Checkpoint Inhibitor Induced Colitis and Arthritis -Immunomodulation With IL-6 Blockade and Exploration of Disease Mechanisms

NCT03601611 | Completed

• 1 other identifier: AA 1820
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Immune checkpoint inhibitors (ICI) might induce inflammatory potentially serious and even lethal immune related Adverse Events (irAEs). Diarrhea and/or colitis are ones of the most frequently reported irAEs in patients taking ICI. Although the immune mechanisms underlying irAEs have not been fully elucidated, studies suggest that Th17 and Tregs cells, increases in expression of immunologically-related genes, eosinophilia, microbiome among others and cytokines may be involved in the pathophysiology of immune-related complications in some diseases that resemble irAEs, such as colitis and rheumatic manifestations. Importantly, interleukin-6 (IL-6) promotes the differentiation of naïve CD4+ T cells into Th17 cells (17), and IL-6 inhibition may rebalance the altered Th17-Treg axis without inhibiting the Th1-CD8+ T-cell subsets that govern antitumor immunity. These findings raise the possibility of using IL-6 blockade as a strategy for treating colitis and arthritis induced by immune checkpoint blockade.

Conditions

Solid Tumor; Colitis; Arthritis

Outcome Measures

Primary Outcomes (1)

• Rate of at least one grade improvement using the NCI CTCAE v5.0

  Clinical benefit of IL-6 inhibition by tocilizumab on diarrhea and/or colitis and/or arthritis induced by checkpoint inhibitors in patients with solid tumors within 8 weeks of treatment start

  2 months

Secondary Outcomes (3)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  6 months

• Rate of at least one grade improvement without prednisolone using the NCI CTCAE v5.0

  2 months

• Rate of sustained glucocorticoid-free remission

  6 months

Other Outcomes (1)

• Biomarkers

  6 months

Study Arms (1)

Experimental

EXPERIMENTAL

Tocilizumab 8 mg/kg is to be given as an IV infusion over 60 minutes every 4 weeks (Q4W).

Drug: Tocilizumab (RoACTEMRA®)

Interventions

Tocilizumab (RoACTEMRA®) DRUG

Prednisolon will be given in case of worsening of symptoms

Also known as: Prednisolon

Experimental

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent
• Subjects must have signed and dated an IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
• Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
• Patients with solid tumors treated with PD-1, PD-L1 and /or CTLA-4 inhibitors
• Diarrhea and/or colitis CTCAE grade ˃ 1 and/or arthritis CTCAE grade ˃ 1 induced by PD-1, PD-L1 and /or CTLA-4 inhibitors
• Age 18 years and older
• ECOG/WHO Performance Status (PS) 0-1, PS of 2 due to ongoing irAEs is allowed
• White blood cell count (WBC) ≥ 2 x 10⁹/L and/or absolute neutrophil count (ANC) ≥ 1.0 x 10⁹/L
• Platelet count ≥ 50 x 10⁹/L
• Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)
• ASAT/ALAT ≤ 5 x ULN

You may not qualify if:

• History of allergy to study drug component
• Patients should be excluded if they have a condition and/or other irAEs requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration
• Females of childbearing potential or males of reproductive potential who are not willing to use an effective method of contraception, such as oral, injected, or implanted hormonal methods of contraception, intrauterine device or intrauterine system, condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream, suppository, male sterilization, or true abstinence throughout study and for a minimum of 3 months after study drug therapy.

Sponsors & Collaborators

• Herlev Hospital: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Herlev & Gentofte University Hospital, Denmark

Herlev, 2730, Denmark

Location

Related Publications (1)

• Holmstroem RB, Nielsen OH, Jacobsen S, Riis LB, Theile S, Bjerrum JT, Vilmann P, Johansen JS, Boisen MK, Eefsen RHL, Marie Svane I, Nielsen DL, Chen IM. COLAR: open-label clinical study of IL-6 blockade with tocilizumab for the treatment of immune checkpoint inhibitor-induced colitis and arthritis. J Immunother Cancer. 2022 Sep;10(9):e005111. doi: 10.1136/jitc-2022-005111.

  PMID: 36096534 DERIVED

MeSH Terms

Conditions

Colitis; Arthritis

Interventions

tocilizumab

Condition Hierarchy (Ancestors)

Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases; Joint Diseases; Musculoskeletal Diseases

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: \- Patients will receive tocilizumab 8 mg/kg given as an IV infusion over 60 minutes every 4 weeks (Q4W) for at least 2 cycles or until worsening or lack of improvement of diarrhea and/or colitis and/arthritis, in case of unacceptable toxicity, withdrawal of consent or clear clinical deterioration, according to investigator's judgment. At the initial stage, 7 patients will be enrolled and evaluated for symptom improvement. In case of ≤ 4 patients with at least one grade improvement, accrual will be terminated. If ≥ 5 patients with at least one grade improvement will be observed at the first stage, 13 additional patients will be entered at the second stage to achieve a target sample size of 20 evaluable patients. Further exploration of the treatment strategy is warranted, if at least one grade improvement is observed for ≥14 patients.

Study Record Dates

• First Submitted: July 1, 2018
• First Posted: July 26, 2018
• Study Start: January 1, 2019
• Primary Completion: January 28, 2020
• Study Completion: January 28, 2020
• Last Updated: April 21, 2020

Record last verified: 2020-04

Locations

DK (1)