Vemurafenib and Pembrolizumab in Treating Stage III-IV Melanoma That Cannot Be Removed by Surgery

Inclusion Criteria

• Provide written informed consent obtained prior to the initiation of study procedures
• Histologically confirmed unresectable stage III or stage IV melanoma (American Joint Committee on Cancer [AJCC] 7th edition classification); cutaneous melanoma and mucosal melanoma will be eligible
• Only patients with v-raf murine sarcoma viral oncogene homolog B (BRAF) V600E or V600K mutated tumors will be enrolled
• Baseline skin exam is required for all patients; Note: cutaneous squamous cell carcinoma (SCC) lesions identified at baseline must be excised
• Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST version [v]1.1); baseline measurements must be obtained within 4 weeks prior to registration
• White blood cells (WBC) >= 3,000/mm^3
• Absolute neutrophil count (ANC) >= 1500
• Hemoglobin >= 9g/dL (women) or >= 11g/dL (men)
• Platelets >= 100,000/mm^3
• Serum Creatinine =< 1.5 x upper limit of normal (ULN)
• Serum bilirubin =< 1.5 x ULN
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
• Note: (supportive transfusions will be allowed during treatment as deemed necessary by the treating physician)
• Electrocardiogram (EKG) documenting corrected QT (QTc) interval < 480 mili (m)second and no clinically significant arrhythmia
• Fully recovered from any effects of major surgery, and be free of significant infection
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Patients must be free of active brain metastases by contrast-enhanced computerized tomography (CT)/magnetic resonance imaging (MRI) scans within 4 weeks prior to starting the study drugs; if known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on two successive MRI evaluations at least 4 weeks apart (one of which is at least 4 weeks prior to starting the study drugs)
• Female patients of child bearing potential must have a negative pregnancy test within 7 days from the time of registration
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 26 weeks after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 26 weeks after the last dose of study therapy

Exclusion Criteria

• Serious clinically significant illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, uncontrolled hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia), bleeding disorders, symptomatic autoimmune diseases (such as inflammatory bowel disease, autoimmune hepatitis, uncontrolled hypo or hyperthyroidism), severe obstructive or restrictive pulmonary diseases, retinopathy, active systemic infections, and inflammatory bowel disorders
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or active hepatitis B virus (HBV) and hepatitis C virus (HCV)
• Has a known history of active tuberculosis (TB) (bacillus tuberculosis)
• History of grade 4 immune-related adverse events requiring treatment with prednisone, or grade 3 immune-related adverse events requiring prednisone > 10 mg/kg for > 12 weeks, if previously treated with ipilimumab
• Patients with brain metastases will be excluded if metastases have been symptomatic or actively treated within 4 weeks prior to enrollment
• Prior therapy with a BRAF and/or mitogen-activated protein kinase kinase (MEK) and/or extracellular signal-regulated kinase (ERK) inhibitors
• Refractory nausea, vomiting, small bowel resection or any other gastrointestinal ailment that would preclude study drug absorption
• Cardiac abnormalities: * Mean QTc interval >= 480 msec at screening * Acute coronary syndrome (ACS)/acute myocardial infarction (AMI) –within 24 weeks prior to screening * Percutaneous coronary intervention (PCI)/percutaneous transluminal coronary angioplasty (PTCA) –within 24 weeks prior to screening * Symptomatic heart failure – New York Heart Association (NYHA) class >= II symptoms
• Active infection within one-week prior to study, including unexplained fever
• Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the study
• Lactating females and/or pregnant females
• Any significant psychiatric disease, medical or other condition, which in the opinion of the principal investigator could prevent adequate informed consent or compromise participation in the clinical trial