRI scanning on two occasions (Part 2 only).
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 11/08/2017: 1. If patients were previously taking leflunomide a minimum period of 20 days must have elapsed between the last dose of leflunomide and the first dose of IMP 2. Patients receiving warfarin or other anticoagulation likely to interfere with biopsy procedures (part 2 only) 3. Use of other investigational medicinal products within 30 days prior to trial entry (defined as date of recruitment into trial) 4. Serious or unstable co-morbidity deemed unsuitable by PI e.g. COPD, cardiac failure, other significant autoimmune disease 5. Patients must not drink more than 2 units of alcohol per day and no more than 10 units of alcohol per week during the trial and for a 4 week period after completion of the trial 6. Known active infection at screening visit or at baseline (except fungal nail infection) 7. Infection requiring hospitalization or IV antibiotics within 6 weeks prior to baseline 8. History of recurrent or chronic infection 9. Recent live vaccination (within 6 weeks of baseline) 10. Hb1.5x upper limit of normal 13. Glomerular filtration rate < 60ml/minute (Cockroft formula) 14. Major surgery within 8 weeks prior to baseline or planned within 3 months from baseline 15. Pregnancy, or women planning to become pregnant within the trial period, or women who are breastfeeding 16. Females or males of child bearing potential unwilling to use two forms of adequate contraception whilst taking the IMP and for one month afterwards Previous exclusion criteria: 1. Patients currently taking, and planning to continue, methotrexate, other non-biologic DMARDs or biologic therapies other than anti-TNF therapy. For patients recently receiving non-biologic DMARD therapy at least 8 weeks must have elapsed following discontinuation of treatment prior to enrolment into the current study. If patients were previously taking leflunomide this must have been washed out with cholestyramine or activated charcoal according to leflunomide?s Summary of Product Characteristics 2. Patients receiving warfarin or other anticoagulation likely to interfere with biopsy procedures (part 2 only) 3. Previous participation in this trial (for Part 2 participants) 4. Use of other investigational medicinal products within 30 days prior to trial entry (defined as date of recruitment into trial) 5. Serious or unstable co-morbidity deemed unsuitable by PI e.g. COPD, cardiac failure, other significant auto-immune disease 6. Patient?s must not drink more than 2 units of alcohol per day and no more than 10 units of alcohol per week during the trial and for a 4 week period after completion of the trial 7. Known active infection at screening visit or at baseline (except fungal nail infection) 8. Infection requiring hospitalization or IV antibiotics within 6 weeks prior to baseline 9. History of recurrent or chronic infection 10. Recent live vaccination (within 6
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1: 1. Dose Limiting Toxicities (DLT) at baseline (BL), week 2, 3, 4 and 5 2. Adverse Events and Adverse Reactions (AE/AR) at BL week 2, 3, 4 and 5 Part 2: 1. EULAR and ACR20 response rates at screening, BL, week 2, 3, 4, 7, 10 and within 5 days of final dose 2. Macrophage number in the sub lining layer of synovium at BL and week 12 3. MRI (Rheumatoid Arthritis MRI Scoring System (RAMRIS)) at pre BL and week 12 | — |
Secondary
| Measure | Time frame |
|---|---|
| Part 1: 1. Drug PK parameters and PD biomarkers in peripheral blood at BL and week 4 Part 2: 1. Drug PK parameters and PD biomarkers in peripheral blood at BL and week 12 2. PD biomarkers in synovial tissue at BL and week 12 3. Fatigue questionnaire at screening, BL, week 2, 3, 4, 7, 10 and within 5 days of final dose 4. Urinary metabolomics at screening, BL, week 2, 3, 4, 7, 10 and within 5 days of final dose 5. Rheumatoid factor (RF) and anti-CP status at screening and within 5 days of final dose 6. Optional PET scan pre BL and within 10 days post week 12 visit | — |
Countries
England, Scotland, United Kingdom
Outcome results
None listed