Solid TumorCOLARNCT03601611
Checkpoint Inhibitor Induced Colitis and Arthritis -Immunomodulation With IL-6 Blockade and Exploration of Disease Mechanisms
A study testing Tocilizumab (RoACTEMRA®) in people with Solid Tumor and Colitis, run by Herlev Hospital at 1 site in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Solid Tumor, Colitis, Arthritis
- What is being tested?
- Tocilizumab (RoACTEMRA®)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteDenmark
- Study dates
- 1 Jan 2019to 28 Jan 2020
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 11Show fewer
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Solid Tumor, Colitis, Arthritis
- Being tested
- Tocilizumab (RoACTEMRA®)
- Medical subject headings
- Colitis, Arthritis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tocilizumab (RoACTEMRA®)Drug
Also called Prednisolon
Prednisolon will be given in case of worsening of symptoms
| Study group | Role | What they receive |
|---|---|---|
| Experimental | Experimental | Tocilizumab 8 mg/kg is to be given as an IV infusion over 60 minutes every 4 weeks (Q4W). Receives: Drug: Tocilizumab (RoACTEMRA®) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 2 months
Secondary outcomes (3)
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
Measured: 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
Measured: 2 months
Rate of sustained glucocorticoid-free remission
Prolonged sustained glucocorticoid-free remission
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2018
- Study start1 Jan 2019
- Primary completion28 Jan 2020
- Study completion28 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Solid TumorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Herlev Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Responsible party
- Principal investigator, Inna Chen, MD, Herlev Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03601611
- Sponsor's protocol ID
- AA 1820
- Acronym
- COLAR
- Status last verified
- Apr 2020
- First submitted
- 1 Jul 2018
- Last updated
- 21 Apr 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
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.
PubMed 36096534
Study at a glance
From the registry record, last updated by the sponsor on 21 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Checkpoint Inhibitor Induced Colitis and Arthritis -Immunomodulation With IL-6 Blockade and Exploration of Disease Mechanisms
- ClinicalTrials.gov ID
- NCT03601611
- Acronym / sponsor ID
- COLAR / AA 1820
- Conditions
- Solid Tumor, Colitis, Arthritis
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Herlev HospitalUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb
- Study start
- 1 Jan 2019 (actual)
- Primary completion
- 28 Jan 2020 (actual)
- Study completion
- 28 Jan 2020 (actual)
- First posted
- 26 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- 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.
| Arm | Type | Receives |
|---|---|---|
| Experimental | Experimental | Drug: Tocilizumab (RoACTEMRA®)Tocilizumab 8 mg/kg is to be given as an IV infusion over 60 minutes every 4 weeks (Q4W). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tocilizumab (RoACTEMRA®)Also: PrednisolonPrednisolon will be given in case of worsening of symptoms | Drug | Experimental |
Primary outcome
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
3 secondary outcomes
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time frame: 6 months
Rate of at least one grade improvement without prednisolone using the NCI CTCAE v5.0
Time frame: 2 months
Rate of sustained glucocorticoid-free remission
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Apr 2020.
- Derived from this study: PubMed 36096534Holmstroem 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Tocilizumab (RoACTEMRA®) in people with Solid Tumor and Colitis, run by Herlev Hospital at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of at least one grade improvement using the NCI CTCAE v5.0 (time frame: 2 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03601611, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Apr 2020.