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

April 18, 2020 updated by: Inna Chen, MD, Herlev Hospital
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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
20

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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
2 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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
6 months
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
2 months
Rate of sustained glucocorticoid-free remission
Time Frame: 6 months
Prolonged sustained glucocorticoid-free remission
6 months

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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.
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Herlev Hospital

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Bristol-Myers Squibb

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 28, 2020

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 28, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 1, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 24, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 26, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 21, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 18, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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