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

• ClinicalTrials.gov Identifier: NCT03601611
• Recruitment Status: Completed
• First Posted: July 26, 2018
• Last Update Posted: April 21, 2020
• Sponsor: Herlev Hospital
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Inna Chen, MD, Herlev Hospital

Tracking Information

• First Submitted Date: July 1, 2018
• First Posted Date: July 26, 2018
• Last Update Posted Date: April 21, 2020
• Actual Study Start Date: January 1, 2019
• Actual Primary Completion Date: January 28, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 24, 2018)

Rate of at least one grade improvement using the NCI CTCAE v5.0 [ Time Frame: 2 months ]

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 24, 2018)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 6 months ]
  Safety and tolerability of the treatment regimens assessed by a summary of adverse events and clinical laboratory assessments
• Rate of at least one grade improvement without prednisolone using the NCI CTCAE v5.0 [ Time Frame: 2 months ]
  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
• Rate of sustained glucocorticoid-free remission [ Time Frame: 6 months ]
  Prolonged sustained glucocorticoid-free remission

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 25, 2018)

Biomarkers [ Time Frame: 6 months ]

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.

Original Other Pre-specified Outcome Measures (submitted: July 24, 2018)

Biomarkers [ Time Frame: 6 months ]

To explore predictive biomarkers correlating to development of severe irAEs.

Descriptive Information

• Brief Title: Checkpoint Inhibitor Induced Colitis and Arthritis -Immunomodulation With IL-6 Blockade and Exploration of Disease Mechanisms
• Official Title: Checkpoint Inhibitor Induced Colitis and Arthritis -Immunomodulation With IL-6 Blockade and Exploration of Disease Mechanisms
• 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.
• 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
• Study Phase: Not Applicable

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

- 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.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Solid Tumor
• Colitis
• Arthritis

Intervention

Drug: Tocilizumab (RoACTEMRA®)

Prednisolon will be given in case of worsening of symptoms

Other Name: Prednisolon

Study Arms

Experimental: Experimental

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

Intervention: Drug: Tocilizumab (RoACTEMRA®)

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 24, 2018): 20
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: January 28, 2020
• Actual Primary Completion Date: January 28, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT03601611
• Other Study ID Numbers: AA 1820
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Inna Chen, MD, Herlev Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Herlev Hospital
• Original Study Sponsor: Same as current
• Collaborators: Bristol-Myers Squibb
• Investigators: Not Provided
• PRS Account: Herlev Hospital
• Verification Date: April 2020