Vedolizumab for Immune Mediated Colitis

Study Overview
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Brief Summary
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This is an open label randomized trial to evaluate the efficacy and treatment duration with vedolizumab to patients with immune mediated colitis. The trial will include 82 patients randomized into two arms, either standard treatment with prednisolone (plus infliximab in severe cases) or vedolizumab treatment up front.

Detailed Description
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Background information Immune check point inhibitors (ICPI) have revolutionized the treatment of a growing number of cancer forms resulting in a rapidly increasing number of patients treated with these drugs within the very recent years. The aim is to allow and boost an immune response towards the neoantigens of neoplastic cells, but the blockage of inhibitory signals might also interfere with normal barriers against the development of autoimmunity or autoimmune-like reactions and thus lead to a number of immune-related adverse events (IrAEs). Gastrointestinal inflammation - typically colitis - is the most common IrAE among ICPI treated patients. Vedolizumab, a integrin antibody, has been shown to be highly effective in treating ICPI induced colitis with remission rates of 85%. Vedolizumab has a better safety profile than anti-tumor necrosis factor antibodies, including infliximab, with lower risk of infections and tumor development in inflammatory bowel disease patients. Moreover, vedolizumab does not seem to inhibit tumor specific T cell responses in vitro, suggesting that this treatment is also beneficial with regards to tumor response. The hypothesis Vedolizumab induction and maintenance treatment of patients with ICPI related intestinal symptoms and evidence of colitis: Is effective in inducing remission of the colitis Reduces the risk of progression from grade 2 to grade 3 or 4 colitis Reduces the need of systemic corticosteroid Is not associated with increased risk of tumor progression or other serious adverse events including serious infections Allows reintroduction/continuation of ICPI treatment. Further it is hypothesized that ICPI induced colitis can be diagnosed and monitored by intestinal bowel ultrasound and treatment response is associated with multi-omics changes in intestinal tissue, tumor tissue, feces, blood, and urine, e.g. peripheral blood mononuclear cells (PBMCs) RNAseq profiles, profiles of single cell RNAseq from isolated immune cells from standard pinch biopsies from the inflamed colon and composition of the microbiota. Lastly, it is hypothesized, that anti-tumor T-cell function is affected in vivo by the medication used to treat ICPI induced colitis, and that this can be assessed by changes in single cell RNAseq profiles of tumor resident T-cells (isolated from tumor biopsies).

Official Title
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Open Label Randomized Controlled Clinical Trial of Vedolizumab Versus Conventional Treatment for Checkpoint Inhibitor Induced Colitis

Conditions
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Immune-Mediated Colitis

Intervention / Treatment
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* Drug: Vedolizumab
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with solid tumors treated with PD-1, PD-L1 and /or CTLA-4 inhibitors and where IrAE colitis is preventing further treatment with check point inhibitors IrAE colitis where the oncologist suggests treatment with tablet or IV corticosteroids (prednisolone or equivalent) Negative pregnancy test in fertile women Age ≥ 18. Exclusion Criteria: Any ongoing infectious disease, including GI infections Neutropenia within the last month Known allergy towards vedolizumab or Infliximab Severe heart failure, NYHA grade 3-4 Colorectal cancer Other IrAEs requiring systemic treatment with either prednisolone (> 10 mg daily or equivalents) or other immunosuppressive medications within 14 days before 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 in combination with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, creamer suppository, male sterilization, or true abstinence throughout study and for a minimum of 3 months after study drug therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: vedolizumab<br> | Drug: Vedolizumab<br>* Repeatedly vedolizumab infusion at week 0, 2, 6, 14, 22<br>|
| Active Comparator: Standard treatment<br> | Drug: Prednisolone<br>* tablet prednisolone plus infliximab in severe cases.<br>* Other names: Infliximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| dose of prednisolone | The cumulative dose of corticosteroids (tablets and IV) due to IrAE colitis at week 30 | Week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical remission | Clinical remission at week 2, 10 and 30*, defined as a partial Mayo score ≤ 2. | week 2 | 
| clinical remission | Clinical remission at week 2, 10 and 30*, defined as a partial Mayo score ≤ 2. | week 10 | 
| clinical remission | Clinical remission at week 2, 10 and 30*, defined as a partial Mayo score ≤ 2. | week 30 | 
| time to response | Time to clinical remission and eventual relapse of GI symptoms (measured by patient reported stool chart registered the first 30 days). | 30 days | 
| partial Mayo score | Response defined as decrease in partial Mayo score ≥ 30 % at week 2, 10 and 30 | week 2 | 
| partial Mayo score | Response defined as decrease in partial Mayo score ≥ 30 % at week 2, 10 and 30 | week 10 | 
| partial Mayo score | Response defined as decrease in partial Mayo score ≥ 30 % at week 2, 10 and 30 | week 30 | 
| change in scores | change between clinical scores | change from week 0 and 10 and 30 | 
| fecal calprotectin | change between fecal-calprotectin | change from week 0 and 10 and 30 | 
| IUS | Intestinal ultrasound | change from week 0 and 10 and 30 | 
| endoscopy | endoscopy | change from week 0 and 30 | 
| change in scores | biochemistry | change from week 0 and 10 and 30 | 
| Life qualtity | Changes in quality of life | change from week 0 and 10 and 30 | 
| steroid use for other reasons | Corticosteroid use for non-intestinal indications. | During the 30 weeks period | 
| ICPI treatment | The proportion of patients able to continue ICPI treatment at any time after inclusion and until week 30*. | Week 30 | 
| steroid free remission | Proportion of patients in corticosteroid (tablets or IV) free remission at week 10 and 30* and the cumulative dose corticosteroid at week 10 | week 10 | 
| steroid free remission | Proportion of patients in corticosteroid (tablets or IV) free remission at week 10 and 30* | week 30 | 
| ICPI treatment | Proportion of patients able to continue ICPI treatment at any time after inclusion and until week 30 | week 30 |