Propranolol Hydrochloride and Pembrolizumab in Treating Patients With Stage IIIC-IV Melanoma That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES: I. To determine dose limiting toxicities (DLT) of propranolol hydrochloride (propranolol) in combination with fixed dose pembrolizumab in the treatment of melanoma. II. To evaluate the efficacy of pembrolizumab in combination with propranolol in patients with melanoma, as determined by overall response rate (ORR) per immune-modified Response Evaluation Criteria in Solid Tumors (RECIST) (1). SECONDARY OBJECTIVES: I. To evaluate the efficacy of pembrolizumab in combination with propranolol in patients with melanoma, as determined by secondary measures of efficacy, including: progression free survival (PFS) and overall survival (OS). TERTIARY OBJECTIVES: I. To correlate baseline or changes in the levels of biomarkers, like, peripheral T-cell subsets/myeloid derived suppressor cells (MDSC)/cytokines/urinary catecholamine and perceived stress scale (PSS) with efficacy (ORR, PFS, OS) in melanoma patients treated with pembrolizumab and propranolol. OUTLINE: This is a phase Ib, dose-escalation study of propranolol hydrochloride followed by a phase II study. Patients receive propranolol hydrochloride orally (PO) twice daily (BID) and pembrolizumab intravenously (IV) over 30 minutes of day 1. Courses repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 3 months for 6 months, and then every 6 months thereafter.