PD-1 Antibody Therapy + Infliximab for Metastatic Melanoma

Inclusion Criteria:

• Age greater than or equal to 18 years

• Participants must have histologically confirmed Stage III unresectable or Stage IVmetastatic melanoma

• Patients should be treatment naïve and eligible for treatment with anti-PD-1 oranti-PD-1/LAG3 as a first line therapy (as selected by their treating physician)

• Patients previously treated for melanoma with surgical resection alone who presentwith recurrent Stage III unresectable or Stage IV metastatic melanoma are eligiblefor enrollment

• Patients who were previously treated with systemic neo-adjuvant or adjuvantanti-PD-1 therapy more than 6 months prior to study enrollment will be eligible.There are no restrictions to the use of prior BRAF targeted therapy.

• Participants must have measurable disease, defined as at least one lesion that canbe accurately measured in at least one dimension (longest diameter to be recorded)as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan

• Diagnostic imaging studies such as MRIs and CT scans must be performed within 30days of the date of registration

• 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 directbilirubin is within normal limits or if patients has a documented history ofGilbert's disease

• AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal and ≤5 ULNfor patients with liver metastases

• Baseline laboratory measurements must be documented from tests within 14 days of thedate of registration

• ECOG performance status ≤ 1 (see Appendix A)

• Participants with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen are eligible for this trial

• Participants with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association Functional Classificationwhich 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

• Baseline tumor biopsies are required for all patients who have tumors that aredeemed by the study investigators to be safely accessible

Exclusion Criteria:

• Patients with ocular or mucosal melanoma

• Participants previously treated with anti-PD1/PDL1/CTLA-4 monoclonal antibodies formetastatic or unresectable disease

• Patients who are receiving other anti-neoplastic agents

• Symptomatic or untreated leptomeningeal disease

• Patients carrying a diagnosis of immunodeficiency or receiving systemic steroidtherapy (prednisone or equivalent > 10 mg/day) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of trial treatment.Corticosteroids to prevent contrast reactions is allowable

• Patients with active autoimmune disease that has required systemic treatment in thepast 2 years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment

• Prior history of inflammatory bowel disease, microscopic colitis or segmentalcolitis associated with diverticulosis

• Breastfeeding and pregnant women are excluded from this study since all anti-PD-1drugs are class D agents with the potential for teratogenic or abortifacienteffects.

• Uncontrolled intercurrent illness including, but not limited to:

• A. Ongoing or active infection

• B. Edema > Grade 1

• C. Documented myocardial infarction or unstable/uncontrolled cardiac disease (eg, unstable angina, severe arrhythmias, congestive heart failure [New YorkHeart Association (NYHA) > Class II]) within 6 months of study entry

• D. Arterial thrombosis or vascular ischemic events, such as transient ischemicattack, cerebral infarction, within 6 months prior to study entry

• E. Serious or non-healing wound

• F. History of any medical condition including cardiovascular disease or chronicobstructive pulmonary disease (COPD), that in the opinion of the investigator,may increase the risks associated with study participation or study treatmentsor may interfere with the conduct of the study or interpretation of studyresults

• G. Psychiatric illness/social situations that, in the opinion of theinvestigator, would limit compliance with study requirements

• H. An elevated high-sensitivity troponin T level at baseline will be allowableas long as the patient has no evidence of active, clinically relevant cardiacdisease.

• Patients with a history of a different malignancy are ineligible except for thefollowing circumstances:

• A. Individuals with a history of other malignancies are eligible if they havebeen disease-free for at least 3 years and are deemed by the investigator to beat low risk for recurrence of that malignancy

• B. Individuals with the following cancers are eligible if diagnosed and treatedwithin the past 3 years: cervical cancer in situ and basal cell or squamouscell carcinoma of the skin

• Patients with a history of Hepatitis B infection (HBsAg reactive or HBCAB reactive)or Hepatitis C (HCV RNA is detected). Participants with a history of hepatitis Cvirus (HCV) infection may be enrolled if they have been treated and cured

• Patients with a history of latent or active granulomatous infection, includingtuberculosis, histoplasmosis, or coccidiomycosis

• Has received a live vaccine within 30 days of planned start of study therapy

• Current bacterial infection requiring antibiotic treatment, or systemic fungalinfection

• Patients with a known hypersensitivity to pembrolizumab, nivolumab, or relatlimab orany of its excipients

• Previous adverse reaction or hypersensitivity to infliximab

• Any prior immune-related adverse event while on adjuvant anti-PD-1-basedimmunotherapy with the following exceptions: any endocrine toxicity, any grade 1 or 2 toxicity that completely resolved; if there is uncertainty about the grade ofprior toxicity, this will be adjudicated by the PI.