PD-1 Antibody Therapy + Infliximab for Metastatic Melanoma

This is a randomized, double-blind, phase 2 clinical trial that combines anti-Programmed Death (PD)-1 antibody therapy with or without LAG-3 inhibition (pembrolizumab or nivolumab+relatlimab) with the anti-Tumor Necrosis Factor (TNF)-α antibody infliximab as first line treatment for the management of patients with metastatic or recurrent melanoma. The U.S. Food and Drug Administration (FDA) has not approved infliximab for metastatic melanoma but it has been approved for other uses. The FDA has approved pembrolizumab as a treatment option for metastatic melanoma. The FDA has approved nivolumab+relatlimab as a treatment option for metastatic melanoma. Pembrolizumab is a blocking antibody (a protein used in the immune system to identity and neutralize bacteria, viruses, and other foreign pathogens) that binds to PD-1 (a protein that helps regulate the immune system's response in the body) and blocks the interaction with PD-L1 and PD-L2 (proteins that inhibits the body's immune response). By blocking this interaction, it might lead to an anti-tumor immune response that may decrease tumor growth. Relatlimab is believed to work by attaching to and blocking a molecule called Lymphocyte Activation Gene-3 (LAG-3). LAG-3 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Scientists believe that one way cancers escape the immune system is by shutting it down. Antibodies that block LAG-3 can potentially prevent LAG-3 from shutting down the immune system, thus allowing it to recognize and help the body destroy the cancer cells. Nivolumab is believed to work by attaching to and blocking a molecule called PD-1. PD-1 is a protein that is present on different types of cells in the immune system and controls parts of the immune system by shutting it down. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, thus allowing it to recognize and help the body destroy the cancer cells. Infliximab is an anti-TNFα agent (an antibody that blocks certain inflammatory hormones) that may interact with irEC (immune related (entero)colitis - inflammation that occurs in the digestive tract) which can develop among people with advanced melanoma. Anti- TNFα agents have shown to lead to rapid symptomatic improvement. By combining anti-PD-1 antibody therapy (pembrolizumab or nivolumab+relatlimab) and infliximab we believe it may lead to reduced immune related side effects while increasing effective anti-tumor immune response. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. Participants will be randomized to receive either a) anti-PD-1 antibody therapy (pembrolizumab or nivolumab+relatlimab) plus infliximab or b) anti-PD-1 antibody therapy (pembrolizumab or nivolumab+relatlimab) plus placebo (an intravenous solution without medication). Participants will receive study treatment for as long as their disease does not worsen, they do not experience any unacceptable side effects, or they have completed the two years of anti-PD-1 antibody therapy. Participants will then be followed until the study doctor determines follow-up is no longer needed or until participant withdrawal. It is expected that about 36 people will take part in this research study A research grant, The Bridge Project, is supporting this research study by providing funding for the study.