Infliximab or Corticosteroids for the Treatment of Immune Checkpoint Inhibitor Related Colitis

Status: active

This phase II trial studies the effect of infliximab or corticosteroids (methylprednisolone and prednisone or prednisone alone) in treating patients with inflammation of the intestines (colitis) caused by taking and immune checkpoint inhibitor (ICI). Infliximab is a type of drug that targets a protein called TNF-alpha. This protein is responsible for regulating the inflammatory response in the body. In diseases such as colitis, there is too much of the TNF-alpha protein which causes certain parts of the body to become inflamed. The excess TNF-alpha protein is causing inflammation in the intestines, resulting in colitis. Infliximab is thought to inhibit (stop) the TNF-alpha protein from working correctly which results in the prevention of the inflammation in the intestines causing colitis. Both methylprednisolone and prednisone are corticosteroids. Corticosteroids are anti-inflammatory drugs, and it is believed that they help with the inflammation that causes colitis. Giving infliximab or corticosteroids may reduce inflammation and help fight against colitis caused by ICI.

Inclusion Criteria

Age >= 18
Stage III/IV skin cancer
Treatment with a CTLA-4 inhibitor alone or combination with PD-1or PD-L1 blockade past 8 weeks of symptom onset; investigational combinations will be permitted provided that they include a CTLA-4 inhibitor and a drug targeting PD-1 and/or PD-L1 * NOTE: Investigational CTLA-4 inhibitors will be permitted if: ** The protocol in question allows concurrent enrollment in this study; and ** The principal investigator believes the agent in question is compatible with this study from both a safety and a scientific standpoint
Clinically significant diarrhea resulting in the decision to hold immunotherapy treatment * NOTE: Common Terminology Criteria for Adverse Events (CTCAE) grade will be captured at the time of screening
Exhibits endoscopically visible colitis (Mayo 1 – 3) at the time of screening

Exclusion Criteria

Prior history of inflammatory colitis related to immune checkpoint inhibitors requiring treatment with > 10 mg/day of prednisone or equivalent, or any other immunosuppressive medication
Concurrent immune-related adverse events (irAE) requiring treatment with systemic corticosteroids (dose equivalent of prednisone 10 mg/day or higher) or another systemic immune suppressing medication within the past 10 days
Current use of any immune suppressing biologic medication, or use within the last 4 weeks; immune stimulating medications such as checkpoint blockade are explicitly permitted
Current use (or within 3 half-lives of the agent) of combination treatment with an investigation immunotherapy targeting a pathway other than PD-1 or PD-L1, concurrent chemotherapy, or targeted therapy
Previous adverse reaction to infliximab or corticosteroids
Colonic perforation or abscess present at the time of screening
History of hepatitis B or C with a positive viral load, untreated mycobacterium tuberculosis, or active herpes zoster infection
Current bacterial infection requiring systemic antibiotic treatment, or systemic fungal infection
Prior history of inflammatory bowel disease, microscopic colitis or segmental colitis associated with diverticulosis
Received more than 3 doses of systemic corticosteroids, or received systemic corticosteroids at a dose exceeding 2mg/kg methylprednisolone or equivalent, within 72 hours prior to endoscopy

Additional locations may be listed on ClinicalTrials.gov for NCT04305145.

United States

Massachusetts

Boston

Dana-Farber Cancer Institute

Status: Temporarily closed to accrual

Contact: Elizabeth Iannotti Buchbinder

Email: Elizabeth_buchbinder@dfci.harvard.edu

Massachusetts General Hospital Cancer Center

Status: Active

Contact: Michael Dougan

Phone: 617-726-3527

Email: Michael_Dougan@DFCI.HARVARD.EDU

PRIMARY OBJECTIVE:

I. Compare the rates of steroid-free ICI-related colitis remission at seven weeks, defined as less than 7.5 mg of prednisone per day or equivalent and grade-1 or lower colitis- associated symptoms, for infliximab compared to systemic corticosteroids.

SECONDARY OBJECTIVES:

I. Determine the safety of infliximab compared to systemic corticosteroids for the treatment of ICI colitis.

II. Determine the need for secondary immune suppression in patients with ICI colitis treated with infliximab compared to systemic corticosteroids.

III. Determine the time to steroid-free ICI colitis remission defined as less than 7.5 mg prednisone per day or equivalent and grade 1 or lower symptoms for ICI compared to systemic corticosteroids.

IV. Determine rates of symptom remission at 72 hours and also 4 weeks after start of infliximab or systemic corticosteroids.

V. Determine the effect of infliximab compared to systemic corticosteroids on the composite endpoint of ICI colitis-specific mortality or the need for colectomy.

VI. Determine cumulative steroid exposure (dose x duration) in patients with ICI colitis treated with infliximab compared to systemic corticosteroids.

VII. Compare the progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with ICI colitis treated with infliximab compared to systemic corticosteroids.

EXPLORATORY OBJECTIVES:

I. Define the immunologic microenvironment in colonic tissue and blood from patients with ICI colitis and track the response to treatment.

II. Assess changes in circulating tumor deoxyribonucleic acid (DNA) (ctDNA) levels in patients with ICI colitis following treatment with infliximab or systemic corticosteroids.

III. Determine the features of the microbiome associated with ICI colitis and response to infliximab and systemic corticosteroid treatment.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive infliximab intravenously (IV) over 2 hours on day 1. Patients who do not have complete symptomatic resolution (grade 1 or less) within 1 week or who develop recurrent symptoms may receive additional doses of infliximab on days 15 and 43 per physician discretion.

ARM II: Inpatients receive methylprednisolone IV over 30 minutes twice daily (BID) on day 1 until symptoms resolve and then receive prednisone orally (PO) once daily (QD) for up to 7 weeks in the absence of disease progression or unacceptable toxicity. Outpatients receive prednisone PO QD for up to 7 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo endoscopy with biopsies during screening and blood and stool sample collection throughout the study.

After completion of study treatment, patients are followed up at 28 days and then every 3-6 months for up to 3 years.

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Infliximab or Corticosteroids for the Treatment of Immune Checkpoint Inhibitor Related Colitis

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Eligibility Criteria

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Trial Objectives and Outline

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