Infliximab for Treatment of Immune Checkpoint Inhibitor Colitis

March 12, 2024 updated by: Michael Dougan, Massachusetts General Hospital

Phase II Study of Infliximab for the Treatment of Immune Checkpoint Inhibitor Colitis

The goal of this clinical trial is to compare the safety and effectiveness of infliximab compared to steroids for the treatment of immune checkpoint inhibitor-induced colitis (ICI colitis) in patients with stage III/IV skin cancer.

The main questions this study aims to answer are:

  • How many patients treated with infliximab experience steroid-free disease resolution after 7 weeks?
  • How many patients treated with steroids experience steroid-free disease resolution after 7 weeks?

Study Overview

Detailed Description

This is a phase II, randomized, signal-detection trial to evaluate the efficacy and safety of the drugs infliximab, methylprednisolone, and prednisone to manage the side of effect of colitis caused by immune checkpoint inhibitors (ICIs) that target a protein called CTLA-4. An example of one of these ICIs is ipilimumab, which has been approved by the FDA to treat metastatic melanoma.

The names of the treatments involved in this study are:

  • Infliximab
  • Methylprednisolone
  • Prednisone

The FDA has approved infliximab, methylprednisolone, and prednisone to treat many conditions affecting the immune system, including colitis.

Participants will receive a CTLA-4 inhibitor, like ipilimumab, and any other cancer treatments as part of their regular care for stage III/IV skin cancer at the discretion of treating oncologist.

Participants who enroll in this study will undergo one or more flexible sigmoidoscopies or colonoscopies as part of their clinical care. The first of these procedures would occur at the time of study enrollment, and the second may occur after several weeks of treatment at the discretion of the study doctor. During these procedures, biopsies will be collected for clinical purposes as well as for research purposes. Blood will also be collected for research at the time of enrollment and at the time of study completion. Any extra samples for research would only be collected if it is safe for the participant.

Participants will also complete weekly follow-ups either over the phone or in-person that may last about 10 minutes. During these visits, participants will be asked about any new symptoms or changes in their health, their medications, and their GI symptoms. Blood for research may be collected at one or more of these visits if it coincides with a scheduled clinical blood draw.

Participants are expected to be on study treatment for approximately 7 weeks. Once participants complete the study treatment, the study team will review their medical records every 6 months for any changes in their health.

It is expected that about 42 people will take part in this research study.

Study Type

Interventional

Enrollment (Estimated)

42

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥ 18
  • Stage III/IV skin cancer
  • Treatment with CTLA-4 inhibitor alone or in combination with PD-1or PD-L1 blockade within the past 8 weeks
  • Clinically significant diarrhea resulting in the decision to pause immunotherapy treatment
  • 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 Event (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 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 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 receive dsystemic corticosteroids at a dose exceeding 2mg/kg methylprednisolone or equivalent, within 72 hours prior to endoscopy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Infliximab

Patients randomized to this arm will receive IV infliximab regardless of whether they are hospitalized due to their colitis.

  • Infliximab: Predetermined dose of intravenous infliximab, up to 3 times over 7 weeks
  • Crossover for inadequate response: Patients who do not respond to initial treatment within 3 days with a decrease in symptoms by one grade, or who do not improve to grade 2 or less symptoms by 5 days will add combination therapy from the other treatment arm (corticosteroids) at full initial dosing.
Infusion
Other Names:
  • Remicade
  • Ixifi
  • Renflexis
  • AVSOLA
Experimental: Corticosteroids

Patients randomized to this arm will receive IV steroids or oral steroids depending on whether the severity of their colitis requires hospitalization ("inpatient").

  • Inpatient: Predetermined intravenous dose of methylprednisolone, 2x daily up until patients can safely be transitioned to an oral prednisone taper
  • Outpatient: Predetermined oral dose of predisone, daily over 7 weeks

Crossover for inadequate response: Patients who do not respond to initial treatment within 3 days with a decrease in symptoms by one grade, or who do not improve to grade 2 or less symptoms by 5 days will add combination therapy from the other treatment arm (infliximab) at full initial dosing.

Infusion
Other Names:
  • Medrol
  • Solu-Medrol
  • Duralone
  • Medralone
  • M-Prednisol
Orally
Other Names:
  • Deltasone
  • Rayos
  • Prednicot
  • predniSONE Intensol
  • Sterapred
  • Sterapred DS

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients with Steroid-Free Colitis
Time Frame: 7 weeks
Proportion of Patients with Steroid-Free Colitis at seven weeks with steroid-free colitis remission defined as less than 7.5 mg a day of prednisone or equivalent and grade-1 or lower symptoms.
7 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of Participants with Treatment Related Adverse Events as Assessed by CTCAE 5.
Time Frame: 6 Months
National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
6 Months
The proportion of patients requiring secondary immune suppression-Infliximab
Time Frame: 7 Weeks
patients randomly assigned to infliximab, secondary immune support will be defined as requiring subsequent treatment with steroids. The proportions of patients in each treatment arm requiring secondary immune suppression will be summarized and presented with 90% exact binomial confidence intervals
7 Weeks
The proportion of patients requiring secondary immune suppression-Steroids
Time Frame: 7 Weeks
patients randomly assigned to steroids, secondary immune support will be defined as requiring subsequent treatment with steroids. The proportions of patients in each treatment arm requiring secondary immune suppression will be summarized and presented with 90% exact binomial confidence intervals
7 Weeks
Time to steroid-free remission
Time Frame: randomization to grade-1 or lower symptoms of colitis and less than 7.5 mg a day of prednisone or equivalent or up to 6 months
The initial analysis of steroid-free remission will be based on cumulative incidence (1-Kaplan-Meier estimates).
randomization to grade-1 or lower symptoms of colitis and less than 7.5 mg a day of prednisone or equivalent or up to 6 months
Rate of Symptom Remission at 72 hours
Time Frame: 72 hours
The proportion of patients in each treatment arm who have colitis symptom reduction to grade-1 or less within 72 hours of starting randomized treatment will be summarized and presented with 90% exact binomial confidence intervals. The treatment arms will be compared using Fisher's exact tests.
72 hours
Rate of Symptom Remission at 4 Weeks
Time Frame: 4 weeks
The proportion of patients in each treatment arm who have colitis symptom reduction to grade-1 or less within 72 hours of starting randomized treatment will be summarized and presented with 90% exact binomial confidence intervals. The treatment arms will be compared using Fisher's exact tests.
4 weeks
Proportion of patients with colectomy or colitis-specific mortality
Time Frame: 7 weeks
The proportions of patients with colectomy or colitis-specific mortality (investigator assessed) will be presented by treatment arm with 90% exact binomial confidence intervals
7 weeks
Cumulative steroid exposure
Time Frame: 7 weeks

Cumulative steroid exposure over time for each patient will be calculated by adding the number of doses multiplied by strength of dose over the total follow-up time. Steroid exposure will be summarized descriptively for each treatment arm, and compared using a Wilcoxon rank-sum test.

With 20 patients per treatment arm, a Wilcoxon rank-sum test will have 80% power to detect a 41difference in cumulative steroid exposure that is 0.85 times the common standard deviation, assuming a one-sided, type-I error of 10

7 weeks
Progression Free Survival
Time Frame: duration of time from start of randomization to time of progression or death, whichever occurs first or up to 24 months.
summarized using the method of Kaplan-Meier and compared using stratified log-rank tests
duration of time from start of randomization to time of progression or death, whichever occurs first or up to 24 months.
Overall Survival
Time Frame: the duration of time from start of randomization to time of death or up to 24 months
summarized using the method of Kaplan-Meier and compared using stratified log-rank tests
the duration of time from start of randomization to time of death or up to 24 months
Overall Response Rate
Time Frame: proportion of evaluable patients who achieve either a (complete response) CR or (partial response) PR or up to 24 Months
Response rates will be summarized by treatment arm and presented with 90% exact binomial confidence intervals. The comparison of response rates between treatment arms will use Fisher's exact test
proportion of evaluable patients who achieve either a (complete response) CR or (partial response) PR or up to 24 Months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Michael Dougan, MD, PHD, Massachusetts General Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 31, 2020

Primary Completion (Estimated)

June 30, 2030

Study Completion (Estimated)

June 30, 2030

Study Registration Dates

First Submitted

March 9, 2020

First Submitted That Met QC Criteria

March 10, 2020

First Posted (Actual)

March 12, 2020

Study Record Updates

Last Update Posted (Actual)

March 15, 2024

Last Update Submitted That Met QC Criteria

March 12, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

IPD Sharing Time Frame

Data can be shared no earlier than 1 year following the date of publication

IPD Sharing Access Criteria

Massachusetts General Hospital (MGH) - Contact the Partners Innovations team at http://www.partners.org/innovation

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Melanoma Stage IV

Clinical Trials on Infliximab

3
Subscribe