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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, infliximab (a monoclonal antibody) and steroids, to determine which is more effective for treating colitis (inflammation of the colon) caused by certain cancer drugs. Researchers aim to assess how many patients can discontinue steroid use after seven weeks. This trial targets individuals with stage III/IV skin cancer who have experienced severe diarrhea, leading to a pause in their cancer treatment. Participants should show visible signs of colitis when examined with an endoscope (a camera that looks inside the body). As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant medical advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that infliximab is generally safe for people with inflammatory bowel disease, with studies finding its safety comparable to that of its biosimilars. Doctors are familiar with its safety profile due to its long-term use in treating conditions like Crohn's disease and ulcerative colitis.

Some patients might experience side effects, such as infections or allergic reactions, which are carefully monitored. Evidence suggests a higher risk of certain skin cancers in patients with inflammatory bowel disease who use biologics like infliximab, but more research is needed to fully understand this risk.

Overall, infliximab's extensive history of use in other conditions provides insight into its safety, making it a relatively safe option for new trials. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about infliximab for colitis in melanoma patients because it offers a targeted approach that differs from standard treatments like corticosteroids. While corticosteroids broadly suppress the immune system, infliximab specifically targets and blocks a protein called tumor necrosis factor-alpha (TNF-alpha), which plays a key role in inflammation. This targeted action can potentially lead to quicker symptom relief and fewer side effects. Additionally, infliximab is delivered intravenously, which can ensure consistent dosing and fast action, making it an attractive option for managing severe colitis symptoms in melanoma patients.

What evidence suggests that infliximab might be an effective treatment for ICI colitis?

Research has shown that infliximab, one of the treatments studied in this trial, effectively treats inflammatory conditions like Crohn's disease and ulcerative colitis. Studies have found that infliximab reduces inflammation and relieves symptoms in these conditions. It targets a specific protein that causes inflammation, calming the immune system. Although no direct evidence exists for infliximab in treating colitis caused by immune checkpoint inhibitors, its success in similar conditions suggests potential benefits. Early findings indicate that infliximab could be a promising option for managing inflammation in patients with significant immune-related conditions. Participants in this trial may receive infliximab or corticosteroids, with the possibility of switching to the other treatment if the initial response is inadequate. ^{1 3 6 7 8}

Who Is on the Research Team?

Michael L. Dougan

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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 have been diagnosed with advanced stage skin cancer.

I had severe diarrhea that stopped my immunotherapy treatment.

I've been treated with specific immune therapies within the last 8 weeks.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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) 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]

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]

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]

Citations

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Infliximab Monotherapy Effective as Combo Therapy for ... Infliximab-dyyb (ZYMFENTRA®) monotherapy was just as effective as a combination therapy with immunosuppressants (IS) to treat Crohn's disease (CD) and ...

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Infliximab: Remicade®; Inflectra®; Renflexis ; Avsola Switching from infliximab to biosimilar in inflammatory bowel disease: overview of the literature and perspective. Therap Adv Gastroenterol. 2019; 12 ...

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Comparative Safety of Biologic Agents in Patients With ... Comparative safety of biologic agents in patients with inflammatory bowel disease with active or recent malignancy: a multi-center cohort study.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2838486/

Increased Risk for Non-Melanoma Skin Cancer in Patients ... Patients with inflammatory bowel disease (IBD) might be at increased risk for certain malignancies. We evaluated the risk of non-melanoma skin cancer (NMSC) ...