Vedolizumab for Immune Mediated Colitis

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

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.

Study Overview

• Status: Recruiting
• Conditions: Immune-Mediated Colitis
• Intervention / Treatment: Drug: Vedolizumab; Drug: Prednisolone

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).

• Study Type: Interventional
• Enrollment (Anticipated): 82
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Emilie Dahl; Phone Number: +4538686391; Email: emilie.kristine.dahl@regionh.dk

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Recruiting
    • Herlev University Hospital
    • Contact: Emilie Dahl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
T-cell response	Tumor-specific T cell responses in patients under systemic prednisolone treatment or treatment with infliximab or vedolizumab.	Change from week 0 to week 15.
pharmacogenomic	Pharmacogenomic profiling of genes correlated to ICPI colitis treatment outcome	week 0 to week 30
Omics	Omics profiles from blood (buffy coat RNA sequencing transcriptome), urine (metabonome), feces (microbiota, metabonome), and colonic biopsies (RNA sequencing transcriptome)	week 0 to week 30.
Single cells	Single cell RNAseq profiles of PMBCs and single cell RNAseq profiles of immune cells isolated from the mucosal area	week 0 to week 30
Subgroup analysis	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	week 30
subgroup analysis	all outcomes mentined above in patients without the need of prednisolone during screening	week 30

Collaborators and Investigators

• Sponsor: University of Copenhagen
• Investigators: Study Director: Jakob B Seidelin, professor, University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2021
• Primary Completion (Anticipated): April 1, 2025
• Study Completion (Anticipated): April 1, 2025

Study Registration Dates

• First Submitted: February 2, 2021
• First Submitted That Met QC Criteria: March 11, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Actual): August 17, 2022
• Last Update Submitted That Met QC Criteria: August 16, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Colitis; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Prednisolone; Vedolizumab; Infliximab
• Other Study ID Numbers: 01012121; 2020-005793-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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