Infliximab for Colitis in Melanoma

Recruiting at 1 trial location

Overseen By Keri Sullivan

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: Immune suppressing biologics

Disqualifiers: Inflammatory bowel disease, Hepatitis B, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 7 weeks

42 Participants Needed

Trial Summary

What is the purpose of this trial?

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?

Will I have to stop taking my current medications?

The trial requires that you stop taking any immune suppressing biologic medications at least 4 weeks before joining. If you're on systemic corticosteroids or other immune suppressing medications, you must not have used them in the past 10 days.

What evidence supports the effectiveness of the drug infliximab for treating colitis in melanoma patients?

Research shows that infliximab, a drug used to treat inflammation, was effective in managing severe colitis (inflammation of the colon) caused by cancer treatments in melanoma patients. In a study, infliximab successfully treated colitis in most patients, and it did not negatively impact their cancer treatment outcomes. ^{1 2 3 4 5}

Is infliximab safe for treating colitis in melanoma patients?

Infliximab has been used safely in patients with severe colitis caused by melanoma treatments, with most patients responding well after just one infusion. It is generally considered safe, but like all medications, it may have side effects, and its use should be monitored by healthcare professionals. ^{1 2 3 6 7}

How does the drug infliximab differ from other treatments for colitis in melanoma patients?

Infliximab is unique because it is used to treat severe colitis caused by immune checkpoint inhibitors in melanoma patients, especially when steroids are not effective. It works by blocking tumor necrosis factor alpha (TNFα), a substance in the body that causes inflammation, and is administered intravenously, often leading to successful remission without affecting melanoma outcomes. ^{1 2 3 8 9}

Research Team

Michael L. Dougan

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for adults over 18 with stage III/IV melanoma who've had recent treatment with specific immune therapies and are experiencing moderate to severe diarrhea as a side effect. It's not for those on other immune suppressants, have certain infections or hepatitis, inflammatory bowel diseases, or previous bad reactions to infliximab or steroids.

Inclusion Criteria

I am 18 years old or older.

I have been diagnosed with advanced stage skin cancer.

I had severe diarrhea that stopped my immunotherapy treatment.

Exclusion Criteria

I have a history of inflammatory bowel disease or related conditions.

I am currently being treated for a bacterial infection or have a systemic fungal infection.

I am currently taking medication for an immune system side effect.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either infliximab or corticosteroids for the treatment of ICI colitis over 7 weeks

7 weeks

Weekly follow-ups (in-person or phone)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with medical records reviewed every 6 months

6 months

Long-term Follow-up

Participants' progression-free survival and overall survival are monitored

24 months

Treatment Details

Interventions

• Infliximab

Trial Overview The study compares infliximab against steroids in treating colitis caused by cancer immunotherapy. Participants will be randomly assigned to receive either infliximab or steroids and monitored for steroid-free disease resolution after 7 weeks.

Participant Groups

Group I: Infliximab Experimental Treatment 1 Intervention

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.

Group II: Corticosteroids Experimental Treatment 2 Interventions

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.

Infliximab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Remicade for:

• Ankylosing Spondylitis
• Crohn's Disease
• Ulcerative Colitis
• Psoriatic Arthritis
• Rheumatoid Arthritis
• Plaque Psoriasis

Approved in United States as Remicade for:

• Ankylosing Spondylitis
• Crohn's Disease
• Ulcerative Colitis
• Psoriatic Arthritis
• Rheumatoid Arthritis
• Plaque Psoriasis

Approved in Canada as Remicade for:

• Ankylosing Spondylitis
• Crohn's Disease
• Ulcerative Colitis
• Psoriatic Arthritis
• Rheumatoid Arthritis
• Plaque Psoriasis

Approved in Japan as Remicade for:

• Ankylosing Spondylitis
• Crohn's Disease
• Ulcerative Colitis
• Psoriatic Arthritis
• Rheumatoid Arthritis
• Plaque Psoriasis

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Findings from Research

In a retrospective review of 13 metastatic melanoma patients treated with infliximab for severe steroid-refractory colitis caused by ipilimumab, only 31% achieved resolution of colitis symptoms after treatment, indicating limited efficacy of infliximab in this context.

Despite infliximab treatment, 33% of patients required surgical intervention, highlighting the serious nature of ipilimumab-induced colitis and the need for more effective management guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infliximab for ipilimumab-induced colitis: A series of 13 patients. Hillock, NT., Heard, S., Kichenadasse, G., et al.[2018]

In a study of 27 patients with advanced melanoma, severe immune checkpoint inhibitor (ICI)-induced colitis requiring anti-TNFα treatment occurred in only 1% of cases, primarily associated with the drug ipilimumab.

Treatment with infliximab for severe colitis did not negatively impact overall survival or progression-free survival, with 12-month survival rates of 41% and progression-free survival of 3 months, indicating that this treatment strategy is safe and does not compromise cancer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and Clinical Impact of Anti-TNFα Treatment of Severe Immune Checkpoint Inhibitor-induced Colitis in Advanced Melanoma: The Mecolit Survey. Lesage, C., Longvert, C., Prey, S., et al.[2023]

Patients with inflammatory bowel disease (IBD) have a higher risk of developing malignant melanoma, particularly those with more extensive forms of IBD, such as pancolitis and ileal and colonic Crohn's disease.

Despite having a lower N-stage of melanoma, patients with IBD do not experience impaired survival rates compared to non-IBD melanoma patients, regardless of whether they are receiving immunosuppressive or anti-TNF therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma. Nissen, LHC., Pierik, M., Derikx, LAAP., et al.[2023]

In a study of 274 elderly patients with advanced melanoma, the risk of developing colitis was similar for those treated with anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab or pembrolizumab) therapies.

However, when considering patients across all stages of melanoma, anti-PD1 treatment was associated with a significantly lower risk of colitis compared to anti-CTLA4, suggesting a safer profile for anti-PD1 in this broader patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. Almutairi, AR., Slack, M., Erstad, BL., et al.[2022]

Patients with inflammatory bowel disease (IBD) using TNF-α inhibitors have a significantly increased risk of developing melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC), as shown by a study analyzing data from the FDA Adverse Event Reporting System (FAERS) from 2003 to 2012.

The risk is even higher for patients on TNF-α inhibitors combined with thiopurines, indicating that this combination therapy poses a greater threat for developing these types of skin cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanoma and non-melanoma skin cancer in inflammatory bowel disease patients following tumor necrosis factor-α inhibitor monotherapy and in combination with thiopurines: analysis of the Food and Drug Administration Adverse Event Reporting System. McKenna, MR., Stobaugh, DJ., Deepak, P.[2022]

In a study of 508 adults with moderate-to-severe Crohn's disease, combination therapy with infliximab and azathioprine resulted in a higher rate of corticosteroid-free clinical remission (56.8%) at week 26 compared to infliximab alone (44.4%) and azathioprine alone (30.0%).

The combination therapy also showed a trend towards better mucosal healing (43.9%) compared to infliximab (30.1%) and azathioprine (16.5%), with similar safety profiles across all treatment groups regarding serious infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infliximab, azathioprine, or combination therapy for Crohn's disease. Colombel, JF., Sandborn, WJ., Reinisch, W., et al.[2022]

Infliximab has improved treatment for inflammatory bowel diseases (IBD), but it does not cure the condition and can lead to secondary loss of response due to its immunogenicity.

Newer anti-TNF agents like adalimumab and certolizumab-pegol have shown efficacy in maintaining treatment for Crohn's disease, with adalimumab recently approved for moderate-to-severe luminal CD, although more research is needed for its use in ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adalimumab in Crohn's disease. Van Assche, G., Vermeire, S., Rutgeerts, P.[2023]

A 54-year-old woman with metastatic melanoma achieved clinical and radiological remission after treatment with the immune checkpoint inhibitors nivolumab and ipilimumab, highlighting the efficacy of dual checkpoint inhibition in cancer therapy.

Following treatment, she developed immune checkpoint inhibitor-induced colitis, which was successfully managed with infliximab and mesalazine, leading to long-lasting remission without the need for steroids and no recurrence of melanoma after 2 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of an Immune-Mediated Colitis Induced by Checkpoint Inhibitor Therapy in a Patient with Advanced Melanoma. Paparoupa, M., Stupperich, S., Goerg-Reifenberg, L., et al.[2020]

In a study of 131 hospitalized patients with steroid-refractory acute severe ulcerative colitis, those receiving an accelerated induction regimen of infliximab had lower 30-day colectomy rates compared to those on a standard induction regimen (27% vs 57%, P = 0.048).

While the accelerated regimen showed short-term benefits in reducing colectomy rates during the initial treatment period, there was no significant difference in overall colectomy rates at 12 months, indicating that the long-term outcomes may be similar between the two treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infliximab induction regimens in steroid-refractory acute severe colitis: a multicentre retrospective cohort study with propensity score analysis. Sebastian, S., Myers, S., Argyriou, K., et al.[2020]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Infliximab for ipilimumab-induced colitis: A series of 13 patients. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Incidence and Clinical Impact of Anti-TNFα Treatment of Severe Immune Checkpoint Inhibitor-induced Colitis in Advanced Melanoma: The Mecolit Survey. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Association of immune-checkpoint inhibitors and the risk of immune-related colitis among elderly patients with advanced melanoma: real-world evidence from the SEER-Medicare database. [2022]

5. Romania pubmed.ncbi.nlm.nih.gov

Melanoma and non-melanoma skin cancer in inflammatory bowel disease patients following tumor necrosis factor-α inhibitor monotherapy and in combination with thiopurines: analysis of the Food and Drug Administration Adverse Event Reporting System. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Infliximab, azathioprine, or combination therapy for Crohn's disease. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Adalimumab in Crohn's disease. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Treatment of an Immune-Mediated Colitis Induced by Checkpoint Inhibitor Therapy in a Patient with Advanced Melanoma. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Infliximab induction regimens in steroid-refractory acute severe colitis: a multicentre retrospective cohort study with propensity score analysis. [2020]