Clinical trial NCT04797325: Vedolizumab for Immune Mediated Colitis
Official title: Open Label Randomized Controlled Clinical Trial of Vedolizumab Versus Conventional Treatment for Checkpoint Inhibitor Induced Colitis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Immune-Mediated Colitis
Lead sponsor: University of Copenhagen
Sponsor class: OTHER
First posted: 2021-03-15
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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

Primary outcomes:
measure: dose of prednisolone
timeFrame: Week 30
Secondary outcomes:
measure: clinical remission
timeFrame: week 2
measure: clinical remission
timeFrame: week 10
measure: clinical remission
timeFrame: week 30
measure: time to response
timeFrame: 30 days
measure: partial Mayo score
timeFrame: week 2
measure: partial Mayo score
timeFrame: week 10
measure: partial Mayo score
timeFrame: week 30
measure: change in scores
timeFrame: change from week 0 and 10 and 30
measure: fecal calprotectin
timeFrame: change from week 0 and 10 and 30
measure: IUS
timeFrame: change from week 0 and 10 and 30
measure: endoscopy
timeFrame: change from week 0 and 30
measure: change in scores
timeFrame: change from week 0 and 10 and 30
measure: Life qualtity
timeFrame: change from week 0 and 10 and 30
measure: steroid use for other reasons
timeFrame: During the 30 weeks period
measure: ICPI treatment
timeFrame: Week 30
measure: steroid free remission
timeFrame: week 10
measure: steroid free remission
timeFrame: week 30
measure: ICPI treatment
timeFrame: week 30
Other outcomes:
measure: T-cell response
timeFrame: Change from week 0 to week 15.
measure: pharmacogenomic
timeFrame: week 0 to week 30
measure: Omics
timeFrame: week 0 to week 30.
measure: Single cells
timeFrame: week 0 to week 30
measure: Subgroup analysis
timeFrame: week 30
measure: subgroup analysis
timeFrame: week 30
Locations:
city: Herlev
country: Denmark
facility: Herlev University Hospital
Study officials:
affiliation: University of Copenhagen
name: Jakob B Seidelin, professor
role: STUDY_DIRECTOR
References: