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

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.

Study Overview

• Status: Completed
• Conditions: Arthritis; Solid Tumor; Colitis
• Intervention / Treatment: Drug: Tocilizumab (RoACTEMRA®)

Detailed Description

Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway 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, occurring after an average of three infusions. The incidence is higher among patients taking combination anti-CTLA-4/ anti-PD-1 therapy (44%) than those receiving anti-CTLA-4 (23-33%) or anti-PD-1 (≤19%) monotherapy. The most common autoimmune and musculoskeletal irAEs reported in clinical trials are represented by arthralgia and arthritis. The incidence of arthralgia and/or inflammatory arthritis secondary to nivolumab therapy ranges from 5% to 16% and 5%, respectively. 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. Previous studies report Th-17, that drives interleukin-17 (IL-17) production, as a key mediator of many immune diseases, including inflammatory bowel disease and ICI-induced colitis, and IL-17 elevations have been observed in experimental colitis. 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. An imbalance of Th17/Treg may cause the onset and progression of immune-mediated side effects. Thus, a 3-fold increase of IL-17 and IL-6 by week 12, concomitant with the development of fulminant colitis has been reported in a patient who developed presumed ipilimumab-induced colitis. These findings raise the possibility of using IL-6 blockade as a strategy for treating colitis and arthritis induced by immune checkpoint blockade.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Herlev & Gentofte University Hospital, Denmark

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Tocilizumab 8 mg/kg is to be given as an IV infusion over 60 minutes every 4 weeks (Q4W).	Drug: Tocilizumab (RoACTEMRA®); Prednisolon will be given in case of worsening of symptoms; Other Names: Prednisolon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Safety and tolerability of the treatment regimens assessed by a summary of adverse events and clinical laboratory assessments	6 months
Rate of at least one grade improvement without prednisolone 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 without corticosteroids within 8 weeks of treatment start	2 months
Rate of sustained glucocorticoid-free remission	Prolonged sustained glucocorticoid-free remission	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers	IL-6, IL-8, IL-17, CD4+ and CD 8+ T cells, Tregs, Th17 T cells, ANA RF, anti-CCP, CRP, WBC, ANC, CD163 and a profile of 90 proteins associated with cancer and inflammation (Olink array), fecal composition of the microflora, imaging changes and inflammation changes in colon if biopsies are available.	6 months

Collaborators and Investigators

• Sponsor: Herlev Hospital
• Collaborators: Bristol-Myers Squibb

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Actual): January 28, 2020
• Study Completion (Actual): January 28, 2020

Study Registration Dates

• First Submitted: July 1, 2018
• First Submitted That Met QC Criteria: July 24, 2018
• First Posted (Actual): July 26, 2018

Study Record Updates

• Last Update Posted (Actual): April 21, 2020
• Last Update Submitted That Met QC Criteria: April 18, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Joint Diseases; Musculoskeletal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Arthritis; Colitis; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: AA 1820

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No