Immune-Mediated Colitis
Conditions
Brief summary
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
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: 1. Is effective in inducing remission of the colitis 2. Reduces the risk of progression from grade 2 to grade 3 or 4 colitis 3. Reduces the need of systemic corticosteroid 4. Is not associated with increased risk of tumor progression or other serious adverse events including serious infections 5. 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).
Interventions
DRUGVedolizumab
Repeatedly vedolizumab infusion at week 0, 2, 6, 14, 22
DRUGPrednisolone
tablet prednisolone plus infliximab in severe cases.
Sponsors
University of Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| dose of prednisolone | Week 30 | The cumulative dose of corticosteroids (tablets and IV) due to IrAE colitis at week 30 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| change in scores | change from week 0 and 10 and 30 | change between clinical scores |
| IUS | change from week 0 and 10 and 30 | Intestinal ultrasound |
| endoscopy | change from week 0 and 30 | endoscopy |
| Life qualtity | change from week 0 and 10 and 30 | Changes in quality of life |
| steroid use for other reasons | During the 30 weeks period | Corticosteroid use for non-intestinal indications. |
| ICPI treatment | Week 30 | The proportion of patients able to continue ICPI treatment at any time after inclusion and until week 30\*. |
| steroid free remission | week 10 | Proportion of patients in corticosteroid (tablets or IV) free remission at week 10 and 30\* and the cumulative dose corticosteroid at week 10 |
| clinical remission | week 2 | Clinical remission at week 2, 10 and 30\*, defined as a partial Mayo score ≤ 2. |
| time to response | 30 days | Time to clinical remission and eventual relapse of GI symptoms (measured by patient reported stool chart registered the first 30 days). |
| partial Mayo score | week 2 | Response defined as decrease in partial Mayo score ≥ 30 % at week 2, 10 and 30 |
| fecal calprotectin | change from week 0 and 10 and 30 | change between fecal-calprotectin |
Other
| Measure | Time frame | Description |
|---|---|---|
| Omics | week 0 to week 30. | Omics profiles from blood (buffy coat RNA sequencing transcriptome), urine (metabonome), feces (microbiota, metabonome), and colonic biopsies (RNA sequencing transcriptome) |
| Single cells | week 0 to week 30 | Single cell RNAseq profiles of PMBCs and single cell RNAseq profiles of immune cells isolated from the mucosal area |
| Subgroup analysis | week 30 | all outcomes in the subgroup of patients with verified colitis defined as f-calprotectin \>200 or endoscopic mayoscore \> 0 or intestinal biopsies with evidence of enterocolitis |
| subgroup analysis | week 30 | all outcomes mentined above in patients without the need of prednisolone during screening |
| pharmacogenomic | week 0 to week 30 | Pharmacogenomic profiling of genes correlated to ICPI colitis treatment outcome |
| T-cell response | Change from week 0 to week 15. | Tumor-specific T cell responses in patients under systemic prednisolone treatment or treatment with infliximab or vedolizumab. |
Countries
Denmark
Contacts
Primary ContactEmilie Dahl
Outcome results
None listed