CITAR - Comparison of the efficacy and safety of early use of IL-6R blockade with tocilizumab in combination with short-term glucocorticoids versus glucocorticoids alone for the treatment of arthritis induced by cancer immunotherapy by check point inhibitors: a randomized, open, multicentre, proof of concept, superiority, controlled clinical trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Karolinska University Hospital

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Immune System Phenomena [G13], Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

11 Oct 2023 → ongoing

Decision date (initial)

2025-04-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Region Stockholm, clinical researcher · Wallström foundation · ALF agreeement from the government

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Does early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids have a superior efficacy in controlling the arthritis (arm B) compared to GCs alone (arm A) (assessed as CDAI low disease activity or remission) at week 16?

Secondary objectives 8

1. 1) Does early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids have a superior efficacy in controlling the arthritis (arm B) compared to GCs alone (arm A) (assessed as CDAI low disease activity or remission) at week 24?
2. 2) Does early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids have a superior efficacy inducing remission in ICI-induced arthritis, compared to GCs?
3. 3) Does early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids have a superior efficacy inducing sustained low disease activity or remission in ICI-induced arthritis AND low dose cortisone, compared to GCs
4. 4) Does early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids have a superior efficacy inducing sustained GCs-free low disease activity or remission in ICI-induced arthritis, compared to GCs?
5. 5) Does early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids have a superior efficacy in patient-reported outcomes in ICI-induced arthritis, compared to GCs?
6. 6) Is early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids associated with longer progression-free survival and overall survival in patients with ICI-induced arthritis, compared to GCs?
7. 7) Is early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids associated with lower number of missed treatment cycles in patients with ICI-induced arthritis, compared to GCs?
8. 8) Does early use of IL6R blockade with tocilizumab in combination with short-term glucocorticoids have an acceptable safety profile, compared to GCs?

Conditions and MedDRA coding

Patients with histologically (or via cytology) confirmed cancer that develop arthritis secondary to treatment with immune checkpoint inhibitors.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. The subject is willing and able to give informed consent to participate in the trial
2. ≥ 18 years of age on day of signing informed consent
3. Patients with histologically (or via cytology) confirmed cancer who develop arthritis (as diagnosed by a rheumatologist) secondary to treatment with immune checkpoint inhibitors. *Patients can be on or have received monotherapy with ICI or combination therapy with two ICIs (e.g. ipilimumab and nivolumab). Patients can be on or have received ICI in combination with chemotherapy. All the different ICI that are currently approved by EMA and in clinical use will be allowed (ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, relatlimab). Additional ICI under investigation can also be authorized, as long as the patient is not participating already in a clinical trial.
4. At least 2 joints involved (clinically defined) AND CDAI >10.
5. The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS) 0-1, PS of 2 due to ongoing irAEs is allowed
6. Patients already on glucocorticoids regardless of dose for the treatment of the arthritis can be included, if the duration of the glucocorticoid treatment is maximum 1 week
7. Women of child-bearing potential must have a negative pregnancy test (serum or blood) at inclusion.
8. Female subjects must be 1 year post-menopausal or be willing and able to use highly effective contraception during the treatment and up to 3 months after the last dose of IMP. Oral, injected or implanted hormonal contraceptive, intrauterine device, intrauterine hormone-releasing system, surgical sterilization, transdermal delivery, congenital sterility, vasectomised partner or sexual abstinence are considered acceptable forms of birth control.

Exclusion criteria 23

1. Mild arthritis that does not require treatment other than NSAID (non-steroidal anti-inflammatory drugs) or analgetics
2. History of human immunodeficiency virus (HIV) infection or other immunodeficiency
3. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
4. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
5. History of chronic viral hepatitis, alcoholic or metabolic liver disease. Carriers of hepatitis B and patients with a history of hepatitis B infection or positive serology are excluded except in situations where the potential benefit is determined to justify the risk of possible hepatitis B reactivation, which can be fatal. Patients with positive serology should have viral DNA levels checked and a gastrointestinal consultation obtained
6. Central nervous system (CNS) metastases, with the following exception: Subjects who have previously-treated CNS metastases, are asymptomatic, and have no requirement for steroids in the management of CNS disease (steroids for irAEs are allowed) at least 14 days prior to first dose of study drug. Note: Subjects with carcinomatous meningitis or leptomeningeal spread are excluded regardless of clinical stability
7. History of or current positive purified protein derivative tuberculin skin test (PPD) ( >5mm induration, regardless of Bacille Calmette Guerin (BCG) vaccine administration), or positive QuantiFERON®-TB Gold In-Tube Test (QuantiFERON®), or historical chest x-ray unless completion of treatment has been documented for active tuberculosis (TB), latent TB (a positive test, a negative chest x-ray, and no symptoms or risk factors), unless one month of prophylaxis has been completed prior to inclusion, an indeterminate QuantiFERON® unless followed by a subsequent negative PPD or negative QuantiFERON® as well as a consultation with and clearance by local infectious disease (ID) department
8. Transplanted organs (except corneas with transplant performed >3 months prior to screening)
9. Active infection, including opportunistic infections, requiring systemic therapy within the past 2 weeks. A deep space infection within the past 2 years (including, but not limited to meningitis, epiglottitis, endocarditis, septic arthritis, fasciitis, abdominal or pleural abscess, or osteomyelitis).
10. Pregnancy or Breastfeeding
11. Preexisting central nervous system demyelinating or seizure disorders
12. Concomitant life or organ threatening irAE which requires high doses of glucocorticoids (e.g. pneumonitis, myocarditis etc). This is assessed and defined clinically at screening by the treating oncologists and rheumatologists.
13. History of diverticulitis, diverticulosis requiring antibiotic treatment, or other symptomatic lower gastrointestinal (GI) conditions that might predispose to perforations
14. Have adequate organ and marrow function as defined below: Absolute Neutrophil Count ≥1,000/microliters Platelets ≥100,000 Hemoglobin ≥ 7.0g/dL (without transfusion in past 2 weeks). Note: Patients with cytopenias (e.g immune thrombocytopenia, autoimmune hemolytic anemia) clinically consistent with irAE will be eligible at the discretion of principal investigator. Aspartate aminotransferase (AST)(SGOT)/ alanine aminotransferase (ALT)(SGPT) ≤2 × institutional upper limit of normal Creatinine clearance of ≥ 30 mL/min. Creatinine clearance (CrCl) should be calculated at screening using the Cockcroft-Gault formula
15. Current treatment with glucocorticoids for other indications (i.e. cerebral metastasis) that is not possible to discontinue
16. Patients with a history of inflammatory rheumatic disease prior to cancer diagnosis
17. Current participation in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
18. Diagnosis of immunodeficiency or ongoing systemic immunosuppressive therapy other than steroids prior to the first dose of trial treatment
19. Treatment with a non-biologic immunosuppressive or immune-modulating drug (e.g. methotrexate, azathioprine, mycophenolate, cyclosporine, hydroxychloroquine, penicillamine) within 4 weeks prior to treatment
20. Treatment with other immune-modulating biologic agents (other than the ICI) within 4 weeks prior to treatment initiation
21. History of anaphylaxis or immunoglobulin E-mediated hypersensitivity to murine proteins or any component of tocilizumab. History of allergic reactions attributed to compounds of similar chemical or biologic composition to tocilizumab
22. Vaccination with a live vaccine within 4 weeks prior to the first dose of study drug or expected need of live vaccination during study, including at least 30 days after the last dose of study drug.
23. History of hypersensitivity to Prednisolone or to any of the excipients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. % of patients in arm A and arm B with Clinical Disease Activity Index (CDAI): CDAI ≤10 at week 16

Secondary endpoints 8

1. 1. % of patients in arm A and arm B with Clinical Disease Activity Index (CDAI): CDAI ≤10 at week 24
2. 2. % of patients in arm A and arm B with CDAI ≤2.8 at week 16 and 24
3. 3. % of patients in arm A and arm B with CDAI ≤10 AND Prednisolone 0-5mg/d at week 16 and 24
4. 4. % of patients in arm A and arm B with CDAI ≤10 AND Prednisolone 0 mg/d at week 16 and 24
5. 5. Improvement in pain (VAS 0-100mm), general health (VAS 0-100mm), fatigue (VAS 0-100mm), functional status (HAQ questionnaire) and quality of life (EQ5D questionnaire) in arm A and B, at week 16 and 24
6. 6. Progression-free survival and overall survival of patients in arm A and arm B at week 16 and 24
7. 7. Total number of missed treatment cycles with ICI, at week 24
8. 8. % of patients with AEs and SAEs in arm A and B from baseline to week 24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Karolinska University Hospital

Sponsor organisation

Karolinska University Hospital

Address

Eugeniavagen 3

City

Solna

Postcode

171 64

Country

Sweden

Scientific contact point

Organisation

Karolinska University Hospital

Contact name

Jon Lampa

Public contact point

Organisation

Karolinska University Hospital

Contact name

Jon Lampa

Locations

2 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications