Infliximab for Treatment of Ipilimumab Colitis

Study Overview
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Brief Summary
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This research study is evaluating the effectiveness and safety of infliximab therapy compared with steroids in the treatment of ipilimumab-induced colitis in patients with III/IV melanoma.

Detailed Description
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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 from the standard of care drug ipilimumab The names of the study drugs involved in this study are: Infliximab Methylprednisolone Prednisone Participants will receive ipilimumab and any other cancer treatments per standard of care for stage III/IV melanoma at the discretion of treating oncologist. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Participants are expected to be on study treatment for up to 7 weeks and followed every to 6 months as agreed. It is expected that about 42 people will take part in this research study. The FDA has approved infliximab, methylprednisolone, and prednisone as treatment options for colitis. Patients will also receive ipilimumab as part of the standard of care for stage III/IV melanoma. The U.S. Food and Drug Administration (FDA) has approved ipilimumab as a treatment option for III/IV melanoma.

Official Title
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Phase II Study of Infliximab for the Treatment of Ipilimumab Colitis

Conditions
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Melanoma Stage III, Melanoma Stage IV, Side Effect of Drug, Colitis

Intervention / Treatment
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* Drug: Infliximab
* Drug: Methylprednisolone
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 Stage III/IV melanoma Treatment with ipilimumab or ipilimumab in combination with PD-1or PD-L1 blockade within the past 8 weeks; investigational combinations will be permitted provided that they include ipilimumab and a drug targeting PD-1 and/or PD-L1 Meets eligibility requires for treatment with ipilimumab Patients with brain metastases and who have received radiation are eligible Prior treatment with targeted or alternative immunotherapy is allowed, provided that these medications were discontinued prior to initiation of the current ipilimumab containing treatment regimen Grade 2-4 diarrhea by Common Terminology Criteria for Adverse Events (CTCAE) onset after treatment Prior to randomization, endoscopically determined colitis, according to Mayo Scoring system, score of 1-3 Patients will be permitted to have received up to 3 doses of systemic corticosteroids within 72 hours (up to a maximum dose of 2 mg/kg) prior to endoscopy and randomization Hepatitis B surface antigen, surface antibody, and core antibody must be sent but will not need to be resulted prior to enrollment 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 History of Hepatitis B or C with a positive viral load, untreated mycobacterium tuberculosis, or active herpes zoster infection; current negative testing results will not be required to be sent prior to study enrollment Positive testing for C Difficile or another colonic 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infliximab<br>The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Infliximab: Predetermined intravenous single dose, up to 3 doses over 7 weeks. Cross over 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 at full initial dosing | Drug: Infliximab<br>* Infusion<br>* Other names: Renflexis;|
| Experimental: Inpatient<br>The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. methylprednisone-Predetermined intravenous dose, 2x daily up to 7 weeks prednisone Oral daily predetermined dose Cross over 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 at full initial dosing | Drug: Methylprednisolone<br>* Infusion<br>* Other names: M-Prednisol;Drug: Prednisone<br>* Orally<br>* Other names: Sterapred DS;|
| Experimental: Outpatient<br>The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits Prednisone Predetermined oral dose, 2x daily up to 7 weeks Cross over 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 at full initial dosing | Drug: Prednisone<br>* Orally<br>* Other names: Sterapred DS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with Steroid-Free Colitis | 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. | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colitis, Melanoma Stage III, Melanoma Stage IV, Side Effect of Drug