Pembrolizumab + Infliximab for Melanoma

Overseen By Ryan Sullivan, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must not be taking: Antineoplastics, Immunosuppressants

Disqualifiers: Ocular melanoma, Autoimmune disease, 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

Compensation: Varies

Number of Visits: 3

Duration: Up to 2 years

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the safety and effectiveness of combining infliximab (a medication used to reduce inflammation) with anti-PD-1 therapy (a type of immunotherapy) to treat metastatic melanoma, a severe form of skin cancer that has spread to other parts of the body. Participants will receive either infliximab alongside pembrolizumab or nivolumab+relatlimab, or a placebo with the same. The trial focuses on individuals with melanoma that cannot be surgically removed or has spread and who have not yet received systemic therapy for their condition. Those diagnosed with stage III or IV metastatic melanoma and eligible for anti-PD-1 therapy might be a good fit for this trial. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are receiving other anti-neoplastic agents or systemic steroid therapy (prednisone or equivalent > 10 mg/day) within 7 days prior to the first dose of trial treatment. Please consult with the trial team for guidance on your specific medications.

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

Research has shown that pembrolizumab, when used alone, effectively treats advanced melanoma, with survival rates similar to those in clinical trials. This indicates it is generally well-tolerated by patients. Infliximab often manages side effects from immune therapy treatments like pembrolizumab. One study found that infliximab can be used safely without reducing the cancer treatment's effectiveness.

Since this trial is in Phase 2, some safety information is available from earlier studies. However, the safety and effectiveness of using pembrolizumab with infliximab together are still under investigation. Notably, there have been no significant reports of negative effects when using infliximab for immune-related side effects, which is promising for its safety when combined with pembrolizumab. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine anti-PD-1 therapies with either infliximab or a placebo to potentially enhance efficacy against melanoma. Infliximab, typically used to treat autoimmune conditions, is being paired with pembrolizumab or nivolumab+relatlimab to see if it can help control immune-related side effects and improve overall outcomes. Unlike standard treatments that solely target PD-1 proteins to unleash the immune system against cancer cells, this combination approach could offer a novel way to manage immune responses, potentially leading to more effective and tolerable treatments for melanoma patients.

What evidence suggests that this trial's treatments could be effective for metastatic melanoma?

Research has shown that pembrolizumab and nivolumab, both anti-PD-1 therapies, are promising for treating metastatic melanoma by enhancing the immune system's ability to attack cancer cells. Studies have found that these medicines can extend the lives of patients with advanced melanoma. In this trial, participants will receive either anti-PD-1 therapy with infliximab or anti-PD-1 therapy with a placebo. Although infliximab is primarily used for inflammatory conditions, evidence suggests it does not negatively affect outcomes when combined with melanoma treatments. Infliximab may help manage immune-related side effects, improving the overall treatment experience. While infliximab alone has been associated with a higher risk of melanoma in other conditions, its use with anti-PD-1 therapy here aims to create a balanced treatment approach. ^{6 7 8 9 10}

Who Is on the Research Team?

Ryan Sullivan, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults over 18 with Stage III unresectable or Stage IV metastatic melanoma, who haven't been treated for it yet, or only had surgery before. They must have normal organ and marrow function, no severe heart conditions (class 2B NYHA or better), measurable disease, and understand the study. Excluded are those with ocular/mucosal melanoma, prior immunotherapy for advanced disease, active infections/autoimmune diseases needing recent treatment, certain cancer histories unless low risk of recurrence or specific minor cancers within 3 years.

Inclusion Criteria

I had surgery for melanoma and now have Stage III or IV melanoma that cannot be removed with surgery.

I have not received any treatment yet and can be treated with pembrolizumab.

Participants must have normal organ and marrow function as defined below: Leukocytes (WBC) > 3,000/uL, Absolute neutrophil count > 1,500uL, Platelets > 100,000/uL, Total bilirubin < 1.5 X institutional upper limits of normal; total bilirubin > 1.5X above institutional upper limits of normal will be allowed if direct bilirubin is within normal limits or if patients has a documented history of Gilbert's disease, AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal and ≤5 ULN for patients with liver metastases, Baseline laboratory measurements must be documented from tests within 14 days of the date of registration, ECOG performance status ≤ 1, Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial, Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification which can be performed by the study investigators. To be eligible for this trial, participants should be class 2B or better, Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

You are allergic to pembrolizumab or any of its ingredients.

I have symptoms or untreated cancer spread to the lining of my brain and spinal cord.

You had a bad reaction or were very sensitive to infliximab before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive anti-PD-1 antibody therapy with or without LAG-3 inhibition and infliximab or placebo

Up to 2 years

Pembrolizumab every 3 weeks or Nivolumab+relatlimab every 4 weeks; Infliximab or placebo on weeks 0, 2, and 6

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Infliximab
• Pembrolizumab

Trial Overview

The trial is testing a combination of pembrolizumab (an immune therapy) and infliximab (a drug that reduces inflammation) to see if they're safe and effective against metastatic melanoma when given together compared to a placebo alongside pembrolizumab.

How Is the Trial Designed?

Group I: Anti-PD-1 therapy + Placebo Experimental Treatment 4 Interventions

Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and placebo. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Placebo. will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses

Group II: Anti-PD-1 therapy + Infliximab Experimental Treatment 4 Interventions

Participants will be randomly assigned to receive physician's choice of anti-PD-1 therapy (pembrolizumab or nivolumab+relatlimab) and infliximab. * Pembrolizumab will be administered every 3 weeks for up to 2 years * Nivolumab+relatlimab will be administered every 4 weeks for up to 2 years * Infliximab will be administered on weeks 0, 2, and 6 (+/- 3 days) for a total of 3 doses

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+

Massachusetts Institute of Technology

Collaborator

Trials

104

Recruited

12,810,000+

Published Research Related to This Trial

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 103 Chinese patients with advanced melanoma, pembrolizumab demonstrated a 16.7% objective response rate, indicating its effectiveness as a second-line treatment, particularly in aggressive melanoma subtypes.

The treatment was well tolerated, with 84.5% of patients experiencing treatment-related adverse events, but only a small percentage (8.7%) had severe side effects, and no treatment-related deaths occurred.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151). Si, L., Zhang, X., Shu, Y., et al.[2020]

In a study involving 173 patients with advanced melanoma who had not responded to previous treatments, pembrolizumab showed an overall response rate of 26% at both 2 mg/kg and 10 mg/kg doses, indicating its potential effectiveness in this challenging patient population.

The treatment was well tolerated with no drug-related deaths, and the safety profiles were similar across both doses, with fatigue, pruritus, and rash being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Robert, C., Ribas, A., Wolchok, JD., et al.[2022]

Ipilimumab, an anti-CTLA-4 antibody, was the first treatment to show a significant overall survival benefit in melanoma, marking a breakthrough in therapy for this previously resistant cancer.

Vemurafenib, a BRAF-inhibitor, has demonstrated substantial improvements in both progression-free and overall survival for patients with the BRAF(V600E) mutation, highlighting the effectiveness of targeted therapies in melanoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current advances and perspectives in the treatment of advanced melanoma. Livingstone, E., Zimmer, L., Vaubel, J., et al.[2018]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Citations

1.

avsola.com

avsola.com/hcp/totality-of-evidence

AVSOLA®(infliximab-axxq)'s Totality of Evidence

EFFICACY RESULTS. AVSOLA® DEMONSTRATED SIMILAR RESPONSE RATES TO REMICADE® ACROSS MULTIPLE ENDPOINTS3. PRIMARY ENDPOINT RESULT: RD of ACR20 achieved at week ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4065572/

Risk of Melanoma and Nonmelanoma Skin Cancer Among ...

Immunosuppression increases the risk of melanoma and NMSC among patients with IBD. The risk of melanoma is increased by use of biologics, and the risk of NMSC ...

3.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/32432649/

Melanoma Risk in Patients Treated With Biologic Therapy ...

The findings suggest that clinically important increases in melanoma risk in patients treated with biologic therapy for common inflammatory ...

4.

ascopubs.org

ascopubs.org/doi/10.1200/jco.2015.33.15_suppl.9045

Evaluation of the impact of infliximab use for the treatment ...

Conclusions: In our series infliximab does not negatively affect the outcome of patients with advanced melanoma treated with ipilimumab and ...

5.

jamanetwork.com

jamanetwork.com/journals/jamadermatology/fullarticle/2766278

Melanoma Risk in Patients Treated With Biologic Therapy ...

Biologic-treated patients with inflammatory bowel disease, rheumatoid arthritis, and psoriasis had an increased risk of melanoma compared with those who ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12454464/

Real-World Outcomes of Pembrolizumab in Advanced ...

Real-world Australian data indicate pembrolizumab monotherapy for advanced melanoma achieves survival outcomes consistent with clinical trials, ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10649345/

Infliximab for Treatment of Immune Adverse Events and Its ...

The study helps to support the safe and effective use of infliximab in treatment of irAEs without significant impact on tumor response.

8.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05034536

PD-1 Antibody Therapy + Infliximab for Metastatic Melanoma

The purpose of this research is to test the safety and effectiveness of the investigational combination of anti-Programmed Death (PD)-1 antibody therapy with or ...

9.

mdpi.com

mdpi.com/2072-6694/16/10/1892

Studying Outcomes after Steroid-Sparing ...

Our results suggest that SSIAs used for irAE treatment may not negatively impact cancer outcomes in malignant melanoma and non-small cell lung cancer.

10.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/nda/2014/125514orig1s000medr.pdf

125514Orig1s000 - accessdata.fda.gov

The confirmed overall response rate for 89 patients receiving 2mg/kg of MK-3475 every. 3 weeks in Part B2 of trial P001 was 24% (95% CI: ...